Yong-Ku Kim Editor Clinical Manifestations, Diagnosis And

Yong-Ku Kim Editor Understanding Depression

Clinical Manifestations, Volume 2 Diagnosis and Treatment

123 Understanding Depression Yong-Ku Kim Editor

Understanding Depression

Volume 2. Clinical Manifestations, Diagnosis and Treatment Editor Yong-Ku Kim College of Medicine Korea University Kyonggi-do South Korea

ISBN 978-981-10-6576-7 ISBN 978-981-10-6577-4 (eBook) https://doi.org/10.1007/978-981-10-6577-4

Library of Congress Control Number: 2017963749

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This Springer imprint is published by Springer Nature The registered company is Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface

This book, in two volumes, focuses on contemporary issues and dilemmas in relation to depression. The aim is to equip readers with an up-to-date understanding of the clinical and neurobiological underpinnings of depression, its clinical manifestations, and the development of more effective treatments. This second volume is devoted specifically to clinical and management issues. Readers will find detailed information on a wide range of frequently encountered and more complicated clinical presentations, with examination of risk factors and links to other conditions. Diagnostic aspects, including progress toward biological classification and the role of neuroimaging, are explored. Current trends in therapy are examined at length, drawing on the latest evidence and covering not only antidepressant medications but also the roles of neurostimulation, combined pharmacotherapy and psychotherapy, mindfulness-based cognitive therapy (MBCT), and complementary and alternative medicine (CAM). The companion volume is dedicated to the underlying biomedical and neurobiological basis of depression. Understanding Depression will be an excellent source of information for both researchers and practitioners in the field. Part I (Chaps. 1–6) deals with diagnostic issues of depression. The perspectives on depression—past, present, and future—and issues about current changes and criticism based on the DSM-5 are discussed. Currently, the diagnosis of depression is based primarily on symptoms rather than objective biological markers. So, biological diagnostic classification for depression is also needed in biological psychiatry. The possibility of current and future biological classifications of depression in view of blood biological markers, neuroimaging, and voice analysis is addressed. Chapter 1 highlights the changes to diagnostic criteria for depressive disorders from the DSM-IV to DSM-5. Depressive disorders have been reformulated based on a combination of categorical and dimensional approaches in the DSM-5. However, despite the transdiagnostic specifiers, severity assessments, and cross-cutting measure assessments contained in the DSM-5, depression is still defined using a symptom-based classification, and its heterogeneity is of significant concern. It is necessary to develop an etiology- based classification of depressive disorders and to consider humanistic approaches together with potential cultural and social influences. Chapter 2 focuses on the differentiating features and contemporary treatment approaches between major depressive disorder and bipolar disorder. Major depressive disorder and bipolar disorder are distinct conditions with

v vi Preface differences in clinical presentation and treatment modalities. Since current treatments are palliative rather than curative in nature, there is an urgent need to foster a better understanding of the underpinning pathogenic mechanisms and discover novel therapies. Chapter 3 discusses the potential diagnostic biomarkers for depression. Since depression is so heterogeneous and associated with different clinical presentations and symptoms, the development of a single biomarker is highly unlikely. A reliable panel or a set of biomarkers, when developed, will have significant clinical use and lead toward personalized treatment strategies. Chapter 4 provides a detailed overview of biological markers that may serve as reliable tools for the diagnosis and treatment of depression. Some of the frequently reported findings include abnormalities in neurotransmitter systems, such as those for 5-HT, dopamine, norepinephrine, glutamate, and GABA, and alterations in the levels of growth factors, such as BDNF, VEGF, and FGF. Evidence also indicates that there are conspicuous changes in the levels of inflammatory, endocrine, and metabolic markers and the presence of structural and functional abnormalities in specific cortico-limbic regions of depressed patients. Future studies are needed to indicate whether these changes constitute a direct cause of depression or a compensatory mechanism for specific neurobiological alterations. Chapter 5 sheds light on the application of neuroimaging in the diagnosis and treatment of depression. Accumulating neuroimaging studies suggest potential biomarkers, such as metabolic activity and structural or functional connectivity, within the cortico-limbic circuitry. The continuous progress in neuroimaging studies will help produce better consistent data, which contribute to the identification of biomarkers for personalized, prognostic, predictive, and preventive medicine. Chapter 6 introduces the clinical application of pathophysiological voice analysis for the diagnosis and monitoring of depression. Pathophysiological analysis by voice is noninvasive, remote, and continuous, without requiring special equipment. Therefore, this technique is effective as a screen for many subjects and long-term continuous monitoring at home. In clinical settings, it is possible to give objective indicators to medical areas that previously had only subjective indicators in depression. Part II (Chaps. 7–11) refers to clinical manifestations of depression. Anhedonia has been understood as a “loss of pleasure,” but neuropsychological and neurobiological studies reveal a multifaceted reconceptualization. The current methodology to measure anhedonia and its neurobiological underpinnings and treatment are discussed. The current knowledge of neurocognitive mechanisms in depression and several psychological models that may explain how cognitive impairment works in depression are addressed. Disturbances in the sleep-wake cycle and chronobiological rhythm are very common in depression and serve as sensitive biological markers. The clinical treatment options available for sleep-wake disturbances and abnormal circadian rhythms in depression are discussed. Suicidal behavior in depression is more than just a severe form of depression, and distinct predispositions to suicide behaviors in depression should be better understood. Preface vii

Chapter 7 highlights the neurobiology, measurement, and treatment of anhedonia, a core symptom of depression. Several key brain regions and connections have been identified in reward processing, particularly within the prefrontal cortex. It is possible that neural dysfunction in any aspect of reward processing could lead to the clinical symptom of anhedonia. There are various treatments that target anhedonia symptoms due to their effect on the dopaminergic and noradrenergic systems; however, further research is needed to elucidate the effects of conventional antidepressants on anhedonia. The development of new assessment tools, including self-report scales and behavioral tasks, improves our understanding of the underlying neurobiology. Chapter 8 discusses the differential diagnosis and management of various sleep patterns in depression and the clinical treatment options available for sleep-wake disturbances that are comorbid with depression. Sleep-wake disturbances are not only prevalent symptoms of depression but also are a biological marker for depression. Primary sleep disorders, such as obstructive sleep apnea, restless leg syndrome, and REM sleep behavior disorder, are also prevalent in depression. Antidepressants can have a variety of effects on sleep, depending on their mechanism and characteristics. Cognitive behavioral therapy of insomnia (CBT-I), which is the treatment of choice for chronic insomnia, is also effective for the treatment of insomnia comorbid with depression. Chapter 9 focuses on the mechanisms and treatment of sleep homeostasis abnormalities and circadian rhythm disruptions in depression. Chronotherapies, which synchronize and stabilize biological rhythms (including sleep-wake patterns), such as bright light therapy, melatonin and its agonists, sleep deprivation, and social rhythm therapies, may be useful treatments in depression. Four types of chronotherapies (bright light therapy, agomelatine, sleep deprivation, and phase advance) show efficacy in the treatment of depression both in unipolar or bipolar disorders and seasonal or nonseasonal subtypes. Chapter 10 reviews the risk factors, neurobiological changes, and reconceptualization of suicidal behaviors in depression. The interplay between interconnected neural systems contributes to suicidal behaviors in depression, and these neurobiological changes underlie the psychological vulnerability of suicidal behavior. Reconceptualization of suicidal behavior as a distinct disorder improves suicide risk screening and detection in clinical practice and helps expand suicide research by using a well-defined phenotype. Chapter 11 investigates the psychological and biological mechanisms and assessments of cognitive impairments in depression. A psychological hypothesis states that depressed patients cannot effectively distribute and utilize cognitive resources. A biological hypothesis states that weakened top-down cognitive control and enhanced bottom-up emotion activation result in cognitive impairment. To assess cognitive function in depression, typical neurocognitive function tests to assess overall cognitive function are preferred over specific examination tools. Amyloid PET is being highlighted for its usefulness in patients with depression and cognitive impairment. viii Preface

Part III (Chaps. 12–15) considers complicated clinical manifestations of depression. Chronic pain and depression show shared psychological and neurobiological mechanisms. Neuroimaging studies, genetic and molecular factors in the pathophysiology, and current novel therapeutic strategy in both conditions are described. Depression with medical illness, such as cancer or diabetes, is differentiated from functional depression without medical illness. The clinical, biological, and therapeutic characteristics between depression with and without medical illness are discussed. Burnout syndrome has been defined as a combination of emotional exhaustion, depersonalization, and reduced personal accomplishment caused by chronic occupational stress. The current state of the science suggests that burnout is a form of depression rather than a differentiated type of pathology. Increasing evidence has pointed to the association between obesity and depression. The association between both conditions has been described as bidirectional and convergent, and several biological and psychosocial factors may be influencing the association. Chapter 12 proposes several biological hypotheses regarding pathophysiology and treatments of chronic pain in depression. The role of activation of inflammatory cytokine systems and abnormal neurotransmitter systems, such as glutamine, serotonin, noradrenaline, and dopamine, explains the overlapping pathophysiology in chronic pain and depression. Neuroimaging studies show alterations in regions involved in pain perception and structures considered part of the neural bases of depression. The usefulness of tricyclic antidepressants and serotonin-noradrenaline reuptake inhibitors in neuropathic pain and functional somatic syndromes (fibromyalgia and irritable bowel syndrome) is convincingly documented, whereas the superiority of antidepressants from different classes in the treatment of painful physical symptoms in depression is still a matter of debate. Chapter 13 focuses on the clinical, biological, and therapeutic characteristics in depression with and without medical illness. Depressive symptoms can be easily affected by symptoms due to accompanying physical illnesses, sometimes resulting in difficulties differentiating between sole physical illness and comorbid depression, which comes from inflammatory pathways, alteration in the hypothalamic-pituitary-adrenal (HPA) axis, and dysfunctional regulation of hormones and change in neurotransmitters. Considering the significant prevalence of depression in medical illnesses and its impact on prognosis of medical illnesses expressed as morbidity or mortality, careful assessment of depressive symptom screening and severity should be completed with validated assessment tools. Chapter 14 provides a comprehensive overview of burnout syndrome and describes the shift from an initial exploratory and qualitative approach to more systematic, quantitative research on burnout syndrome. Recent studies clarify the issue of burnout-depression overlap at theoretical and epistemological levels and provide compelling evidence that the pathogenesis of burnout is depressive in nature. Burnout syndrome highlights the need for more conceptual parsimony and theoretical integration in psychology and psychiatry and calls for enhanced transdisciplinary communication in the fields of stress and depression research. Preface ix

Chapter 15 examines the biological and psychosocial associations between depression and obesity. The bidirectional association between obesity and depression is complex and affected by several common pathways. HPA axis dysfunction and leptin, insulin, and inflammatory signal disturbances are thought to bridge obesity and depression. In addition, the moderating effects of behavioral and social actors should be considered when examining the relationship between obesity and depression. Recently, several novel interventions that target metabolic or inflammatory mechanisms have been proposed for both obesity and depression. Part IV (Chaps. 16–23) raises therapeutic issues in depression. Ketamine has received a great deal of attention over the last 20 years, due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. To date, treatment strategies for depression have been devised based on the insights gained from brain pathophysiology, including alterations in the monoamine systems. Recent novel antidepressants and promising treatments related to the monoamine systems are addressed. Regarding antipsychotic agents, short-term clinical trials support their efficacy as adjuncts to antidepressants in treating major depressive disorder in individuals inadequately responsive to antidepressant treatment alone. Novel neuromodulation treatments (deep brain stimulation (DBS), vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS)) are a treatment option for treatment-resistant depression. Internet-based MBCT is considered an adjunctive therapy to depression, and CAM receives attention, given that depression is a strong predictor of CAM use. Chapter 16 introduces ketamine, an NMDA antagonist, which produces robust and rapid antidepressant effects after just a single dose. It was originally believed that the antidepressant effects of ketamine were mediated through its antagonism of NMDA receptors and subsequent downstream effects on the enhanced expression of process and proteins leading to synaptogenesis, but more recently, preliminary evidence suggests that the behavioral effects are mediated through AMPA receptors via hydroxynorketamine, a ketamine metabolite. Given that a growing number of providers have begun offering ketamine off-label for the treatment of psychiatric disorders, future research is urgently needed to better understand long-term risks, as well as evidence-based treatment regimens. Chapter 17 provides updates on antidepressant therapy for depression. Emerging knowledge of key pathogenic mechanisms, such as the impairment of non-monoaminergic and monoaminergic neurotransmission, HPA axis hyperactivity, alterations in neurogenesis signaling pathways, and enhanced brain oxidative stress and inflammatory activity, has led to a host of new molecular drug targets. Several of these have been validated through the preliminary use of lead compounds and therapeutic agents in animals and humans. Chapter 18 focuses on the efficacy and effectiveness of prescribing atypical antipsychotics in depression. Each possible antipsychotic agent is useful x Preface in the treatment of depression, particularly in cases of treatment-resistant depression and mixed states associated with depressive episodes. In the future, the therapeutic potentialities of newer atypical antipsychotics in the treatment of depression, both as monotherapy and as adjunctive therapy, should be further investigated. Chapter 19 reviews the neurobiology and evidence for novel therapeutic strategies for treatment-resistant depression (TRD). Although numerous antidepressants are available, there are still very few alternatives for TRD. Among those, ECT emerges as an evidence-based approach. Ketamine, anti- inflammatory treatments, and DBS might be promising, but further studies are needed. Chapter 20 addresses neurostimulation techniques, such as ECT, repeated TMS, MST, tDCS, VNS, and DBS, in the treatment of depression. Neurostimulation is a good alternative treatment for patients who do not achieve remission after several psychopharmacological treatments and psychotherapy. Currently, ECT and TMS are the most extensively studied neurostimulation methods, while MST, tDCS, VNS, and DBS must be studied thoroughly so their efficacy and safety can be evaluated. Risks and benefits of neurostimulation methods should also be weighed in each case. Chapter 21 provides an overview of the superiority of the combination of pharmacotherapy and psychotherapy to each treatment alone in depression, from the perspective of learning theory and neuroplasticity. The synergistic effects of combined therapy can be explained by the pharmacological augmentation of memory reconstruction updating. In this regard, a different class of pharmacological agents, such as histone deacetylase (HDAC) inhibitors, has received attention in the research of combination therapy in depression. Chapter 22 introduces Internet-based MBCT as an adjunctive treatment for depression. MBCT is developed as an 8-week face-to-face group program for relapse prevention of depression. Internet-based delivery modes for MBCT provide benefits over traditional group formats. Several challenges for the successful implementation of web-delivered MBCT programs remain and need to be addressed in the future. Chapter 23 reviews evidence-based studies of CAM in the treatment of depression. Depression has been identified as one of the most frequent indications for CAM use. The evidence on the efficacy of CAM treatments in depression indicates that the approaches that have generated the most research interest include acupuncture, Chinese herbs, hypericum (St. John’s wort), mindfulness, and omega-3 fatty acids. Based on a critical review of the evidence, it appears that the most promising evidence is for hypericum (but with concerns for adverse effects and interactions), mindfulness, relaxation, and yoga. I wish to give my heartfelt thanks to all chapter authors for their valuable time spent in preparing manuscripts. They are leading research scientists with knowledge and expertise in their respective fields. It goes without saying that, without their support, this book would not exist. I also wish to thank Dr. Sue Lee at Springer Nature for her assistance in all aspects of this book. I believe that this book will function as a step on the path toward the ultimate goal of understanding and treating depression.

Kyonggi-do, South Korea Yong-Ku Kim Contents

Part I Diagnostic Issues of Depression

1 Depression in DSM-5: Changes, Controversies, and Future Directions �� 3 Seon-Cheol Park and Yong-Ku Kim 2 Major Depressive Disorder and Bipolar Disorder: Differentiating Features and Contemporary Treatment Approaches �� 15 Ather Muneer 3 Biomarkers of Depression: Potential Diagnostic Tools �� 35 Matea Nikolac Perkovic, Gordana Nedic Erjavec, Dubravka Svob Strac, and Nela Pivac 4 Diagnosis of Major Depressive Disorders: Clinical and Biological Perspectives �� 53 Marc Fakhoury 5 Application of Neuroimaging in the Diagnosis and Treatment of Depression �� 69 Ayla Arslan 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression �� 83 Shinichi Tokuno

Part II Clinical Manifestations of Depression

7 Anhedonia as a Crucial Factor of Depression: Assessment, Neurobiological Underpinnings and Treatment �� 99 Troy K. Chow, Sidney Kennedy, and Sakina J. Rizvi 8 Sleep and Sleep Disorders in Depression �� 113 Seung-Gul Kang, Heon-Jeong Lee, Leen Kim, and John Weyl Winkelman 9 Chronobiology and Treatment in Depression �� 123 Pierre A. Geoffroy and Sunthavy Yeim

xi xii Contents

10 Suicidal Behavior in Depression: A Severe Form of Depression or a Distinct Psychobiology? �� 143 Subin Park and Jin Pyo Hong 11 Cognitive Dimensions of Depression: Assessment, Neurobiology, and Treatment �� 151 Sang Won Jeon and Yong-Ku Kim

Part III Complicated Clinical Manifestations of Depression

12 Overlapping Chronic Pain and Depression: Pathophysiology and Management �� 163 Jan Jaracz 13 Clinical, Biological, and Therapeutic Characteristics Between Depression with and Without Medical Illness �� 175 Kiwon Kim and Hong Jin Jeon 14 Burnout Syndrome and Depression �� 187 Renzo Bianchi, Irvin Sam Schonfeld, and Eric Laurent 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms �� 203 Young Sup Woo and Won-Myong Bahk

Part IV Therapeutic Issues of Depression

16 Experimental Animal Models for Depressive Disorders: Relevance to Drug Discovery �� 223 Boldizsár Czéh, Ove Wiborg, and Eberhard Fuchs 17 Antidepressant Therapy for Depression: An Update �� 235 Deepali Gupta and Radhakrishnan Mahesh 18 Atypical Antipsychotics in Major Depressive Disorder �� 251 Laura Orsolini, Federica Vellante, Alessandro Valchera, Michele Fornaro, Alessandro Carano, Maurizio Pompili, Giampaolo Perna, Gianluca Serafini, Marco Di Nicola, Giovanni Martinotti, Massimo Di Giannantonio, and Domenico De Berardis 19 Neurobiology and Evidence-Based Review on Novel Therapeutic Strategy for Treatment-Resistant Depression (TRD) �� 263 Salih Selek and Jair C. Soares 20 Clinical Application of Neurostimulation in Depression �� 271 Rafael C.R. Freire, Patricia C. Cirillo, and Antonio E. Nardi 21 Is a Combination of Pharmacotherapy and Psychotherapy Superior to Each Alone? �� 283 Kwang-Yeon Choi and Yong-Ku Kim Contents xiii

22 Internet-Based Mindfulness-Based Cognitive Therapy for the Adjunctive Treatment of Major Depressive Disorder �� 299 Jennifer Apolinário-Hagen and Christel Salewski 23 Current Research on Complementary and Alternative Medicine (CAM) in the Treatment of Depression: Evidence-Based Review �� 311 Karen Pilkington Index �� 323 Part I Diagnostic Issues of Depression Depression in DSM-5: Changes, Controversies, and Future 1 Directions

Seon-Cheol Park and Yong-Ku Kim

1.1 Introd uction taxonomy of depressive disorders has been revised in the DSM-5. Revision of the Diagnostic and Statistical Highlights of the changes to diagnostic criteria Manual of Mental Disorders, fifth edition (DSM- for depressive disorders from DSM-IV to DSM-5 5) (American Psychiatric Association 2013), are as follows: (1) splitting of mood disorders into involved a paradigm shift from using a categori- bipolar and related disorders and depressive disor- cal approach to using a dimensional approach for ders; (2) adding “hopelessness” to the subjective psychiatric diagnoses in order to encourage descriptors of depressive mood; (3) introduction of research beyond our current ways of thinking and disruptive mood dysregulation disorder and pre- the adoption of an etiologically and pathophysi- menstrual dysphoric disorder as diseases entities ologically based diagnostic system (Adam 2013). for the first time; (4) renaming dysthymic disorder However, the grand ambition to use a dimen- as persistent depressive disorder; (5) removal of sional approach encountered furious resistance in the bereavement exclusion in the definition of the DSM-5 revision process (Whooley and major depressive episode; and (6) changes to the Horowitz 2013). Hence, the DSM-5 development specifiers for depressive disorders, including “with goal was changed to “bridging the gap between psychotic features,” “with anxious stress,” “with presumed etiologies based on symptomatology mixed features,” and “with peripartum onset.” In and identifiable pathophysiologic etiologies” in this chapter, detailed changes, controversies, and the context of a combined categorical and dimen- future directions in relation to depression in sional approach (Kupfer and Regier 2011). DSM-5 will be explained and discussed (American Consistent with this approach, the psychiatric Psychiatric Association 1994, 2013).

S.-C. Park Department of Psychiatry, Inje University College of Medicine and Haeundae Paik Hospital, Busan, South Korea Y.-K. Kim (*) Department of Psychiatry, College of Medicine, Korea University, Seoul, South Korea Department of Psychiatry, College of Medicine, Korea University Ansan Hospital, Ansan, Gyeonggi Province, South Korea e-mail: [email protected]

1.2 Changes in Depressive 1.2.2 Adding “Hopelessness” Disorders from DSM-IV to the Subjective Descriptors to DSM-5 of Depressive Mood

1.2.1 Splitting Mood Disorders into The term “hopelessness,” which was not included Bipolar and Related Disorders in the DSM-IV, has been newly added to the sub- and Depressive Disorders jective descriptors of depressive mood in the DSM-5. The addition of hopelessness to the Among the changes in the description of DSM-5 is in accordance with the “bleak and pes- depressive disorders from the DSM-IV to the simistic view of the future” contained in the defi- DSM-5, splitting the chapter titled “Mood nition of depressive mood in the International Disorders” into the chapters “Bipolar and Classification of Disease, tenth revision (ICD- Related Disorders” and “Depressive Disorders” 10). Hopelessness is regarded as a psychopatho- might be the most notable (Uher et al. 2014). logical feature different from depressive mood, This split is in accordance with deconstruction because it can be present in the absence of depres- of the Kraepelinian dichotomy, which was an sive mood (Greene 1993; Beck et al. 1993; Joiner important issue in terms of redefining schizo- et al. 2001; Marsiglia et al. 2011). Moreover, phrenia and bipolar disorder using a dimen- hopelessness is considered to be a cognitive atti- sional rather than a categorical approach in the tude of pessimism rather than a specific emo- development process of the DSM-5 (Vieta and tional state (Moller et al. 2015). Herein, we Philips 2010; Kim et al. 2017). The split into speculate that, as a consequence of adding hope- bipolar and related disorders and depressive lessness to the definition of depressive mood, the disorders is based on findings that bipolar and diagnosis of MDD will broaden, and its reliabil- depressive disorders present similar degrees of ity will be reduced (Uher et al. 2014). symptomatologic and genetic overlap to those between schizophrenia and depressive disorder (Lichtenstein et al. 2009; Cross-Disorder 1.2.3 Introduction of Disruptive Group of the Psychiatric Genomics Consortium Mood Dysregulation Disorder 2013; Rasic et al. 2013). However, this split is and Premenstrual Dysphoric partly inconsistent with the fact that the switch Disorder from depressive to bipolar disorder is regarded as one of the most significant transitions in The disease entities disruptive mood dysregulation psychiatric taxonomy (Berk et al. 2006; Etain disorder (DMDD) and premenstrual dysphoric et al. 2012). disorder (PMD) have been newly introduced in the As a consequence of splitting mood disorders chapter titled “Depressive Disorders” in the DSM- into bipolar and depressive disorders, the diag- 5. The diagnosis of DMDD initially originated nostic entity “mood disorder not otherwise speci- from that of severe mood dysregulation (SMD) in fied,” which reflects an undefined condition order to include chronic irritability in children and between “bipolar disorder not otherwise speci- adolescents in terms of psychiatric diagnoses fied” and “depressive disorder not otherwise (Biederman et al. 2004; Carlson et al. 2009; specified,” has disappeared in the DSM-5. Herein, Leibenluft 2011; Rao 2014). Patients with SMD a rigidly dichotomous view of bipolar and depres- were characterized by high rates of attention-defi- sive disorders is necessarily required in the con- cit hyperactivity disorder and oppositional defiant text of mood disorders in the DSM-5 and could disorder over their lifetime, a significant rate of be a challenging issue in the early course of bipo- comorbid anxiety disorder, and higher risk of anxi- lar and depressive disorders (Lish et al. 1994; ety and depressive disorders rather than bipolar Uher et al. 2014). disorders (Brotman et al. 2007; Leibenluft 2011). 1 Depression in DSM-5: Changes, Controversies, and Future Directions 5

Based on the high prevalence rates of SMD in chil- 1.2.4 Renaming Dysthymic dren and adolescents, temper dysregulation disor- Disorder as Persistent der with dysphoria (TDD) was proposed as a Depressive Disorder potential entity by the DSM-5 task force (American Psychiatric Association Taskforce DV 2010). Although dysthymic disorder (dysthymia) was However, since there were no significant systemic firstly introduced in the DSM-III and regarded as studies in the realm of TDD at the time of revision a distinct diagnostic entity with homogenous and the word “temper” had the potential to be erro- characteristics, there was significant criticism neously considered only as a temperament varia- that dysthymic patients were heterogeneous in tion (Stringaris 2011), TDD was finally renamed terms of depressive, anxiety, and personality fea- as DMDD in the DSM-5. Furthermore, partly due tures (Klein et al. 2000; Blanco et al. 2010; to longitudinal study findings suggesting that Rhebergen and Graham 2014). Hence, it has been patients with SMD presented with high rates of proposed that dysthymic disorder can be opti- depressive disorder outcomes (Stringaris and mally defined as a subtype of depressive disorder Goodman 2009a, b), DMDD was included in the and differentiated from MDD by the low level of chapter “Depressive Disorders.” However, the sta- symptoms and high level of chronicity (Judd and bility of the DMDD entity is controversial; several Akiskal 2000). In terms of temperament domains, studies have reported that it has low prevalence, dysthymia, compared to MDD, is more closely frequently co-occurs with other psychiatric disor- associated with harm avoidance (Dinya et al. ders, and is difficult to differentiate from opposi- 2012). Moreover, it has been suggested that dys- tional defiant disorder and conduct disorder thymia might be more closely associated with (Axelson et al. 2012; Copeland et al. 2013). personality disorder than with Axis I disorders in In contrast, PMD is considered a distinct inde- the DSM-IV (Rhebergen and Graham 2014). In pendent disease entity in the DSM-5, whereas addition, a neuroimaging study reported that, late luteal phase dysphoric disorder was an initial compared with normal controls, patients with diagnostic entity for PMD in Appendix A of the dysthymia had less activation in left frontal DSM-III, renamed as PMD in the DSM-IV regions including left ventro- and dorsolateral (Epperson et al. 2012). Both age and gender were prefrontal cortices during working memory tasks regarded as important issues in the definition of (Vilgis et al. 2014). Chronic MDD is also psychiatric illnesses in the revision process of the regarded to be a subtype of a larger group of DSM-5 (Narrow et al. 2007). Hence, diagnosis of affective disorders (Rubio et al. 2011). Finally, DMDD and PMD based on the DSM-5 should be dysthymic disorder and chronic MDD have been considered in the context of age and gender. The integrated into persistent depressive disorder mean prevalence rate of PMD is estimated to be (PDD). In accordance with this change, the about 2% (Sveinsdottir and Backstrom 2000; specifier “chronic,” which denotes a major Gehlert et al. 2009). The Mood Disorders Work depressive episode continuing for more than Group for the DSM-5 proposed the following 2 years, has been removed from the DSM-5. benefits of including PMD as a category in the However, there are several significant criti- DSM-5: greater feasibility of detecting women cisms of PDD as a diagnostic entity. First, given with PMD, promoting accurate collection of data the significant overlap in diagnostic criteria for regarding treatment needs and delivery of ser- PDD, MDD, and generalized anxiety disorder vices, and facilitating the development of specific (GAD), the validity of differentiating PDD from medications (Epperson et al. 2012). Moreover, MDD and )GAD is questionable (Rhebergen and the Carolina Premenstrual Assessment Scoring Graham 2014). Secondly, several meta-analyses System (C-PASS) has been proposed as a valid found few differences in treatment modalities and reliable method for diagnosing PMD between PDD and MDD (Iovieno et al. 2011; (Eisenlohr et al. 2017). Cuijper et al. 2013; von Wolff et al. 2013). Third, 6 S.-C. Park and Y.-K. Kim because few neuroimaging and pathophysiology of the medicalization of a condition or behavior studies of PDD have been performed, it is unclear (Bandini 2015; Moller et al. 2015). Herein, in whether significant conclusions can be drawn. relation to the removal of the bereavement exclusion, medicalization of normal grief and normalization of MDD should be avoided through the 1.2.5 Elimination of Bereavement introduction of appropriate methods in the area Exclusion in the Definition of psychiatric nosology (Pies 2014). of MDD

The most prominent change in the area of depres- 1.2.6 Changes in Specifiers sive disorders from the DSM-IV to the DSM-5 is for Depressive Disorder the elimination of the bereavement exclusion in the diagnosis of MDD (Pies 2014; Uher et al. 1.2.6.1 With Psychotic Features 2014). The reasons for this removal are as fol- In the DSM-IV, coding the specifier “with psy- lows. First, in the context of clinical characteris- chotic features” was permitted only in severe tics, including sadness, sleep disturbance, and MDD and a relatively high prevalence of the spec- decreased appetite; course; and outcome, there ifier “mood-congruent psychotic features” com- are few significant differentiating features pared to “mood-incongruent psychotic features” between bereavement-related and bereavement- was reported. The definition of the specifier “with unrelated depressive disorders (Zisook et al. psychotic features” in the DSM-IV was in accor- 2012). Second, MDD is an important issue in dance with the severity-psychosis hypothesis that global mental health, as it is closely associated the presence of psychotic symptoms was limited with overall suicidal rate (Coryell and Young to severe MDD in patients with psychotic depres- 2005). Third, individuals with bereavement- sion. However, this hypothesis has been rejected related MDD are characterized by past personal by several studies (Ohayon and Schatzberg 2002; and family histories of major depressive episodes. Maj et al. 2007; Østergaard et al. 2012a). Both bereavement-related and bereavement- Moreover, in the context of deconstructing the unrelated MDD have been reported to be influ- Kraepelinian dichotomy, the following factors enced by genetics and to have associations with have been emphasized in the definition of psy- similar personality characteristics, patterns of chotic depression in the DSM-5 revision process: comorbidity, and risks of chronicity and/or recur- potential co-occurrence of psychotic symptoms rence (American Psychiatric Association 2013). independent of the severity of depressive disor- Purely based on symptoms, an operational ders, more adequate definition of psychotic diagnosis of MDD regardless of any environmen- symptoms, and clinical relationship and overlap tal factors can be made with removal of the between unipolar psychotic depression and bipo- bereavement exclusion. Hence, study of environ- lar psychotic depression (Keller et al. 2007a, b). mental factors in the etiology of MDD could ben- Thus, in the DSM-5, the specifier “with psychotic efit from the expected decrease in confounding features” can be coded in PDD and mild to severe effects of the diagnostic procedure on outcome. MDD, and the notion of prevalence of mood- However, it is unclear how to distinguish between congruent and mood-incongruent psychotic fea- normal grief and MDD (Uher et al. 2014). Thus, tures has been removed. There is still an intuitive elimination of the bereavement exclusion could distinction between mood-congruent and mood- result in overdiagnosis and overtreatment of incongruent psychotic features. The revised con- MDD, a potentially expanded market for phar- cept of psychotic depression has been suggested maceutical companies, and loss of traditional and as a distinct disease entity as well as a “meta- cultural ways of grieving. In addition, appropri- syndrome,” which includes unipolar and bipolar ateness and rationality from social and medical psychotic depression in the diagnostic criteria perspectives have been proposed as key features proposal of ICD-11(Østergaard et al. 2012b). 1 Depression in DSM-5: Changes, Controversies, and Future Directions 7

However, the specifier “with psychotic features” treatment studies (Kendler et al. 1992; First 2014; might still be associated with depressive subtyp- Flint and Kendler 2014). ing models (Harald and Gordon 2012). 1.2.6.3 With Mixed Features 1.2.6.2 With Anxious Distress “With mixed features” is also a new coding spec- The specifier “with anxious distress” was intro- ifier in the depressive disorder section of the duced in the DSM-5. This specifier can be coded DSM-5. In the DSM-IV, a mixed episode is in MDD in the presence of two or more of five defined as a condition that simultaneously meets symptoms (feeling keyed up or tense, feeling the criteria for manic episode and depressive epi- unusually restless, difficulty concentrating due to sode; in the DSM-5, this has been removed and worry, fear that something awful will happen, replaced with the specifier “with mixed features,” and fear of losing control of oneself) most days. which can be coded in manic, hypomanic, and Grading of the specifier “with anxious distress” depressive episodes. Herein, a definite distinction is as follows: mild, moderate, and moderate- between episodes being predominantly depres- severe levels involve the presence of two, three, sive or predominantly manic is needed given the and four or more of the five symptoms, respec- removal of mixed episodes in the DSM-5. The tively (Uher et al. 2014). A large cohort study specifier “mixed features” for depressive disorder reported that individuals with MDD “with anx- can be coded for subthreshold bipolar features ious distress” showed poorer clinical outcomes during the predominantly depressive episode, than those with MDD “without anxious distress,” and subthreshold bipolarity denotes a condition and the specifier “anxious distress” was found to that does not meet the threshold of manic or have significant discriminant performance and hypomanic episodes. Coding the specifier “mixed convergent validity (Gaspesz et al. 2017). features” is permitted with the presence of three The symptoms feeling tense, feeling restless, or more of seven symptoms, namely, elevated difficulty concentrating, and fear that something mood, inflated self-esteem, pressure of speech, awful will happen overlap with and/or share racing thoughts, goal-directed activity, involve- diagnostic criteria for both the specifier “with ment in risky activities, and decreased need for anxious distress” and GAD. In the development sleep (Uher et al. 2014; Moller et al. 2015). A process of the DSM-5, the problem of differen- large-sample study has reported that individuals tially diagnosing MDD and GAD was considered with MDD “with mixed features” had signifi- an important issue. Introduction of the specifier cantly more severely depressive phenotypes than “with anxious distress” is in accordance with the individuals with MDD without mixed features significant overlap between MDD and GAD in (McIntyre et al. 2015). Another study found an terms of familial/genetic factors, childhood envi- association between the presence of mixed ronment, personality traits, and demographic features and complex clinical course/reduced characteristics (Hettema 2010). In contrast, due treatment response in individuals with comorbid to insufficient evidence from clinical research, MDD and borderline personality disorder (Pergi the entity “mixed anxiety and depressive disor- et al. 2015). Furthermore, it has been proposed der,” which denotes a combination of subthresh- that additional medications beyond antidepres- old anxiety and subthreshold depression, is sants or lurasidone monotherapy might be effica- regarded to be a useless category in clinical psy- cious for individuals with MDD “with mixed chiatry and is not included in the section for fur- features” (Rosenblat et al. 2016; Targum et al. ther research in the DSM-5 (Moller et al. 2015). 2016). The Clinically Useful Depression To determine the diagnostic boundary between Outcome Scale supplemented with questions MDD and GAD, sharing and separation of regarding the DSM-5 “mixed features” depressive and anxious symptoms should be (CUDOS-M) has been developed and showed systematically analyzed in appropriate epide- high reliability and validity for measuring the miological hypotheses and pharmacological specifier “mixed features” in the Rhode Island 8 S.-C. Park and Y.-K. Kim

Methods to Improve Diagnostic Assessment and the belief that pregnancy has a protective effect Services project (Zimmerman et al. 2014). against development of a major depressive epi- The specifier “with mixed features” can be sode. In addition, the specifier “with peripartum criticized in terms of difficulties in reliably iden- onset” emphasizes the clinical significance of the tifying subsyndromal hypomanic presentations, management of depressive disorders both during operationalizing subthreshold bipolarity, differ- pregnancy and after delivery (di Florio et al. entiating subthreshold bipolarity from borderline 2013; Uher et al. 2014). personality disorder, overdiagnosing bipolar However, there are several controversies spectrum disorders, and uncertainties about opti- about the specifier “with peripartum onset.” A mal interventions for subthreshold bipolarity study of a nationally representative sample from (Nusslock and Frank 2011). Specifically, agita- the United States reported that the clinical pre- tion and irritability have been excluded from the sentation of depressive symptoms in women of definition of the specifier “with mixed features” childbearing age was not significantly different in the DSM-5 due to potential diagnostic non- during pregnancy, after delivery, and outside the specificity, whereas agitation and irritability are period of peripartum (Hoertel et al. 2015). The regarded as hallmarks of mixed mood states in recurrence of MDD was also shown to be closely the DSM-IV (Koulopoulos et al. 2013). While associated with the discontinuation of antide- the frequency rate of mixed mood states accord- pressant treatments during the period of plan- ing to the DSM-5 definition (depressive episode ning pregnancy or pregnancy (Cohen et al. with euphoric mood excluding agitation) ranges 2006; Yonkers et al. 2011). In addition, postpar- from 0 to 12% in empirical studies (Koukopoulos tum onset depressive episodes have been associ- and Sani 2014), the frequency rate using the defi- ated with obsessive-compulsive and psychotic nition including agitation and irritability ranges disorder, whereas depressive episodes during from 33 to 47% (Koukopoulos et al. 2007; Angst pregnancy have been associated with the recur- et al. 2011). Psychomotor agitation and fatigue/ rence of MDD (Altemus et al. 2012). loss of energy were identified as factors that Furthermore, it has not been established if there could differentiate between predominantly are differential responses to treatment in depres- depressive and predominantly manic episodes in sive episodes during pregnancy and after deliv- an empirical study. Based on these findings, ery (Uher et al. 2014). Malhi et al. (2015) proposed splitting mixed mood states into mixed mania and mixed depres- 1.2.6.5 With Catatonia sion. Moreover, agitated depression, which “Catatonia associated with another mental dis- denotes depressive syndromes with psychomotor order” has been newly conceptualized as a agitation and which was initially included in the semi-independent category in the chapter original research diagnostic criteria, was pro- “Schizophrenia Spectrum and Other Psychotic posed as an alternative diagnostic entity by Disorders” in the DSM-5. Hence, the specifier Koulopoulos et al. (2013). “with catatonia” is coded for a condition that has three or more of the following symptoms: 1.2.6.4 With Peripartum Onset stupor, catalepsy, waxy flexibility, mutism, neg- The specifier “with postpartum onset” in the ativism, posturing, mannerism, stereotypy, agi- DSM-IV has been expanded to “with peripartum tation, grimacing, echolalia, and echopraxia. onset” in the DSM-5 and can be coded not only As a consequence of this revision, the definition within 4 weeks after delivery but also during the of catatonia has been broadened, and validation entire pregnancy. Expansion of the specifier through response to specific treatments includ- “with peripartum onset” accepts the finding that ing benzodiazepines and electroconvulsive postpartum depressive episodes can start during therapy is needed (Moller et al. 2015; Uher pregnancy and worsen after delivery and rejects et al. 2014). 1 Depression in DSM-5: Changes, Controversies, and Future Directions 9

1.3 Controversies interest) (Uher et al. 2014). Hence, 227 depressive symptom combinations can meet the diag- 1.3.1 Categorical Versus nostic criteria of MDD. In real situations, Dimensional Approaches Zimmerman et al. (2014) reported 170 symptom combinations in more than 1500 MDD patients In the development process of the DSM-5, com- diagnosed using the DSM-IV, while Park et al. bination of categorical and dimensional (2017) reported 119 different combinations in approaches to express the main distinction 853 MDD patients diagnosed using the DSM-IV between affective psychosis (e.g., bipolar disor- who scored ≥8 on the Hamilton Depression der and psychotic depression) and non-affective Rating Scale. Moreover, several of the diagnostic psychosis (e.g., schizophrenia and schizophreni- criteria for MDD consist of multiple or alterna- form disorder) was proposed to deconstruct the tive symptoms, including psychomotor agitation Kraepelinian dichotomy (Adam 2013; Moller or retardation, impaired concentration or indeci- et al. 2015). However, symptom-based classifica- siveness, worthlessness or guilt, insomnia or tion of schizophrenia and bipolar disorder hypersomnia, decreased or increased appetite, remains, and dimensional approaches were aban- and death wish or suicidal ideation. Separation of doned in the DSM-5, although the Clinician- each component symptom of the six compound Rated Dimensions of Psychosis Symptom criteria means that 14,528 symptom combina- Severity in the emerging measures and models of tions can meet the diagnostic criteria of the DSM-5 contain psychometric properties of MDD. Thus, Zimmerman et al. (2010) proposed dimensional approaches for hallucinations, delu- defining MDD in a simpler way through the elim- sions, disorganized speech, abnormal psychomo- ination of four somatic symptoms in the DSM-IV tor behavior, negative symptoms, impaired definition in order to overcome the epistemologi- cognition, depression, and mania domains cal restriction associated with the heterogeneity (Heckers et al. 2013; Moller et al. 2015). In of MDD. In addition, a high concordance rate accordance with the distinction between schizo- between the simpler definition and the DSM-IV phrenia and bipolar disorder, differentiating definition of MDD was reported in 2907 psychi- between MDD and GAD was regarded as a sig- atric outpatients (Zimmerman et al. 2011). nificant issue in the DSM-5 revision process However, the simplification proposal was aban- (Hettema 2010). In addition, symptom-based doned in the DSM-5 revision process (Uher et al. classification of MDD and GAD is still present, 2014). The heterogeneity of MDD in terms of its and the specifier “with anxious distress” was polythetic diagnostic criteria has often been criti- introduced to express comorbid anxiety symp- cized (Østergaard et al. 2011; Olbert et al. 2014; toms, whereas dimensional grading is used for Fried and Nesse 2015; Zimmerman et al. 2015) both MDD (mild, moderate, and severe) and the and regarded as a concept corresponding to a lan- specifier “with anxious distress” (mild, moderate, guage game in Wittgensteinian philosophy, moderate-severe, and severe). because a single or “essential” characteristic of MDD cannot be identified, and cases of MDD comprise a set of “family resemblances” 1.3.2 Heterogeneity of MDD (Rosenman and Nasti 2012). Moreover, one in the Context of Polythetic study reported that the heterogeneity of depres- Diagnostic Criteria sive syndromes likely contributes to the limited knowledge and understanding of depression In both the DSM-IV and DSM-5, the diagnostic among nursing personnel in general hospitals criteria for MDD are the presence of five or more (Park et al. 2015). of nine specific depressive symptoms (necessity Moreover, because each of the symptoms in of the presence of depressive mood or loss of the DSM depression criteria is etiologically 10 S.-C. Park and Y.-K. Kim heterogeneous, individual symptoms rather 2015). To achieve a better neurobiological than symptom sum-scores should be consid- understanding in the area of psychiatry, the ered to gain a holistic understanding of MDD diagnostic classification of depressive disorders (Fried et al. 2014). For example, the symptom should take into account the following com- combination of helplessness and hopelessness ments of Thomas Insel (2013): “Unlike defini- has been proposed as the most important dis- tions of ischemic heart disease, lymphoma, or tinguishing feature between depressed patients AIDS, the DSM diagnoses are based on a con- and healthy controls (McGlinchey et al. 2006). sensus about clusters of clinical symptoms, not In addition, weight gain rather than weight loss any objective laboratory measure. In the rest of is more closely associated with chronic stress- medicine, this would be equivalent to creating ors (Keller et al. 2007a, b). Moreover, the co- diagnostic systems based on the nature of chest occurrence of disturbed sleep and appetite was pain or the quality of fever. Indeed, symptom- shown to be more closely associated with bipo- based diagnosis, once common in other areas of lar than with unipolar depressive episodes medicine, has been largely replaced in the past (Papadimitriou et al. 2002). The interest-activ- half century as we have understood that symp- ity symptom dimension, including low interest, toms alone rarely indicated the best choice of reduced activity, indecisiveness, and lack of medicine.” enjoyment, was identified as a predictor of In addition, Kato et al. (2016) proposed that poor outcomes after treatment of 811 adults modern-type depression in Japanese younger with moderate to severe depression with flexi- generations is characterized by fatigue, feel- bly dosed escitalopram or nortriptyline (Uher ings of worthlessness, blaming others, impul- et al. 2012). A network analysis of data from sive suicidal action, and occasional depressive the Sequenced Treatment Alternatives to symptoms mainly during work/school and is a Relieve Depression (STAR*D) study rejected distinctive entity associated with Japanese cul- the assumptions that depression symptoms tural and social influences. Diagnostic criteria equivalently indicate MDD and that DSM for modern-type depression should consider symptoms of depression have greater clinical depressive syndromes in the context of specific relevance than non-DSM depression symptoms cultural and social backgrounds. Moreover, a (Fried et al. 2016). humanistic approach that considers subjectiv- ity and interpersonal context needs to be emphasized in future etiologically based clas- 1.4 Future Directions sification systems (Castiglioni and Laudisa 2015). Although transnosological specifiers as well as severity and cross-cutting assessments enable us Conclusions to individualize treatments and differentially Depressive disorders have been reformulated describe treatment outcomes (Moller et al. based on a combination of categorical and 2015), the grand ambition of the paradigm shift dimensional approaches in the DSM-5. from categorical to dimensional approaches in However, despite the transdiagnostic specifi- the realm of depressive disorders was frustrated ers, severity assessments, and cross-cutting in the DSM-5 revision process, and symptom- measure assessments contained in the DSM-5, based classification of depressive disorders MDD is still defined using a symptom-based remains in the DSM-5 (Whooley and Horowitz classification, and its heterogeneity is of sig- 2013). Although the Research Domain Criteria nificant concern. Moreover, it is necessary to project has been suggested as an alternative develop an etiology-based classification of research-related methodology (Insel et al. depressive disorders and to consider humanis- 2010), it does not provide routine framework tic approaches together with potential cultural conditions for clinical psychiatry (Moller et al. and social influences. 1 Depression in DSM-5: Changes, Controversies, and Future Directions 11

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Ather Muneer

2.1 Introduction Statistical Manual’s 5th edition in which a necessary shift has been implemented by segregating Primary mood disorders, including major depres- the two conditions into separate chapters, whereas sive disorder (MDD) and bipolar disorder (BD), previously these were described under the com- are among the most prevalent psychiatric condi- mon rubric of “mood disorders.” tions. In a relatively recent international survey Affective disorders are complex gene x envi- of 18 countries, the average lifetime prevalence ronment diseases and are heterogeneous in phe- of major depressive episodes (MDE) was 14.6% notypic expression. Current knowledge assumes in 10 high-income countries and 11.1% in 8 low- that these disorders lie on a spectrum with depres- to middle-income nations (Bromet et al. 2011). sion and mania being opposite poles of a distur- The population studied was not stratified accord- bance that has myriad presentations confounded ing to the type of affective disorder, so that it can by such factors as personality characteristics, be assumed that the patients comprised of both neuropsychiatric comorbidities, and psychosocial MDD and BD as long as they fulfilled DSM-IV incumbencies (Becker and Grilo 2015). In the criteria for a major depressive episode. The cur- early phase of the illness, stress factors are identi- rent nosological classifications do not differenti- fied as precipitating events, but with advance- ate between these disorders as far as the diagnostic ment of the diathesis, mood episodes recur features of MDE are concerned, but prevailing spontaneously. Further, asymptomatic periods viewpoint dictates that MDD and BD have funda- become progressively shorter and an unrelenting mental neurobiological distinctions with thera- disease state ensues with impairments in cogni- peutic and prognostic implications. In this vein it tive and functional domains (Moylan et al. 2013). must be appreciated that these disorders are dis- These phenomena are epitomized by such nega- crete conditions, with differences that encompass tive attributes as rapid cycling, residual affective genetic and pathophysiologic aspects impacting states and subthreshold symptoms. The overall on illness trajectory and longitudinal course consequence of this process which has been aptly (Duman and Monteggia 2006). Such emerging termed as “neuroprogression” is a decline in insights are reflected in the Diagnostic and autonomy, impairment in role functioning, and loss of personal independence. In this regard the later stages of mood disorders are typified by severe psychosocial and biological disturbances, A. Muneer with incremental damage to all body systems Islamic International Medical College, Riphah because of the derangement of the homeostatic International University, Rawalpindi, Pakistan e-mail: [email protected] balance caused by increased “allostatic load”

Mood ↑ Allostatic Homeostatic Episodes load disturbance

Impaired role Loss of Psychosocial functioning autonomy

Neuroprogression/ ↑ morbidity Biological systemic ailments and mortality

Fig. 2.1 The pernicious nature of mood disorders. Mood static load. The resulting homeostatic imbalance has a disorders, whether MDD or BD, are conceptualized as pervasive negative effect with such consequences as cog- very serious conditions with profound consequences in nitive impairment, physical comorbidities, persistent the biopsychosocial realm. Repeated affective episodes affective symptoms, and role impairment leading to even- increase “wear and tear” in the body with increased allo- tual loss of autonomy

(McEwen 2003). Figure 2.1 gives a schematic description of the genetic aspects and pathophys- representation of the pernicious nature of mood iologic implications; lastly, therapeutic measures disorders with ensuing profound negative conse- are considered. quences for all bodily systems (Fig. 2.1). The burden imposed by these ailments in the biopsychosocial realm is immense, as subjects of 2.2 Clinical Considerations both sexes are initially afflicted in youth or early adulthood and suffer from relapses and recur- The sine qua non of BD is a manic episode, but rences throughout their lifetimes. Modern per- in actual practice depression is its most fre- spective states that these are in essence quent clinical presentation (Muneer 2016b). multisystem disorders, affecting essentially all Longitudinal naturalistic studies show that bipolar parts of the body and leading to increased mor- patients spend the majority of their time in the bidity and mortality from such conditions as dia- depressed state, rather than being manic or hypo- betes mellitus, cardiovascular diseases, and manic (De Dios et al. 2012). The former can mani- immunological disorders (Mansur et al. 2015). fest as major depressive episodes or as subthreshold Further, the neurobiology of mood disorders is symptoms. Additionally, depressive manifesta- incompletely understood, and presently available tions can intermingle with manic or hypomanic treatments are of palliative rather than curative symptoms and give rise to mixed states, which are value. Despite continued research efforts, gaps in more severe and lead to adverse psychosocial knowledge are significant which translate into sequelae (Valenti et al. 2015). Whereas in MDD, less than optimal therapeutic measures with depressive episodes occur in the mid-20s onward, adverse consequences for the sufferers, their fam- bipolar depression has a much earlier onset in ilies, and the society as a whole (Muneer 2016a). early teenage years, is often the index episode, and In this scenario it is crucial to inculcate a better usually has melancholic features (Muneer 2016c). understanding of these ailments so that the BD is notorious in masquerading in myriad forms, patients are managed more effectively and their and the presenting illness can be in the way of disease burden is reduced. With this preamble, anxiety spectrum disorders, conduct disorders, the manuscript is dedicated to discussing the and substance use disorders. Because of these rea- most relevant issues in the etiology, pathogene- sons, the condition is misidentified, and the lag sis, and treatment of mood disorders. However, period in diagnosis is of the magnitude of several first clinical features are mentioned followed by a years (Nasrallah 2015). 2 Major Depressive Disorder and Bipolar Disorder 17

The major depressive episodes in MDD can be from recurrent episodes which are of greater single or recurrent but tend to be discrete, with severity, so that there may be a history of psychi- well-characterized periods of remission. In the atric hospitalizations (Shapiro et al. 2014). Of case of BD, patients are symptomatic for longer note, major depression which is treatment resis- periods; they may have full blown severe mood tant to two or more first-line antidepressant episodes or subsyndromal symptoms in the inter- medications should raise the suspicion of a mas- episode which has a pervasive negative effect on querading bipolar diathesis. Unipolar patients the overall prognosis. Rapid cycling is a phenom- who shift to mania or hypomania when treated enon in which bipolar patients have four or more with antidepressants, ECT, or chronobiological affective episodes in a 12-month period. This is measures are considered to lie on the bipolar regarded as an extreme form of the disorder with spectrum. In this regard seasonal variation may harmful consequences in the functional and psy- be marked in BD, with patients experiencing chological domains (Carvalho et al. 2014). With repeated depressive episodes during fall and win- repeated mood episodes, there is deterioration in ter months (Akhter et al. 2013). all aspects of living and neuroprogression, which With respect to clinical presentation, patients in essence implies the persistence of a deficit with bipolar depression often experience mixed state with eventual loss of autonomy (da Costa features such as racing thoughts, irritability, et al. 2016). The suicide rate is very high in BD, grandiose ideation, and increased energy. and this may be attributable to many factors, Moreover, they are prone to having recurrent sui- chief among which are greater number and sever- cidal ideation, and a history of repeated self- ity of episodes, existence of mixed states, and injurious behavior in unipolar depression should presence of such comorbidities as anxiety spec- raise the specter of underlying bipolar illness trum and substance use disorders (Rajewska- (Musliner et al. 2016). Neuropsychiatric and Rager et al. 2015). physical comorbidities are frequently associated In this situation, a primary question for the with BD including panic disorder, posttraumatic treating psychiatrist is the correct identification stress disorder, alcohol and other substance use of the mood disorder when a patient presents disorders, borderline personality disorder, and with a major depressive episode. Although there eating disorders (Simhandl et al. 2016). are no validated criteria for such a distinction, Neurological conditions found more often in certain features should alert the clinician in this bipolar patients comprise of migraine, idiopathic regard. This is important because treatment of neuropathic pain, vertigo, and restless legs syn- bipolar disorder is primarily with mood stabiliz- drome (Fornaro and Stubbs 2015). An important ers, whereas unipolar depression is best managed caveat with respect to the bipolar diathesis is its with standard antidepressant medications association with the metabolic syndrome, obe- (Karanti et al. 2016). Administration of antide- sity, and diabetes mellitus so that cardiovascular pressants without adjunctive mood stabilizers to diseases are considered as the foremost cause of bipolar subjects can result in manic/hypomanic premature mortality in this group of subjects switch, induction of mixed states, and rapid (Grover et al. 2014). In conclusion, it can be con- cycling (Muneer 2015). strued that among mood disorders BD is a much When a patient first presents with an MDE, more severe condition than MDD and is chal- the presence of family history of bipolar disorder lenging to manage because of the facts men- is a cautionary sign. Age of onset is also signifi- tioned above. Table 2.1 gives a summary of cant, with the index episode occurring in adoles- clinical features that should alert clinicians for cence or teenage years in BD, while in the case the possible presence of bipolar spectrum disor- of major depression, this is usually in the mid- ders in patients presenting with major depressive 20s. Furthermore, bipolar subjects tend to suffer episodes (Table 2.1). 18 A. Muneer

Table 2.1 Likely indicators of bipolarity in patients pre- human studies, an immense range of method- senting with major depressive episodes ologically diverse approaches including the Onset in adolescence or early teenage years exploration of different stressors, self-report 1. Family history of bipolar disorder questionnaires, imaging techniques, investigation 2. Comorbid anxiety, substance use or conduct of the HPA axis, and postmortem brain examina- disorders 3. Major depressive episode with melancholic features tion have given credence to an association 4. Psychotic depression between the s allele and stress-induced reactivity 5. Repeated mood episodes (Hildebrandt et al. 2016). 6. Increased severity of episodes, with history of s allele carriers are discovered to exhibit hospitalization 7. Treatment-resistant depression increased and rapid activation in the amygdala, a 8. Mixed states structure implicated in regulating homeostatic 9. Seasonal affective disorder and behavioral responses to outside stressors and 10. Suicidal behavior/repeated attempts at self-harm fearful stimuli. Further, alterations in the func- 11. Switching on antidepressants tional and microstructural connectivity of the amygdala and the medial prefrontal cortex are also described in s allele carriers (Savitz and 2.3 Etiology of Mood Disorders Drevets 2009). The gene for the serotonin transporter protein, 5-HTTLPR, is involved in other 2.3.1 Genetic Aspects possible mood disorder antecedents such as subthreshold depression and affective temperaments. Depression is a prevalent mental illness that is In an important prospective study, Caspi et al. projected to be among the most common causes showed the effect of s allele of the 5-HTTLPR of morbidity by 2020. Research efforts have polymorphism on the development of depressive shown that the share of genetic factors in the cau- symptoms in the presence of stressful events sation of depression is 30–40%, and there is a (Caspi et al. 2003). This finding was afterward growing literature that is linking this vulnerabil- substantiated by a very large meta-analysis, ity to biological substrates (Lohoff 2010). The which included 54 studies on overall 41,000 sub- methodology adopted for research purposes is jects. In some of the earlier studies, conflicting greatly varied, ranging from candidate gene findings regarding the link between different approaches to genome-wide association studies. types of stressors, 5-HTTLPR genotype, and In this regard, the serotonergic system is a princi- depression were related to distinctions concern- pal target due to its involvement in the regulation ing the definition, evaluation, inclusion of and of mood and anxiety. Of particular significance is delineation between diverse stressors, and life the serotonin transporter protein responsible for events. However, the said meta-analysis clarified 5HT synaptic reuptake, which is also the key tar- these issues and further demonstrated that child- get of monoaminergic antidepressants. The gene hood and adolescent maltreatment, proximal life coding for this protein is SLC6A4, and in humans events, and serious medical conditions were all the s (short) allele of the 5-HTTLPR polymor- liable to cause depression in those carrying the s phism of the serotonin transporter gene is incrim- allele or the ss genotype of the 5HT transporter inated in anxiety related attributes and neuroticism gene (Karg et al. 2011). In a European study (Daniele et al. 2011). This variation conveys comprising of a large population sample, compa- increased attention and sensitivity to environ- rable and statistically significant associations mental stressors, and carriers of the genotype were observed in subjects carrying the ss geno- have a tendency to experience neutral stimuli as type and a moderately significant association in negative and threatening. Accompanied by less sl cases when they were investigated for a rela- efficient coping strategies in the face of stress, tionship between threatening life events and these individuals are more liable to developing mood symptoms as assessed by the Zung Self- depressive disorders (Kuzelova et al. 2010). In Rating Depression Scale. Whereas extreme 2 Major Depressive Disorder and Bipolar Disorder 19 stressors individually explained 2.4% of the vari- monoamine metabolism (MAOA, COMT), neu- ance in affective manifestations, this proportion rotrophins (BDNF), endocannabinoids (CNR1), increased approximately twofold to 4.2% upon transport, and other proteins (SLC1A1, SLC6A2, including the intermediary effect of 5-HTTLPR CREB1, KCNJ6, CACNA1, GLUR7). In many genotype and climbed to 5.9% when genotype studies CNR1, the gene of the cannabinoid CB1 data of other polymorphisms of the serotonin receptor has been strongly implicated in depres- transporter gene were incorporated in the model sion besides the SERT gene and has been further (Lazary et al. 2008). These statistics clearly show associated with trait anxiety and neuroticism. An that genetic variability and environmental influ- SNP (rs2180619) in the CNR1 gene interacts with ences act together in regulating mood. ss 5-HTTLPR genotype to increase trait anxiety manifold (Lazary et al. 2009). The substrate of this interaction is purportedly a sustained high 2.3.2 New Understanding 5HT concentration following activation of the of Depression serotonergic neurons in response to stress, resulting from a low expression of the inhibitory CB1 In the case of depression, the interaction between receptors and high synaptic serotonin concentra- the environment and genetic factors is complex. tion because of low SERT levels. Comparable Previous models posit that in the existence of observation was reported in fMRI studies where inherited predisposition, adversities experienced heightened amygdala activation was seen in ss during childhood or adolescence contribute to carriers and this correlated with increased neuroti- enhanced susceptibility to depressive illnesses in cism scores. These findings suggest that SERT adult life in the face of stressful life events. In this and CB1 receptor genes are the most strongly regard carriers of the s allele are at a greater risk implicated among the candidate genes and further of affective illnesses when encountering severe point out that depressed mood manifests on the stressors; however, recent research underscores basis of diverse DNA regions mediating the the importance of other DNA regions in this gene effects of varied environmental influences. x environment model. For example, one study Additionally, the depressive phenotype arises showed no association between seasonal affec- from an interaction of these genes at the substrate tive disorder and 5-HTTLPR s allele (Molnar level (Bagdy et al. 2012). et al. 2010), while in another paper specific link- The genes incriminated in depression can be age between rumination, a trait-like cognitive classified into seven groups or sets, some of style, and depression was mapped to CREB1 and which confer resiliency while others induce vul- BDNF genes (Juhasz et al. 2011). These instances nerability. Varied gene sets have a role in the allude to the fact that everyday stressors are development of personality, mediation of the diverse including among others childhood mal- effects of environmental influences, and interplay treatment, losses, health problems, hormonal of diverse aspects of temperament with external changes, and seasonal variations and each person factors. Environmental dynamics comprise of has a discrete liability profile toward adverse and internal and external factors; several of the early protective events and occurrences. Therefore, dif- influences directly affect the formation of person- ferent genes may have distinct contributory or ality traits and temperaments. While some of the ameliorative effects in the development of a com- genes, for example, tryptophan hydroxylase 2, plex phenotype, namely, depression. are included in one set, others (5-HTTLPR and In an emerging synthesis of the depression CB1) are constituents of several groups. model, several other genes besides 5HT trans- Intriguingly, even without one gene set, discrete porter play a role in the causation of the diathesis. genes may have separate roles, and not all genes These include genes involved in serotonergic neu- are engaged in every function. As an example, rotransmission (HTR1A, HTR2A, TPH1), dopa- 5-HTTLPR has a profound influence in mediat- minergic neurotransmission (DRD2, DRD4), ing the effects of particular aggravating life 20 A. Muneer events, but has no significant role in seasonal depression. Further, this could be instrumental in depression (Mushtaq et al. 2016). Table 2.2 delin- identifying those individuals who are at increased eates candidate genes grouped in sets and identified risk for mood disorders and be of assistance in in large-scale population studies, conferring resil- choosing appropriate treatment for the patients iency or predisposing to mood disorders in the wake (Fabbri et al. 2013). of environmental stressors (Table 2.2). Figure 2.2 is an illustrative rendition of a new model of depression that emphasizes the interaction between gene 2.3.3 Epigenetic Influences sets, personality, and environment in the development of mood disturbance (Fig. 2.2). In the case of neuropsychiatric disorders, the The s allele of 5-HTTLPR has a significant but contribution of hereditary factors is estimated to weak association with depression provoking exceed 30%, but even with state of the art meth- effects of stress so that it cannot be utilized for ods, only a fraction of this variance can be direct screening of the susceptibility to this dis- mapped to specific genes and DNA base sequence ease. Further, in the absence of multiple severe alterations. In this scenario, epigenetic effects stressors, s allele carriers may not show more have become the focus of attention as these play depressive symptomatology than those carrying a role in regulating protein synthesis, are only other genotypes. Nonetheless, in the presence of partially heritable, but subject to modification by extreme and manifold life stresses, s allele carri- environmental influences. Two chief epigenetic ers are more prone to dysthymic mood, poor mechanisms can adapt the function of genes: coping, and full-blown depressive illness. Addi tionally, these subjects show worse therapeutic 1. Acetylation or methylation of histones that response to SSRIs, the most commonly used anti- direct the availability of DNA for biological depressants. They show slower onset of action, processes lower rates of response, poor tolerability, and fre- 2. Methylation of the DNA itself, which inhibits quent side effects with this group of medications, the transcriptional activity of the CpG-rich while drugs with different pharmacodynamics regions of the genome (e.g., norepinephrine-selective agents) are more effective in s allele carriers. When vulnerability Since these alterations are allele specific, and resiliency factors are viewed together, it can genetic polymorphisms are linked to different be surmised that screening for 5-HTTLPR geno- probability and type of epigenetic changes upon type can be part of a working assumption in bet- environmental exposure, and consequently con- ter understanding the evolving etiopathology of siderable variance occurs in sensitivity to such

Table 2.2 Gene sets responsible for heritable traits that interact with environmental factors in the causation of mood disorders Factors linked to mood disorders Gene products (proteins) Involved genes Neuroticism, trait anxiety SERT, CB1 SLC6A4, CNR1 Stress/negative life events SERT, CB1 SLC6A4, CNR1 Depressogenic/anxiogenic effect of medications SERT, CB1 SLC6A4, CNR1

Stress coping (resiliency versus vulnerability) 5-HT1A, 5-HT1B HTR1A, HTR1B Rumination CREB1, GIRK, BDNF CREB1, KCNJ6, BDNF Hopelessness TPH2 TPH2

Impulsiveness 5-HT1A, COMT HTR1A, COMT

Seasonal variations 5-HT2A HTR2A BDNF brain-derived neurotrophic factor, CB1 endocannabinoid receptor 1, COMT catechol-O-methyltransferase, CREB cyclic AMP response element-binding protein, GIRK G protein-coupled inwardly rectifying potassium channel, SERT serotonin transporter protein, TPH tyrosine hydroxylase, 5-HT serotonin 2 Major Depressive Disorder and Bipolar Disorder 21

EXTERNAL GENE SETS FACTORS

GENE SETS

PERSONALITY AND TEMPERAMENTAL FACTORS GENE SETS INTERNAL FACTORS

D E P R E S S I O N

Fig. 2.2 New gene x environment model of depression. ders. The new gene x environment model of depression is Candidate genes comprising gene sets: 5-HTTLPR, CB1, based on diverse gene sets that acting through personality, TPH2, CREB1, BDNF, COMT, GIRK, HTR1A, HTR2A. internal and external factors lead to the development of Personality/temperamental factors (predisposing): neu- depression. Some genes are part of more than one set, for roticism, rumination, stress vulnerability, impulsivity, example 5-HTTLPR and CB1, while others like HTR2A negative cognitive style. Personality/temperamental fac- belong to only one set. These gene sets act with interme- tors (protective): openness, trust, acceptance, stress cop- diaries like temperamental traits or environmental factors, ing. External factors: early life events, provoking life for example seasonal variation to cause the depressive events, seasonal changes, social support. Internal factors: diathesis hormones, biological rhythm generators, comorbid disor- factors. A pertinent example is the catechol-O- depression, probably because epigenetic modifi- methyltransferase gene in which the existence of cations altered the gene function in patients (Pap Val 158 allele in the rs4680 SNP creates a CpG site et al. 2012). This mechanism might clarify why for methylation, the repressive effect of which can childhood abuse amplifies the risk for later depres- compensate for the enhanced dopamine elimina- sive disorders. In a rodent study, maternal mal- tion in the prefrontal cortex in the high-activity treatment evoked long-lasting methylation of the Val allele carriers. However, life stressors dimin- BDNF gene in the prefrontal cortex, and these ish the methylation of this area of the gene, animals showed impaired rearing behavior toward leading to increased activity of COMT with resul- their offspring (Roth et al. 2009). In line with this tant impaired working memory due to decreased observation, the BDNF gene in a human popula- dopamine availability in this key brain region tion study was associated with increased risk of (Ursini et al. 2011). In a study investigating the depression exceptionally in the presence of child- effect of COMT gene on depressed mood, it was hood trauma (Juhasz et al. 2011). In this vein it discovered that variations in the said gene were must be understood that the salient attribute of associated with depressive symptom scores in epigenetic imprint is its tissue and cell specificity, those who had not been depressed previously in so that different parts of the brain show discrete contrast to those who had already suffered from methylation and acetylation patterns, severely 22 A. Muneer hampering the ability to investigate this in vivo are linked to the development, symptom severity, human brain. There is no method yet to study epi- and duration of affective disturbances like depres- genetic changes in the living brain, but gathering sion, anxiety, and posttraumatic stress disorder in-depth knowledge concerning genetic base (Mills et al. 2013). Severe and persistent stress sequence and its interaction with environmental can by itself induce a low-grade inflammatory factors is crucial to understanding the pathophysi- state which can precipitate mood perturbation ology of mood disorders, as well as predicting reminiscent of major depressive disorder. The medication beneficial and adverse effects. inflammatory receptor-ligand interaction invoked in this process has been termed danger-associated molecular patterns (DAMPs), mediated by 2.4 Pathogenesis of Mood inflammasome-dependent signaling which Disorders appears to play an overarching role in the pathogenesis of mood disorders (Iwata et al. 2013). Mood disorders afflict innumerable people every year and cause a great deal of morbidity and mortality, but their neurobiology is only partially elu- 2.4.1 Inflammatory Molecular cidated. In this situation, a growing body of Patterns evidence points to the involvement of the immune-inflammatory system in their inception The main effectors of the inflammatory response and progression. During acute affective episodes, are the innate immune cells, while adaptive patients have elevated levels of inflammatory immune cells are important partners. The former proteins, i.e., cytokines and chemokines in the are found throughout the body and CNS and peripheral circulation (Rosenblat et al. 2014). It respond to pathogenic challenges, cellular stress, is now known that repeated and severe stressors, and tissue damage. Receptor-ligand recognition in the absence of pathogenic disease, can induce schema is a notable and fundamental differenti- an inflammatory response and this has been aptly ating attribute between innate and adaptive called “sterile inflammation.” Recently, in the immune cells. The former use germline-encoded last decade or so, it has become clear that psycho- receptors intended to identify conserved molecu- logical stress, in the nonexistence of overt tissue lar patterns and have been named pattern recog- damage, can trigger systemic and CNS sterile nition receptors (PRRs). A huge number of inflammation with homeostatic imbalance that ligands are capable of binding PRRs and include can have profound effects and damage all organ both pathogenic and commensal microbes, systems in the body (Fleshner 2013). This has termed microbe-associated molecular patterns or been substantiated in laboratory experiments on MAMPs, whereas typically pathogenic patterns animals with such paradigms as social conflict, are labeled pathogen-associated molecular pat- threat, isolation, and rejection which cause terns or PAMPs (Sirisinha 2011). Examples of increase in C-reactive protein, proinflammatory MAMPs and PAMPs include lipopolysaccharide cytokines (IL-6, IL-1β, TNF-α), and elevated (LPS), a membrane incorporated component of expression of NF-ĸB (Aschbacher et al. 2012). many gram-negative pathogenic bacteria or CpG The behavioral effect of this raised inflammatory DNA, a common viral motif. Of note, a strong status is manifested as an overt expression of the inflammatory reaction is the result of PRR- depressive phenotype in the research animals. PAMP binding. In contrast to these prototypes, In human subjects parallel findings have been DAMPs are endogenous molecules which are described, for example, a study reported that the increased after cellular stress and tissue damage, death of a spouse increased IL-1β and IL-6 activ- and PRR-DAMP binding leads to sterile inflam- ity in older adults (Schultz-Florey et al. 2012). mation (Ibrahim et al. 2013). Newly recognized Intriguingly, increases in inflammatory indicators DAMPs are increasingly being reported and following exposure to an acute traumatic event include extracellular heat shock proteins (Hsp), 2 Major Depressive Disorder and Bipolar Disorder 23 adenosine triphosphate (ATP), high mobility translation, and protein production. Once primed group box 1 (HMGB1), etc. (Frank et al. 2015). in this way, a second activation signal is required There is extensive overlap in a broad array of for mature caspase-1 to cleave pro-IL1β into inflammatory proteins that are mediated after functional IL-1β (Kang et al. 2014). The NLRP3 either LPS (PAMP) or stressor exposure inflammasome appears to react to a wide array of (DAMP). These are detectable in the blood and signals (ATP, K+ efflux,β -amyloid, reactive oxy- peripheral tissues and include cytokines, chemo- gen species, etc.) to get activated and binds to kines, and mRNA transcripts. In this vein, it these stimuli as it expresses several PRRs includ- needs to be recognized that brain tissue and ing TLRs, RAGE, and CD91. As such it has been microglia also respond to PAMPs and DAMPs incriminated in a wide range of sterile inflamma- by increasing the secretion of inflammatory tory diseases including ischemia-reperfusion mediators (Frank et al. 2016). injury, autoimmune disorders, DM II, obesity, atherosclerosis, and Alzheimer’s disease, conditions which have high comorbidity rates with 2.4.2 Sterile Inflammation mood disorders (Li et al. 2014). More specifi- and the Inflammasome cally, patients with depression had increased expression of NLRP3 and caspase-1 in peripheral It has been recently reported that acute and blood mononuclear cells, suggesting that sterile intense psychological stress in the lack of obvi- inflammation mediated by DAMPs and the ous tissue damage can provoke a demonstrable inflammasome and induced by exposure to psy- local and systemic sterile inflammatory response, chological stress is implicated in the pathogenesis with DAMPs playing an inciting role. In this of MDD and other psychopathologies (Alcocer- respect, tail shock in rodents increases tissue and Gomez et al. 2014). blood concentration of many cytokines and chemokines, and both MAMP (derived from the gut bacteria) and DAMP signals are involved in 2.4.3 Neuroinflammation and Mood the inflammatory response. Significantly, in the Disorders said experiments, this was attributed to the inflammasome, more specifically the NLRP3 Peripheral inflammatory processes are liable to inflammasome known as nucleotide-binding incite neuroinflammatory changes through well- oligomerization domain, leucine-rich repeat, and described humoral and neural pathways of pyrin domain protein 3 (Maslanik et al. 2013). immune-to-brain signaling. For instance, the Inflammasomes are intracellular multiprotein humoral pathway may involve blood-borne cyto- complexes that act as sensors of DAMPs and kines provoking neuroinflammatory processes PAMPs, causing activation of catalytic caspases through active transport across the blood-brain and the cleavage and release of proinflammatory barrier, entry into the brain at the circum- cytokines. ventricular organs, or binding of cognate recep- For cytokines that are inflammasome indepen- tors on brain endothelial cells with transduction dent, the process begins with NF-ĸB activation of cytokine signaling into the CNS. In addition, after MAMPs or DAMPs binding to toll-like cytokines as well as PAMPs (e.g., LPS) are capa- receptor-4 (TLR-4), CD14, and other potential ble of stimulating afferent vagal fibers in the PRRs. The subsequent signaling cascade com- periphery, which cause activation of neural path- prises of inflammatory gene transcription, trans- ways in brain regions involved in motivation and lation, protein synthesis, and release. In mood regulation (Marquette et al. 2003). Once a contradistinction, inflammasome-dependent cyto- peripheral inflammatory signal reaches the brain, kine synthesis and release is a two-step process microglia the chief innate immune cells of the that is started after ligation of TLRs and other CNS play a pivotal role in mediating the neuroin- PRRs leading to NLRP3 gene transcription, flammatory response. 24 A. Muneer

Microglia perform several crucial functions in synthesis and release of inflammatory media- the brain including immunosurveillance for tors, including IL-1β. pathogens, cellular debris, apoptotic cells, and 3. The secreted form of this cytokine may drive neuronal phenotypic alterations. Upon activation the induction of indoleamine 2,3-dioxygenase microglia enter a primed position and when stim- (IDO). ulated in this state secrete increased amounts of 4. IDO-mediated catabolism of tryptophan feeds inflammatory mediators, including IL-1β into kynurenine pathway, thereby diverting (Nakagawa and Chiba 2015). As these special- the pool of this essential amino acid from 5HT ized macrophages express pattern recognition synthesis to potentially neurotoxic metabo- receptors including TLR2 and TLR4, TLR liga- lites and reducing the availability of the tion by danger-associated molecular patterns neurotransmitter. (ATP, Hsp, HMGB1, etc.) strongly triggers 5. Decreased availability of serotonin provokes a microglia (Weber et al. 2015). Furthermore, sev- depressive phenotype with attendant psycho- eral inflammasomes have been described in the logical, neurovegetative, and somatic microglia including NLRP1, NLRP3, and symptoms. NLRC4. The NLRP3 inflammasome has been most widely studied in the CNS and is also the As a summarizing note, it must be appreciated focus of the preponderance of studies in animal that understanding the processes involving sterile models of depression. Recent investigations also inflammation, DAMP/MAMP/PAMP signaling in suggest that NLRP3 may be exquisitely sensitive the periphery and CNS and inflammasome activa- to the homeostatic perturbations induced by psy- tion are critical for efficacious therapeutics of chobiological stress, with a mechanistic role for affective disorders. While notable advances are the inflammasome-mediated processing and mat- made in this respect in neurological disorders such uration of IL-1β in the generation of mood disor- as stroke, novel agents have not yet been tested in ders (Li et al. 2016). While space limitation does psychiatric patients. New therapeutic modalities not allow a detailed outline of animal studies emerging from enhanced knowledge can pave the highlighting the link between stress, DAMPs, way for curative treatments for otherwise recalci- and the inflammasome in the instigation of neu- trant conditions (Alcocer-Gomez and Cordero roinflammation and its behavioral sequel, the 2014). Figure 2.3 gives a schematic representation induction of the depressive phenotype, it is clear of this supposed model of depression and depicts that CNS inflammation is caused by acute or the key role of NLRP3 inflammasome and IL-1β in chronic stress in the absence of infection or the expression of depressive phenotype (Fig. 2.3). pathogen exposure (Zhang et al. 2015).

2.5 Treatment of Mood 2.4.4 Purported Model Disorders: The Current of Depression Perspective

In the light of above considerations, a proposed Mood disorders are lifelong, recurring, and dev- model of depression is presented as following astating psychiatric conditions that are a leading (Fleshner et al. 2017): cause of suffering and have grave personal and societal consequences. Major depressive disorder 1. Exposure to stressors results in the release of and bipolar disorder are difficult to manage ail- DAMPs within the brain, presumably from ments because of heterogeneity in presentation, damaged or dying neurons. neuropsychiatric and physical comorbidities, and 2. These neuron-derived DAMPs then target refractoriness to currently available psychophar- their cognate receptors on microglia leading macological agents (Fountoulakis and Vieta to NLRP3 inflammasome activation and the 2008). At different points in the illness, patients 2 Major Depressive Disorder and Bipolar Disorder 25 require complex medication regimens to treat the rather than palliative in nature. With this pream- varied manifestations, and compliance is very ble, in the present section of the manuscript, low due to a whole host of adverse effects caused focus will be directed to promising therapeutic by the psychotherapeutic agents. In this event, options, and a concise overview will be presented there is an immediate unmet need for more effec- of the recent trends in mood disorder tive and tolerable drugs that are actually curative psychopharmacology.

STRESS

NEURONAL APOPTOSIS

DAMP

MICROGLIA SURVEILLANT MICROGLIA PRIMED

IL-1b

IDO TRYPTOPHAN Ø 5HT

KYNURENINE PATHWAY

EXPRESSION OF DEPRESSIVE PHENOTYPE

Fig. 2.3 Stress-induced sterile inflammation and expres- somes, and further this proinflammatory cytokine induces sion of the depressive phenotype. In a supposed model of the enzyme indoleamine 2,3-dioxygenase (IDO). The depression, psychological stressors cause damage to neu- later catabolizes tryptophan, an essential amino acid rons with efflux of a broad range of signals or damage- required in the synthesis of serotonin. Diversion of trypto- associated molecular patterns (DAMPs). These bind to phan metabolism toward the kynurenine pathway leads to pattern recognition receptors like toll-like receptors (TLR a deficiency of serotonin, as well as the formation of 2/4) and purinergic receptors (P2X7R) on microglia and potentially neurotoxic metabolites like quinolinic acid. As cause the formation of NLRP3 inflammasomes via tran- a final step, reduction of this key neurotransmitter at the scription, translation, and protein synthesis. Primed synapse leads to the provocation of sickness behavior and microglia release mature IL-1β via activated inflamma- depressive symptoms 26 A. Muneer

2.5.1 The Emerging Role of Atypical ine/fluoxetine in 2009 and most recently brex- Antipsychotics piprazole in 2015 (Greig 2015).

These medications comprise of second- and third-generation antipsychotics, and although the 2.5.2 Pharmacodynamic first prototype, clozapine, was discovered in the Considerations 1970s, vast strides have been made, and several new agents have been introduced into clinical In the case of new-generation antipsychotics, the practice. Amazingly, there has been a steady exact mechanism responsible for therapeutic increase in their licensed and off-label prescrib- effect in MDD has not been clarified, but based ing in a wide range of neuropsychiatric condi- on current understanding of the etiopathogenesis tions (Maher and Theodore 2012). Initially of mood disorders, their pharmacodynamic indicated for schizophrenia, these medications actions can be as following (Rahola 2012): have become first-line agents for the treatment of manic, mixed, and depressive episodes of BD 1. Modulation of key neurotransmitter receptors and more recently have established a niche as an and transporters, namely, dopamine, sero- augmentation strategy along with standard anti- tonin, and norepinephrine depressants in MDD. In the present paper atypi- 2. Effects on the circadian machinery and cal antipsychotics will be discussed with manipulation of the sleep-wake cycle reference to the treatment of MDD to highlight 3. Exploitation of the steroid hormone homeo- their importance in the current psychopharmaco- stasis, particularly the hypothalamic-pituitary- logical landscape (Pompili et al. 2016). adrenal axis involved in the management of In spite of the availability of several classes of stressful stimuli antidepressants, most MDD patients do not 4. Modification of the immune system with alter- achieve an adequate response or remission with ations in pro- and anti-inflammatory proteins such treatment. This issue is underscored by the 5. Balancing out the antioxidant process with net STAR*D trial in which a 12-week treatment decrease in pro-oxidant radicals with SSRI monotherapy (citalopram) only 6. Increase in trophic support to the neurons, resulted in 30% remission rate in unipolar principally through brain-derived neuro- depression cases (Rush et al. 2009). Further, a trophic factor large meta-analysis including 182 antidepressant RCTs (n = 36,385) revealed that the response Specifically, the chief pharmacological mech- rates were around 54 and 37%, for drug and pla- anism of atypical antipsychotics as antidepres- cebo, respectively (Papakostas and Fava 2009). sant augmentation agents could be explained by In this situation, most guidelines recommend their effects on monoamine neurotransmission. augmentation strategies for MDD partial or non- Third-generation antipsychotics, namely, aripip- responders which mainly comprise of atypical razole, brexpiprazole, and cariprazine, act as par- antipsychotics, mood stabilizers (lithium and tial agonists at D2 and/or D3 receptors and may various anticonvulsants), and thyroid hormones increase dopamine neurotransmission in the pre- (Patkar and Pae 2013). Among these steps, the frontal cortex. These agents also act as 5-HT1A addition of second- and third-generation anti- receptor partial agonists, and this property may psychotics to existing antidepressant regimens further enhance dopamine neurotransmission in has received approval by licensing authorities the prefrontal cortex through an indirect mecha- such as the United States Food and Drug nism (Stahl 2016). The characteristic of 5-HT2A Administration (FDA). In this regard, based on receptor antagonism is shared by all atypical evidence from randomized, placebo-controlled antipsychotics, and this attribute may also medi- trials, the FDA first approved aripiprazole in ate their antidepressant boosting effect in MDD 2007, followed by quetiapine XR and olanzap- nonresponders. Furthermore, the antagonism of 2 Major Depressive Disorder and Bipolar Disorder 27

5-HT2C receptors is incriminated in enhanced tors which enhances the release of norepinephrine dopamine and norepinephrine transmission in from the presynaptic neuron. Unlike any other corticolimbic regions of the brain (Stahl 2014). new-generation antipsychotic, ziprasidone has While both 5-HT6 receptor agonists and antago- been reported in vitro to block the synaptic reup- nists exert antidepressant-like effect in rodent take of monoamines via inhibition of their trans- models of depression, this phenomenon is marked porters. Ionotropic and metabotropic glutamate when standard antidepressants are augmented receptors are being increasingly incriminated in with 5-HT6 antagonists (Liu et al. 2015). With the pathophysiology of treatment-resistant respect to 5-HT7 receptors, preclinical models depression so that modulation of these sites by consistently show their relevance in different newer antipsychotics could lead to normalization experimental paradigms such that new-generation of glutamate neurotransmission, decrease in antipsychotics exhibiting antagonism at this site excitotoxicity, and enhanced neuronal viability may have potential therapeutic role in MDD (Bjorkholm et al. 2015). Table 2.3 gives an over- (Bawa and Scarff 2015). Some atypical antipsy- view of atypical antipsychotics in the treatment chotics have high affinity forα 2-adrenergic recep- of MDE in major mood disorders (Table 2.3).

Table 2.3 Atypical antipsychotics in the treatment of major depressive episodes in MDD and BD Dose range Medication FDA indication Mechanism of action (mg/day) Evidence Aripiprazole Augmentation 5-HT1A/2C partial agonism, 5–15 RCT (adjunctive to AD to AD 5-HT2A/2B antagonism, weak 5-HT7 in MDD). Negative antagonism, D2/3 partial agonism, RCT in bipolar I enhancement of neuroplasticity depression Brexpiprazole Augmentation 5-HT1A and D2 partial agonism, 1–3 RCT (adjunctive to AD) to AD 5-HT2A antagonism Quetiapine XR Augmentation α-2 Receptor antagonism, 50–300 RCT (monotherapy as to AD norepinephrine transporter inhibition well as adjunctive to in PFC (metabolite norquetiapine), AD) 5-HT7 antagonism Olanzapine/ Treatment- 5-HT2A/2C antagonism, 5-HT7 5–20 Positive RCT in fluoxetine resistant antagonism MDD. Positive RCT in combination depression bipolar I depression (monotherapy) Cariprazine None for D2/3 partial agonism, 5-HT1A partial 1.5–3 Positive RCT in bipolar MDD agonism, 5-HT2A/5-HT7 antagonism I depression (monotherapy) Lurasidone Indicated for 5-HT7 antagonism, 5-HT1A partial 60–120 Positive RCT in bipolar bipolar I agonism, weak 5-HT2C antagonism, I depression depression weak α-2 antagonism (monotherapy) Ziprasidone None for 5-HT2A/2C antagonism, 5HT1A 40–160 RCT (adjunctive to AD) MDD agonism, 5-HT, NE, DA transporter inhibition Risperidone None for 5-HT2A antagonism, α-2 receptor 0.5–3 RCT (adjunctive to AD) MDD antagonism, 5-HT7 antagonism Paliperidone None for 5-HT2A antagonism, α-2 receptor 3 Anecdotal reports or MDD antagonism, 5-HT7 antagonism expert opinion Asenapine None for 5-HT2A/2B/2C antagonism, 5-HT6/7 10–20 Anecdotal reports or MDD antagonism, 5HT1A partial agonism, expert opinion α-2 antagonism Iloperidone None for 5HT-2A antagonism, 5-HT6/7 Not Anecdotal reports or MDD antagonism available expert opinion AD antidepressants, BD bipolar disorder, DA dopamine, NE norepinephrine, MDD major depressive disorder, PFC prefrontal cortex, RCT randomized controlled trial, 5-HT serotonin 28 A. Muneer

2.5.3 Individual Medications 2.5.3.2 Aripiprazole This third-generation antipsychotic, first intro- 2.5.3.1 Brexpiprazole duced in 2002 for schizophrenia, is well studied This is a serotonin-dopamine activity modulator as an adjunctive therapy in MDD. With regard to and structurally related to aripiprazole. In July controlled studies, three matching RCTs showed 2015 it received FDA approval for schizophre- that aripiprazole augmentation of traditional anti- nia and augmentation therapy of MDD. It shows depressants was statistically superior to placebo partial agonism at the D2 receptor and possibly in MDD patients who were nonresponders to one functional selectivity at this site. Compared to to three adequate antidepressant trials. A post hoc aripiprazole, brexpiprazole has lower intrinsic analysis of the abovementioned three RCTs activity at the D2R, but exhibits tenfold higher divided patients into two categories—in one affinity at the 5-HT1A receptor where it acts as group were minimal improvers on antidepressant a partial agonist. Two recently published phase monotherapy after 6–8 weeks of administration III trials investigated the potential of brexpipra- and in the second batch were non-improvers as zole as an augmentation agent in treatment- defined by Clinical Global Impression scale resistant MDD. The two identically designed (CGI-I). After 6 weeks of adjunctive aripiprazole studies included subjects who had inadequate or placebo, the remission rates were higher for response to one to three standard antidepres- the active drug in both groups (minimal improv- sants for their current depressive episode. All ers, 38.8% versus 26.6%, p ˂ 0.05; non-improvers, patients entered a prospective 8-week phase of 24.0% versus 10.3%, p ˂ 0.05). The most com- open-label antidepressant therapy, and those mon adverse events with add-on aripiprazole who failed to sufficiently respond were random- were akathisia, restlessness, and insomnia (Casey ized to AD + brexpiprazole or AD + placebo et al. 2014). Another pooled analysis of the same and followed in a double-blind fashion for a RCTs stratified patients according to baseline total of 6 weeks. The primary outcome measure MADRS scores as follows: mild ≤24; moderate was change in Montgomery-Asberg Depression 25–30; and severe ≥31. The results showed that Rating Scale (MADRS) from baseline to week aripiprazole produced greater improvement than 6. In the first study, brexpiprazole 3 mg/day was placebo in the MADRS scores regardless of superior to placebo on MADRS total score MDD severity at baseline (Stewart et al. 2014). A (−8.29 versus −6.33; p = 0.0079), but brexpip- third post hoc analysis investigated the efficacy razole 1 mg/day failed to separate from placebo of adjunctive aripiprazole in MDD patients (−7.64 versus −6.33; p = 0.0737). In the second whose symptoms worsened with antidepressant study, brexpiprazole 2 mg/day showed superior monotherapy. In the prospective, open-label efficacy over placebo in changes from baseline phase, 106 subjects out of 1065 antidepressant to week 6 on MADRS total scores (−8.36 ver- monotherapy non-responders actually deterio- sus −5.15; p = 0.0002). Further, the active agent rated as assessed by MADRS. Those cases, who was also better than placebo on the Sheehan worsened, showed higher response and remission Disability Scale (−1.35 versus −0.89; rates with aripiprazole compared to placebo dur- p = 0.0349). The most common treatment- ing the 6-week double-blind part of the studies related adverse events were weight gain (brex- (36.6% versus 22.5% and 25.4% versus 12.4%, piprazole, 8%; placebo, 3.1%) and akathisia respectively). Similarly, aripiprazole was supe- (7.4% versus 1.0%). Taken as a whole, brexpip- rior to placebo for the 905 subjects who did not razole addition to standard antidepressants was show deterioration on antidepressant monother- safe and well tolerated in the two phase III apy (Nelson et al. 2014). Lastly, a subgroup post RCTs (Thase et al. 2015a, b). hoc analysis of a more recently conducted RCT 2 Major Depressive Disorder and Bipolar Disorder 29 in an Asian population (the ADMIRE study) ies quetiapine XR was statistically superior to revealed that the efficacy was consistently greater placebo on the primary efficacy measure, and this with aripiprazole than placebo and was not change was evident from week 1 (Bauer et al. related to any clinical factors such as gender, age, 2009; El-khalili et al. 2010). In a revealing study, onset of MDD, number of previous episodes, quetiapine was added to the antidepressant regi- duration of current episode, length of illness, men of unipolar depressed patients who were MDD specifiers, and type of SSRI/SNRI used in treatment refractory and had failed to respond to the prospective phase (Ozaki et al. 2015). 3 weeks of lithium augmentation. They were assigned to flexible dose adjunctive quetiapine + 2.5.3.3 Quetiapine CBT or placebo + CBT and followed for This second-generation antipsychotic has been 12 weeks. The former group of subjects had sta- well studied in MDD, both as monotherapy and tistically significant improvement on the two effi- adjunctively to first-line antidepressants. In this cacy measures of HAM-D and MADRS. Although context the first RCT was published in 2007, in the total number of patients was small (N = 22), which quetiapine augmentation of SSRI/venla- this pilot study showed that in refractory MDD faxine was compared to placebo in a small group patients, flexible dose quetiapine (12.5–200 mg/ of MDD patients (N = 58) with comorbid anxiety day) was a valid option in conjunction with stan- (HAM-A ≥ 14) and residual depressive symp- dard antidepressants and CBT (Chaput et al. toms (CGI-S ≥ 4). The mean change in HAM-D 2008). Finally, quetiapine in combination with an and HAM-A total scores from baseline to study SNRI (venlafaxine) was studied under controlled endpoint (week 8) was significantly greater with conditions for the treatment of MDD with psy- quetiapine (average dose 182 mg/day) than pla- chotic features. Subjects (N = 122) were random- cebo: −11.2 versus −5.5, p = 0.008, and −12.5 ized to 7 weeks imipramine (plasma levels versus −5.9, p = 0.002, respectively. The onset of 200–300 μg/L), venlafaxine (375 mg/day), or quetiapine efficacy (HAM-D/ HAM-A/CGI-S) venlafaxine + quetiapine (375 + 600 mg/day). was rapid by week 1 and continued through to Primary outcome was response on HAM-D-17, week 8. Response, defined as≥ 50% decrease in while secondary outcomes were response on CGI baseline HAM-D scores, was numerically but not and remission on HAM-D-17. On the primary significantly higher for quetiapine than placebo. measure, quetiapine + venlafaxine was superior Similarly remission rate (HAM-D total scores to venlafaxine monotherapy and equivalent to ≤7) was also higher for the active agent (31% imipramine, while secondary outcome measures versus 17%), but this difference did not reach sta- also showed similar results. It was revealed that tistical significance. Adverse events for quetiap- for the treatment of unipolar psychotic depres- ine were in line with its known side effect profile, sion, quetiapine in combination with an SNRI and sedation and somnolence were most fre- was superior to the latter alone, but similar con- quently reported. In conclusion, quetiapine was clusion could not be drawn with regard to the shown to be effective as augmentation of SSRI/ TCA, imipramine (Wijkstra et al. 2010). venlafaxine therapy in patients with major Quetiapine XR monotherapy has been studied depression, comorbid anxiety, and residual in several short-term RCTs in MDD, both in depressive symptoms, with no unexpected toler- fixed or flexible dose designs. In the majority of ability issues (McIntyre et al. 2007). The efficacy these trials, the active drug showed superiority of quetiapine XR augmentation was shown in over placebo on such validated efficacy measures two similarly designed (150, 300 mg/day and as the MADRS. The dose of quetiapine XR was placebo) 6 week RCTs (N = 936). In both trials, up to a maximum of 300 mg/day and trial dura- the primary endpoint was mean changes in tions varied from 6 to 8 weeks; the active agent MADRS total score from baseline. In these stud- separated from placebo as early as week 1 and 30 A. Muneer this superiority was maintained until the end of come this underperformance (Papakostas and the study period. The most common adverse Fava 2009). On such approach is augmentation events associated with quetiapine XR were dry with atypical antipsychotics, which has become mouth, sedation, and somnolence, EPS were dis- an important second step as emphasized in cur- tinctly uncommon, but metabolic changes like rent guidelines. In this regard, adjunctive olan- increased serum glucose and lipids were more zapine has been studied in at least four RCTs often observed (Brotnick et al. 2011). The fol- and specifically olanzapine/fluoxetine combina- lowing conclusions can be drawn from the extant tion (OFC) has been compared to both placebo literature: and active comparators. A pooled analysis of these studies showed that OFC had clearly dem- 1. Quetiapine alone or adjunctively to standard onstrated significantly greater improvements in antidepressants has valid efficacy in the treat- MADRS (primary efficacy measure) total score ment of nonpsychotic MDD. than fluoxetine or olanzapine alone and also 2. In patients suffering from major depressive resulted in higher remission rates. The short- disorder with psychotic features, quetiapine in term efficacy of OFC for treatment-resistant conjunction with first line antidepressants is depression was supported by these trials (Trivedi superior to antidepressant monotherapy. et al. 2009). In a more recently published long- 3. Quetiapine augmentation is a convincing term trial of up to 27 weeks, relapse rates were option in treatment-resistant depression. compared for fluoxetine monotherapy and OFC 4. It has shown therapeutic worth in both adults in stabilized patients on the combination treat- as well as the elderly with MDD. ment (Brunner et al. 2014). Time to relapse was 5. It has value in unipolar depressive patients significantly longer in the OFC group than in with comorbid conditions such as anxiety and the fluoxetine monotherapy group (p ˂ 0.001). fibromyalgia. Additionally, with regard to safety no signifi- 6. It is effective despite such demographic vari- cant differences emerged between treatment ables as age, gender, and race. groups in terms of adverse events (p = 0.621). 7. The medication has valid efficacy in MDD However, the rate of patients who experienced regardless of such illness factors as severity, clinically significant ˃( 7%) weight gain was duration, and number of depressive episodes. greater for OFC than fluoxetine (OFC: 11.8%, 8. The effective dose in MDD is from 100 to fluoxetine: 2.3%; p ˂ 0.001). At the endpoint, the 300 mg/day which is less than the maximum mean differences were significant for weight recommended dose of 600 mg/day in gain (OFC: +1.14 kg, fluoxetine:− 2.78 kg; schizophrenia. p ˂ 0.001). Finally, it must be mentioned that 9. While an approved therapy in MDD, it should OFC is not only FDA approved in treatment- be used with the caveat that it has the potential resistant unipolar depression; it also has this to cause metabolic abnormalities and careful endorsement for major depressive episodes in monitoring is warranted in this regard. bipolar I disorder.

2.5.3.4 Olanzapine/Fluoxetine Conclusion Treatment-resistant depression can be conceptu- In this paper an endeavor has been made to alized as an illness that has failed to respond to outline the most pertinent aspects of major at least two different antidepressant monother- mood disorders. The current nosological apy trials of adequate duration and dose. An classifications do not differentiate between enlightening meta-analysis of RCTs revealed MDD and BD as far as the diagnostic criteria that the antidepressant response rate was 53% for a major depressive episode are concerned. compared to 36% for placebo (p ˂ 0.05), so that However, these are discrete disorders with clinicians must employ other strategies to over- etiopathologic differences and distinct man- 2 Major Depressive Disorder and Bipolar Disorder 31

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Matea Nikolac Perkovic, Gordana Nedic Erjavec, Dubravka Svob Strac, and Nela Pivac

3.1 Major Depressive Disorder and Bromet 2013) and is associated with the poor outcome and more severe symptoms (Du and Major depressive disorder (MDD) is a mental ill- Pang 2015). Therefore, it is important to diag- ness that causes a tremendous societal, economic, nose MDD early, in the primary care, especially and emotional burden, results in impairment in if patients who suffer from other chronic illnesses social or occupational functioning, and therefore (Kupfer et al. 2012). The prevalence of MDD is impairs daily living, and it is common, recurrent, more frequent in women than in men (Kessler and costly due to the frequent disability-adjusted and Bromet 2013). life years (DALYs) and morbidity (Kessler and MDD is a disease with high degrees of hetero- Bromet 2013). The prevalence of MDD is geneity and has a complicated clinical picture, increasing worldwide, and MDD was pointed to consisting of symptoms and signs associated be a primary cause of global disease burden. The with mood, cognition, interest, decision-making, MDD prevalence, as an isolated disorder, ranges anxiety, anhedonia, volition and motivation, psy- from 1 to 17% in adults, 3 to 6% in adolescents, chomotor changes, energy, appetite, weight, and 12 to 38% in elderly (Gururajan et al. 2016; speech, sleep, suicidal behavior, circadian effects, Kessler and Bromet 2013; Rantamaki and Yalcin melancholia, depersonalization, and derealiza- 2016). However the prevalence of MDD comor- tion (Kendler 2016). Characteristic symptoms of bid with somatic diseases such as diabetes, MDD (according to DSM-V criteria) are the asthma, and arthritis ranges from 9 to 23% symptoms of depressed mood (sadness, empti- (Kupfer et al. 2012). MDD is also frequently ness, or hopelessness) or a loss of interest or plea- associated with neurodegenerative disorders such sure in daily activities that must last for more as Alzheimer’s disease, Parkinson’s disease, and than 2 weeks, associated with impaired social, Huntington’s disease (Du and Pang 2015). The occupational, and educational functions. It is presence of MDD increases the risk for dementia, associated with specific symptoms, at least five cardiovascular, metabolic, respiratory, and other of these nine symptoms, that have to be present somatic diseases (Breitenstein et al. 2014; Kessler nearly every day: depressed mood or irritable mood present most of the day; reduced interest or pleasure in most activities, most of each day; M.N. Perkovic • G.N. Erjavec • D.S. Strac major alterations in weight or in appetite (weight N. Pivac (*) loss or weight gain); altered sleep, insomnia or Laboratory for Molecular Neuropsychiatry, Division hypersomnia; alterations in activity, psychomo- of Molecular Medicine, Rudjer Boskovic Institute, tor agitation or retardation; fatigue or loss of Zagreb, Croatia e-mail: [email protected] energy; feelings of guilt/worthlessness; problems

© Springer Nature Singapore Pte Ltd. 2018 35 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_3 36 M.N. Perkovic et al. with concentration, reduced ability to think or sion, decreased concentration of the neurotrophin concentrate, or indecisiveness; and suicidal BDNF, elevated proinflammatory cytokine lev- behavior, recurrent thoughts of death or suicide, els, increased immune response, and a dysregu- recurrent suicidal ideation without a specific lated activity of the HPA axis, as well as cortical plan, or a suicide attempt or a specific plan for and subcortical functional and structural brain committing suicide. The diagnosis of MDD is changes in the limbic and prefrontal cortex, are based on patient interviews that offer insight into associated with the etiology of MDD (Belvederi the clinical symptoms which are common with Murri et al. 2014; Young et al. 2016). other psychiatric disorders and therefore the diagnosis, based on physician-administered or patient self-administered interview, is still sub- 3.3 Biomarkers jective since it depends on the individual clinical judgment (Bilello 2016; Young et al. 2016). The key biological substrates that are altered in Additionally, between clinicians with experience MDD (hormones, neurotransmitters, neurotrophin psychiatry, there is a poor inter-rater reliability ins, cytokines, metabolic, genetic, and neuroim- in diagnosing MDD (Bilello 2016), and because aging markers) are also the possible biomarkers, of this inaccuracy, there is an unmet need to i.e., indicators of health or normal biological pro- develop validated and objective blood-based and cesses and disease or pathogenic processes cerebrospinal fluid (CSF) biomarkers for MDD (Young et al. 2016). Due to the MDD heterogene- (Young et al. 2016). ity, complicated clinical picture and heterogeneous clinical symptoms (anhedonia, depressed mood, loss of interest, pleasure and energy, prob- 3.2 The Etiology of MDD lems with cognition, weight, appetite and sleeping, fatigue, anxiety, feelings of worthless- The etiology of MDD is complex and still not ness or guilt, psychomotor problems, and suicid- clearly defined, but it includes alterations in het- ality) that frequently overlap with symptoms in erogeneous biological mechanisms, vulnerability other psychiatric disorders, no single biomarker associated with particular biological background is sensitive and specific for MDD diagnosis. To (genetic, epigenetic, neuroendocrine, and neuro- overcome these problems, it has also been pro- immune), stress exposure, and interaction with posed (Bilello 2016) to determine a MDD diag- other psychosocial and environmental factors nosis based on the endophenotype/s, defined as (Rantamaki and Yalcin 2016; Schneider and reliable and specific measurable characteristics Prvulovic 2013). In MDD, neuronal circuits are that segregate with illness in the general popula- affected and neuronal connectivity is altered, tion, cosegregate in non-affected family mem- leading to the functional neuroanatomy modifica- bers, and are heritable, state independent, and tions (Rantamaki and Yalcin 2016). The key neu- present at a higher rate within affected families robiological pathways altered in MDD are than in the general population. Endophenotypes monoaminergic systems (Di Giovanni et al. might include biological, behavioral and cogni- 2016), neuroendocrinological systems tive characteristic, and they are more restrictively (hypothalamic-pituitary-adrenal (HPA) axis and defined than biomarkers (Bilello2016 ). Both bio- thyroid dysfunction), neurotrophins (such as markers and endophenotypes are crucial diagnos- brain-derived neurotrophic factor or BDNF), oxi- tic instruments that might enable personalized dative stress pathways, and inflammatory pro- medicine, a tailoring therapeutic approach to cesses (Belvederi Murri et al. 2014; Rantamaki individual patient (Prendes-Alvarez and Nemeroff and Yalcin 2016). Besides the genetic back- 2016). Therefore, a well-defined biomarker set or ground that includes risk or protective gene vari- panel, that would include particular biological ants, reduced monoaminergic, i.e., serotonergic, markers or a multi-analyte biomarker panel, is dopaminergic, and noradrenergic neurotransmis- proposed for establishing MDD diagnosis 3 Biomarkers of Depression: Potential Diagnostic Tools 37

(Leuchter et al. 2014; Young et al. 2016). A panel tex of depressed patients and animal depression of selected biomarkers, particular endophenotypes models (Cheetham et al. 1990). However, no or the research domain criteria (RDoC), all seek changes in 5-HT1A receptor expression associ- to determine more accurate diagnosis of MDD ated with depression have been found in dorsal (Young et al. 2016). Biomarkers of MDD diagno- raphe nucleus (Cheetham et al. 1990) or in blood sis are based on genetic, epigenetic, molecular, (Fajardo et al. 2003). Higher levels of 5-HT1A and neuroimaging studies. In addition, intermedi- and 5-HT2 receptors have been also reported in ate endophenotypes (i.e., “quantifiable physio- the brain (Hrdina et al. 1993; Matsubara et al. logical traits or processes that are interposed 1991) and platelets (Zhang et al. 2014) of between gene and clinical phenotype”) were also depressed subjects. Although at the periphery, suggested for characterization of more homoge- increases (Tsao et al. 2006), decreases (Lima nous subgroups of patients with MDD, as bio- et al. 2005), and no changes (Belzeaux et al. markers to help in diagnosis or therapeutic 2010) in serotonin transporter (5-HTT) mRNA response in MDD (Leuchter et al. 2014). levels have been reported in patients with MDD, recent meta-analysis of in vivo and postmortem findings suggested reduced 5-HTT availability in 3.4 Neurotransmitter Markers key regions of the limbic system of patients with MDD (Kambeitz and Howes 2015). Protein and 3.4.1 Serotonin (5-HT) mRNA levels of several enzymes involved in the synthesis of monoamine neurotransmitters, such Although according to the “serotonergic theory” as tryptophan hydroxylase (TPH) and mono- MDD is in general characterized with reduced amine oxidase (MAO), were also altered in serotonergic activity (Gururajan et al. 2016), due depression (Bach-Mizrachi et al. 2006; Meyer to many contradictory results, the exact nature of et al. 2009). In addition, variations in gene coding serotonergic dysfunction in depression still for 5-HTT, various 5-HT receptors, TPH, MAO, remains uncertain (Andrews et al. 2015). etc., have been investigated as potential candi- Regarding serotonin (5-HT) levels in various dates for increased risk of depression (Flint and brain regions, postmortem analyses yielded Kendler 2014; Lohoff 2010). Recent epigenetic inconclusive data. However, decreased 5-HT studies also support the role of serotonergic sys- concentrations in the brainstem of depressed sui- tem in the pathophysiology of depression, dem- cide victims were consistently found (Mann et al. onstrating for instance changes in methylation 1989). Lower number of 5-HT uptake sites has status of 5-HTT gene promoter (Menke and been found in samples from postmortem brains Binder 2014). (Leake et al. 1991) and platelets (Suranyi-Cadotte et al. 1985) of MDD subjects, but these results were not confirmed (Gross-Isseroff et al. 1989). 3.4.2 Dopamine In the CSF of depressed patients, decreased (Lidberg et al. 2000), increased (Reddy et al. The results obtained in both preclinical and clini- 1992), or unchanged (Roy et al. 1985) levels of cal studies indicated the important role of dopa- 5-hydroxyindolacetic acid (5-HIAA), a metabo- minergic system in the pathophysiology of lite of 5-HT, have been reported. In MDD, lower depression (Dunlop and Nemeroff 2007; Nestler (Quintana 1992) or similar (Muck-Seler et al. and Carlezon 2006). Using genetically selected 2002) platelet 5-HT concentrations were Flinders sensitive line (FSL) of rats, as an animal detected. Studies investigating 5-HT1A receptor model of depression, Yadid et al. (2000) reported changes in depression have reported opposing increased dopamine levels in nucleus accumbens, findings (Kaufman et al. 2016). Reduced number striatum, hippocampus, and hypothalamus, sug- and mRNA of 5-HT1A receptors have been gesting higher synthesis or lower release of dopa- reported in the hippocampus and prefrontal cor- mine from these limbic regions. On the other 38 M.N. Perkovic et al. hand, depletion of dopamine levels in humans ies reported lower levels of norepinephrine has been found in depressed patients (Ruhé et al. transporter (NET) and higher levels of 2007). Various symptoms of depression have α2-adrenoceptors in the locus coeruleus (Klimek been associated with decreased levels of dopa- et al. 1997; Ordway et al. 2003). Moreover, mine in the frontal cortex (Krishnan and Nestler altered functional status of α2A-adrenoceptors in 2008) and striatum (Nestler and Carlezon 2006) the frontal cortex was observed (Valdizán et al. of patients with MDD. Human studies also 2010), suggesting an association of depressive reported the downregulation of dopamine trans- disorders with increased α2-adrenoceptors sensi- porter (DAT), as a result of dopamine declining tivity and responsiveness (Cottingham and Wang process. Namely, reduced DAT binding potential 2012). in striatum (Meyer et al. 2001) and decreased DAT levels in basal ganglia (Savitz et al. 2009) have been found in subjects diagnosed with 3.4.4 Glutamate MDD. In addition, reduced density of striatal dopaminergic D2 receptors has been suggested to More recent studies suggested that dysfunction underlie depressive symptoms (Klimke et al. of the glutamatergic system may be also 1999; Meyer et al. 2006). Studies using chronic implicated in MDD (Hashimoto 2009). Increased mild stress in rats, as another animal model of activation of glutamatergic neurotransmission depression, demonstrated a decrease in dopami- and elevated glutamate levels have been observed nergic D2 and D3 receptor number in the nucleus in depressed patients (Sanacora et al. 2004; accumbens (Papp et al. 1994). Regarding dopa- Zarate et al. 2003). The involvement of glutama- minergic D4 receptors, the association of some tergic system in depression is also supported by specific gene polymorphisms with depression has reports of antidepressant effects of glutamate been investigated (Frisch et al. 1999; López León NMDA-receptor antagonists such as ketamine et al. 2005). Although some postmortem analyses (Dutta et al. 2015). In study using FSL rats as an found increased dopaminergic D4 receptor animal model of depression, it has been sug- mRNA expression in the amygdala of depressed gested that chronic stress is necessary in order to patients (Xiang et al. 2008), other studies reported demonstrate altered glutamate-NO signaling decreased (Rocc et al. 2002) or unchanged blood (Wegener et al. 2010). Increased glucocorticoid D4 mRNA levels in subjects with depression levels, which are released under conditions of (Iacob et al. 2014). chronic stress associated with depression, enhance glutamatergic transmission, expression of NMDA receptors, as well as synthesis and 3.4.3 Norepinephrine extracellular glutamate levels (Lu et al. 2003). Upregulated glutamate action via NMDA recep- Although plenty of evidence support the involve- tors leads to an influx of Ca2+ into the neuronal ment of norepinephrine in depression (Moret and cells, resulting in the brain excitotoxicity (Müller Briley 2011), data from preclinical models of and Schwarz 2007), accumulation of reactive depression are limited. However, in FSL rats, oxygen species (ROS) (Coyle and Puttfarcken two- to threefold higher levels of norepinephrine 1993), and these processes, together with were found in the nucleus accumbens, prefrontal increased nitric oxide (NO) concentrations, are cortex, hippocampus, and median raphe nucleus involved in the pathophysiology of depression (Yadid et al. 2000; Zangen et al. 1999). On the (Dhir and Kulkarni 2011; Suzuki et al. 2001). other hand, a reduction of norepinephrine levels Higher expression of glutamatergic genes GRIN1, has been observed in depressed patients (Ruhé GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, et al. 2007), and depression was shown to be GRM5, and GRM7 was detected post-mortem in related to increased urinary norepinephrine the dorsolateral prefrontal cortex of female excretion (Hughes et al. 2004). Postmortem stud- patients with MDD (Gray et al. 2015). On the 3 Biomarkers of Depression: Potential Diagnostic Tools 39 other hand, in the perirhinal cortex of depressed both the mature and unprocessed precursor neu- patients, decreased mRNA expression of GRIA1, rotrophins can interact with pan neurotrophin GRIA3, GRIN1, GRIN2A, GRIN2B, and GRIK1 receptor (p75NTR) (Chao 2003). genes was determined (Beneyto et al. 2007). Previous studies suggest that acute and chronic Lower protein expression of the glutamate recep- stress or depression can lead to hippocampal tor subunits NR2A, NR2B, and mGlu2/3 in the atrophy (Duman 2004) and decreased neurogen- prefrontal cortex of depressed patients was found esis in the adult brain (Dranovsky and Hen 2006), (Feyissa et al. 2009, 2010). which could predict person’s susceptibility to certain psychiatric disorders. The neurotrophin hypothesis of depression proposes that reduced 3.4.5 γ -Aminobutyric Acid (GABA) BDNF mRNA expression and decreased BDNF protein levels in different brain areas, including Various studies implicated GABA in the patho- hippocampus, and at the periphery, could play an physiology of depression (Krystal et al. 2002; important role in the pathophysiology of depres- Luscher et al. 2011). Although some authors sion (Neto et al. 2011; Zhou et al. 2013). This reported no change (Post et al. 1980; Roy et al. hypothesis is supported by studies showing an 1991), other reports demonstrated decreased association between antidepressant treatment and levels of GABA in the CSF of depressed increased peripheral BDNF levels in depressed patients (Gold et al. 1980; Kasa et al. 1982). patients (Cattaneo et al. 2010; Halaris et al. 2015; Since downregulation of GABA was also Sagud et al. 2016). Preclinical studies also sup- observed in the plasma of subjects with MDD, port the relationship between neurotrophins, plasma GABA levels have been proposed as especially BDNF, and stress in rodents (Smith trait biomarker of depression (Petty et al. 1995). et al. 1995; Ueyama et al. 1997). However, the findings regarding the expression Postmortem analysis have detected reduced of glutamic acid decarboxylase (GAD), the BDNF and TrkB expression in different brain enzyme involved in the GABA synthesis, in areas, such as hippocampus, amygdala and pre- patients with depression are contradictory frontal cortex, of depressed patients and suicide (Pehrson and Sanchez 2015). victims (Dwivedi et al. 2003; Guilloux et al. 2012; Karege et al. 2005). Furthermore, treatment of patients with antidepressants increased 3.5 Neurotrophic Biomarkers hippocampal BDNF protein levels (Chen et al. 2001). However, given the limitations of post- 3.5.1 Brain-Derived Neurotrophic mortem studies, there has been a growing interest Factor in exploring the peripheral BDNF as a potential biomarker in psychiatry (Fernandes et al. 2009; Neurotrophins are a family of growth factors that Frey et al. 2013). Peripheral BDNF could be a regulate neuronal plasticity and function during useful biomarker since the assessment of BDNF development and adulthood. There are four neu- plasma and serum levels is relatively simple and rotrophin family members, nerve growth factor noninvasive and due to a strong evidence sug- (NGF), brain-derived neurotrophic factor gesting the correlation between peripheral and (BDNF), neurotrophin (NT)-3, and NT-4/5, central BDNF levels (Karege et al. 2002; Klein known to exist in mammals. Neurotrophins are et al. 2011) indicating that BDNF has the ability synthesized as precursor proteins (proneu- to cross the blood-brain barrier (Pan et al. 1998). rotrophins) which undergo proteolytic cleavage Studies report decreased BDNF levels in plasma to produce mature proteins (Matsumoto et al. and serum samples from depressed patients (Lee 2008; Mowla et al. 2001; Yang et al. 2009). et al. 2007; Yoshida et al. 2012) which can be Mature neurotrophins bind with high affinity to a normalized with antidepressant treatment (Lee specific tyrosine kinase receptor (Trk), while and Kim 2008). There are also reports of reduced 40 M.N. Perkovic et al.

BDNF mRNA expression in peripheral blood information. Hypermethylation at CpG sites, mononuclear cells (Lee and Kim 2010) and located within BDNF gene promoter 4, was decreased platelet BDNF level (Lee and Kim reported to be associated with suicidal ideation in 2009) in depressed patients. These results sug- depressive patients (Kang et al. 2013) and suicide gest that there may be a link between changes in victims (Keller et al. 2010), while DNA methyla- peripheral BDNF levels and predisposition for tion profiles of BDNF promoter 1 were found to the development of depression in healthy indi- be a valuable peripheral biomarker in the diagno- viduals (Lang et al. 2004). sis of depression (Fuchikami et al. 2011). BDNF The most studied variation in BDNF gene is a promoter 4 hypermethylation could also be a single nucleotide polymorphism (SNP) rs6265 potential biomarker for vulnerability to depres- (Val66Met), which results in the substitution of sion after stressful life events such as stroke (Kim the amino acid valine (Val) by methionine (Met) et al. 2013). Further studies should try to evaluate at codon 66. This variation affects the trafficking individual DNA methylation profiles, before and of BDNF mRNA to dendrites and BDNF protein after development of depression, to confirm the secretion by the regulated secretory pathway relationship between such epigenetic modifica- (Egan et al. 2003). Subjects that carry the BDNF tions and a predisposition to develop depression. Met66 variant have smaller hippocampal volumes (Hajek et al. 2012) and abnormal hippocampal function (Egan et al. 2003; Hariri et al. 3.5.2 Other Neurotrophins 2003), and these findings might suggest a possible pro-depressive role of BDNF Met66 allele. There are indications that other neurotrophins, Several studies confirmed reduced hippocampal, like NGF and NT-3, could also be associated with parahippocampal, and amygdala volumes in the pathophysiology of MDD. Several studies patients diagnosed with MDD (Frodl et al. 2007; demonstrated lower serum BDNF, NGF, and Montag et al. 2009), but there are studies that NT-3 concentrations in depressed patients com- have found opposite results (Jessen et al. 2009). pared to healthy controls (de Azevedo Cardoso It was suggested that BDNF Met66 allele could et al. 2014; Ogłodek et al. 2016). Furthermore, also contribute to suicidal behavior in depressed study by Diniz et al. (2012) suggested reduced patients (Sarchiapone et al. 2008) and that BDNF circulating glia cell line-derived neurotrophic Met66 carriers exhibit a higher vulnerability to factor (GDNF) levels in elderly patients with stress than BDNF Val/Val homozygotes (Brown depression, which were associated with the et al. 2014; Hosang et al. 2014). severity of the disease. Future research, which Recently, several studies have focused on the should include larger samples sizes and reduce relationship between epigenetic alterations and variance among different biological parameters, vulnerability to MDD. Higher serum levels of the are necessary to finally clarify the role of neuro- BDNF-related microRNA miR-132 were corre- trophins in depression and their potential as bio- lated with more severe symptoms in depressed markers for the diagnosis of this neurological patients (Li et al. 2013). Preclinical studies in disorder. rodents found that increased levels of BDNF- targeting microRNAs, miR-16 and miR-124, in the rat hippocampus are associated with 3.6 Hypothalamic-Pituitary- depressive-like behavior (Bahi et al. 2014; Bai Adrenal Axis-Related et al. 2012). The upregulation of BDNF, by Markers reducing the expression of specific microRNAs, like miR-30a-5p or miR-206, is the potential Since MDD is a result of the interactions between mode of antidepressant action (Angelucci et al. genes, gender, personality, family history, and 2011; Yang et al. 2014). Changes in DNA meth- environmental factors, including primarily expo- ylation could also provide helpful diagnostic sure to stress, early adversity or abuse/neglect, 3 Biomarkers of Depression: Potential Diagnostic Tools 41 and adverse family relations (Heim and Binder focusing on a late life depression, confirmed 2012), stress-related biomarkers might be used to these findings. In older subjects, the HPA axis determine vulnerability to develop MDD. The alterations were more pronounced, and older major neuroendocrinological system that regu- MDD patients had significantly higher cortisol lates stress response or perceived threat is the values, especially during evening and night, and HPA axis. Stress response initiates the HPA axis showed stronger non-suppression following DST activation and release of corticotrophin releasing (i.e., had higher cortisol response after DST), hormone (CRH) from the paraventricular nucleus suggesting attenuated negative feedback of the of the hypothalamus, a neurohormone acting via HPA axis in late life depression (Belvederi Murri CRH receptors in the pituitary and other brain et al. 2014). Several methodological issues might regions. CRH stimulates the release of adreno- affect findings of the HPA axis function in MDD, corticotropic hormone (ACTH) from the pitu- which are divergent across studies (see Belvederi itary, and ACTH stimulates the secretion of Murri et al. 2014; Stetler and Miller 2011). The glucocorticoid hormones (cortisol in humans) discrepant results across studies might be due to from the adrenal gland. Cortisol binds primarily the sampling of blood vs. saliva; sampling in the to glucocorticoid but also mineralocorticoid different time of the day, due to the circadian receptors in various brain regions. When the cop- rhythm of the HPA axis hormones; measuring of ing mechanisms prevail and adaptation is the basal hormone levels vs. levels after a chal- achieved as a response to stress, the HPA axis lenge test; depressive subtypes, antidepressant goes back to its normal state, since this is a steady treatment, and remission; age and gender of par- system controlled by the cortisol which exerts ticipants; symptom severity, hospitalization sta- negative feedback via its receptors to achieve tus, physical disease, and cognitive status homeostasis (Stetler and Miller 2011). Activation (Belvederi Murri et al. 2014; Stetler and Miller of the HPA axis and subsequent release of CRH, 2011). Collectively, all these results suggest that ACTH, and cortisol exerts a myriad of effects on HPA hyperactivity might be a disease mechanism behavioral, cognitive, emotional, autonomic, in MDD, associated with disturbed immune, met- psychological, and immunologic processes. abolic, and neurocognitive functioning, espe- HPA axis dysregulation is a frequent finding cially in older subjects (Belvederi Murri et al. in MDD, and most data and previous meta- 2014; Stetler and Miller 2011). analysis agree that hyper-activation of the HPA In the prediction of the development of MDD, axis occurs in MDD (Stetler and Miller 2011). Gene × Environment (GxE) interactions were These alterations include higher cortisol values detected for the genetic variants of the corticotro- in approximately 73% of MDD patients com- phin receptor 1 (CRHR1), hsp90 co-chaperone pared to control subjects and higher ACTH levels FKBP5, and the glucocorticoid receptor (Heim and in 60% of MDD patients compared to controls, Binder 2012). Both protective and risk haplotype while CRH levels were slightly reduced in MDD combinations of the CRHR1 were found to interact patients compared to controls. In addition, altered with early adverse experience, child abuse, or negative feedback loop in MDD, that can be doc- physical neglect to increase the risk of MDD umented with a non-suppression of cortisol to (Bradley et al. 2008; Grabe et al. 2010; Tyrka et al. administration of dexamethasone in the dexa- 2009). These findings might suggest that early methasone suppression test (DST), was reported traumatic experience significantly elevates CRHR1 (Stetler and Miller 2011). Our previous studies signaling in adulthood, leading to hyperactivity of found elevated plasma cortisol levels in the HPA axis and vulnerability to develop MDD medication-free patients with MDD compared to (Heim and Binder 2012). The FKBP5, a protein, healthy control subjects (Muck-Seler et al. 2002; co-chaperone that modulates binding of cortisol to Pivac et al. 1997) and DST non-suppression in the glucocorticoid receptor, presumably disturbs MDD patients (Pivac et al. 1997). A more recent the negative feedback of the HPA axis, resulting in meta-analysis (Belvederi Murri et al. 2014), the hyperactivity of the HPA axis by the effects 42 M.N. Perkovic et al. achieved via glucocorticoid receptor (Binder link between MDD and activation of the inflam- 2009). The genetic variants of the CRHR1, matory response system (Eyre et al. 2016). The FKBP5, and glucocorticoid receptor all interact relationship between inflammation and MDD is with early life stress and negative experiences and complex and presumably bidirectional, since increase the risk for depression in adulthood inflammation affects the HPA axis and induces its (Binder 2009; Bradley et al. 2008; Heim and activation, with increased release of CRH, Binder 2012; Tyrka et al. 2009; Zimmermann ACTH, and cortisol, while MDD is characterized et al. 2009). with reduced parasympathetic tone in the autonomic nervous system, associated with elevated inflammatory processes (Howren et al. 2009). 3.7 Inflammatory Markers This association might also be tri-directional, since various cardiometabolic risk factors such as MDD is associated with immune dysregulation high body mass index, hypertension, diabetes, and altered production of the proinflammatory obesity, adiposity, smoking, and cardiovascular cytokines which mediate a typical inflammatory disease (i.e., atherosclerosis) are associated with response, such as C-reactive protein (CRP), inter- chronic systemic inflammation and MDD leukin (IL)-1β, IL-2, IL-6, interferon (IFN)-γ, (Howren et al. 2009; Swardfager et al. 2016). tumor necrosis factor (TNF)-α, the soluble IL-6 receptor (IL-6R), and the IL-1 receptor antagonist (Dowlati et al. 2010; Swardfager et al. 2016). 3.8 Electroencephalography These proinflammatory cytokines induce differ- Markers ent depressive symptoms (Maes 2008; Raison et al. 2006) since they affect neuroplasticity, neu- Electroencephalography (EEG) is a routine diag- rotransmission, oxidative stress processes, and nostic method for neuronal activity measurement neuroendocrine functions, all processes that are and has a great potential as a diagnostic marker disturbed in MDD (see Eyre et al. 2016). In a of neuropsychiatric disorders. MDD is character- meta-analysis, increased production of particular ized with different abnormalities in neuroelectro- proinflammatory cytokines, such as TNF-α and physiology and cognition (Kandel et al. 2000). IL-6, has been found in MDD, while other cyto- These abnormalities are manifested through EEG kines (IL-1β, IL-2, IL-4, IL-8, IL-10, IFN-γ) in changes of band frequencies, different activa- were not significantly different between patients tion of two brain hemispheres (asymmetry) or with MDD and control subjects (Dowlati et al. aberrant cognitive brain behaviors (Deldin and 2010). In the other meta-analysis, there was a sig- Chiu 2005). EEG captures electric activity nificant positive association of CRP, IL-6, IL-1, directly and in real time, having a temporal reso- and IL-1 receptor antagonist (that binds to IL-1 lution in a time scale of milliseconds which receptors and prevents the effects of IL-1) with makes this technique so valuable. depression in the large groups of patients with Electrophysiological activity inside the brain is MDD and control subjects (Howren et al. 2009). measured by different frequency ranges: delta Recently, these data were confirmed in another (<4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta meta-analysis (Haapakoski et al. 2015), showing (14–40 Hz), and gamma (≥40 Hz) (Noachtar elevated levels of IL-6 and CRP levels in patients et al. 1999). with MDD compared to controls. In addition, a The most commonly discussed EEG abnor- meta-analysis detected significantly higher levels mality in MDD is elevated absolute (Jaworska of the chemokine monocyte chemotactic protein et al. 2012a) or relative (Prichep and John 1992) (MCP)-1/CCL2 in patients with MDD compared alpha activity. There are also reports about to control subjects, while chemokine IL-8/ increased relative and absolute beta activity in CXCL8 did not differ between cases and controls depressed male patients compared to male (Eyre et al. 2016). All these findings suggest the healthy controls (Knott et al. 2001), as well as 3 Biomarkers of Depression: Potential Diagnostic Tools 43 increased alpha, beta, and theta power during the Brain connectivity, defined as network of ana- resting EEG in patients with early stage of tomical, functional, and casual interactions depression (Grin-Yatsenko et al. 2010). between different areas of the brain (Sporns et al. Frontal alpha asymmetry is another trait 2004), could be a contributing factor to disorga- observed in MDD, first described as hyper- nization syndrome (impaired cognitive associa- activation (lower alpha) of the right frontal cortex tion) in different psychiatric disorders including and hypo-activation (higher alpha) of left pre- MDD (Leuchter et al. 2012). Well-established frontal cortex (Schaffer et al. 1983). Some other measure of functional connectivity is EEG coher- studies confirmed these results (Chang et al. ence (Fries 2015). Differences were found in 2012; Henriques and Davidson 1991), but there EEG coherence between patients with MDD and are also studies reporting a lack of alpha asym- healthy control subjects (O’Connor et al. 1979), metry in MDD patients (Carvalho et al. 2011; including decrease (Knott et al. 2001; Lee et al. Gold et al. 2013; Price et al. 2008). In addition, 2011; Sun et al. 2008) or increase, mostly in the there are reports indicating low heritability (Smit alpha band (Fingelkurts et al. 2007; Jeong et al. et al. 2007) and moderate stability (Debener et al. 2013; Leuchter et al. 2012), of EEG coherence in 2000) of alpha asymmetry measures. Besides, MDD. Once the reason for these biased findings results can be influenced by anatomical differ- clarifies, EEG coherence could be a reliable bio- ences between patients (Myslobodsky et al. marker of MDD. 1989), or by the technical implementation of Both EEG and event-related potentials (ERP) measurements (Hagemann et al. 2001), which were used in order to discriminate between complicates the use of this trait as a distinguish- MDD and healthy controls. Event-related poten- ing marker between MDD and healthy controls. tials are determined using EEG to measure elec- When MDD patients were compared to trophysiological response to different sensory, healthy controls, a difference in their EEG was cognitive or motor stimulus (Luck 2005). An found that indicates increased vigilance in MDD, ERP signal is a result of averaging the various probably due to hyperactivity of the noradrener- brain responses of similar types, and it consists gic system (Hegerl and Hensch 2014). Namely, of positive and negative peaks that occur at the in resting state during the period of falling asleep, time points of 100 (N100/P100), 200 (N200/ changes in EEG activity associated with decline P200), and 300 (P300) milliseconds (Boutros of vigilance occur, which is missing in MDD et al. 1997). The P300 component of ERP is (Hegerl et al. 2012; Olbrich et al. 2012). This is a included in cognitive information processing, promising electrophysiological marker which such as memory, attention, or executive function outlies clinical symptoms of MDD. (Polich 2004). Some studies reported decreased Other biomarkers linked with clinical symp- amplitude of P300 in MDD (Blackwood et al. toms of MDD, such as sleep initiation problems, 1987; Diner et al. 1985), while other study early awakening, or disrupted sleep, are EEG emphasized a significance of comorbidities in biomarkers in sleep. Patients with MDD usually P300 determination, since P300 amplitude was experience sleep disturbances manifested decreased in MDD and increased in patients through an increased rapid eye movement (REM) with anxiety when compared to healthy controls, density (Goetz et al. 1991), decreased REM while patients with MDD with comorbid anxiety sleep latency (Rotenberg et al. 2002), or changes had the same P300 amplitude as healthy controls in delta sleep (Lopes et al. 2007). Delta sleep dif- (Bruder et al. 2002). ferences are shown to be discriminative between Additionally, it was shown that P300 latency MDD and healthy controls in patients with early is often prolonged in MDD (Bruder et al. 2009; stages of MDD, suggesting even that the matura- Vandoolaeghe et al. 1998). Although it was tional time course of sleep EEG disturbances shown that responsiveness to auditory evoked may differ between men and women with MDD potentials depends on central serotonergic func- (Armitage et al. 2001). tion (Hegerl and Juckel 1993), which is disturbed 44 M.N. Perkovic et al. in MDD, no differences of auditory evoked Angelucci F, Croce N, Spalletta G, Dinallo V, Gravina potentials were found between MDD patients P, Bossù P, Federici G, Caltagirone C, Bernardini S. 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Marc Fakhoury

4.1 Introduction The advances in genetic, molecular, and neuroimaging studies over the past few years have Major depressive disorder (MDD) is one of the significantly improved our understanding of the leading causes of mental disability worldwide, underlying neurobiological mechanisms of MDD with an estimated lifetime prevalence of up to (Fakhoury 2015). Findings from these studies 20–30% (Weissman et al. 1996; Kruijshaar et al. indicate that MDD is characterized by morpho- 2005). Also referred to as major depression or logical and functional changes in cortico-limbic depression, MDD affects more females than structures (Drevets et al. 2008), as well as altered males (Kessler 2003) and constitutes a major bur- level of certain neurotransmitters in the brain, den to the society in terms of ensuing health-care including dopamine, serotonin (5-H), norepi- costs (Kessler 2012). A major depressive episode nephrine, glutamate, and gamma-aminobutyric frequently follows a traumatic or stressful life acid (GABA) (Kendell et al. 2005; Nutt 2008). event (Shapero et al. 2014; Negele et al. 2015), Mounting evidence also indicates that inflamma- and is often exacerbated by the co-occurrence of tory mediators and growth factors contribute to substance use disorders such as alcohol and illicit the development of depression, suggesting that drug abuse (Davis et al. 2008). In the clinic, they may constitute a reliable set of biomarkers MDD manifests itself by a wide variety of symp- to identify at-risk patients (Lotrich 2012; Felger toms and signs including depressed mood, loss of and Lotrich 2013). In addition, findings from interest, changes in weight or appetite, and linkage and association studies have led to the increased thoughts of suicide (American identification of numerous genetic variations that Psychiatric Association 2013). MDD is also may increase vulnerability to MDD (Lohoff commonly associated with the presence of car- 2010; Dunn et al. 2015), thus revealing important diovascular and metabolic complications (Dunbar insights about disease mechanisms. However, et al. 2008; Hare et al. 2014), making it one of the due to the clinical and etiological heterogeneity most significant health problems in modern of MDD, and the complex interaction between society. genetic and environmental factors, the underlying pathophysiology of depression is far from being fully understood and still needs further investigation. Given the vast symptomatic heterogeneity M. Fakhoury among MDD patients, clinicians may sometimes Department of Neurosciences, Faculty of Medicine, misinterpret some behaviors and physical signs, Université de Montréal, Montreal, QC, Canada e-mail: [email protected] leading to inappropriate disease classification

© Springer Nature Singapore Pte Ltd. 2018 53 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_4 54 M. Fakhoury and treatment care. Standardized diagnostic cri- energy, (7) feeling of worthlessness or guilt, (8) teria, such as those outlined in the fifth edition of impaired concentration or indecisiveness, and (9) the Diagnostic and Statistical Manual of Mental recurrent thoughts of death or suicide (American Disorders (DSM-5) and the 10th revision of the Psychiatric Association 2013). In addition, at least International Classification of Diseases (ICD- one of the existing symptoms must be (1) depressed 10), may help guide decisions regarding diagno- mood or (2) loss of interest or pleasure, and the sis and treatment plan by providing a reliable patient must not have any experience of mania and assessment of disease symptoms and severity. hypomania during his lifetime (American The focus of this chapter will be on the DSM-5, Psychiatric Association 2013). the newest available guideline for diagnosis of MDD. Although most of the criteria for MDD are identical between the previous and current edi- 4.2.2 Subtypes of MDD tion of the DSM, several changes were made in the DSM-5 so as to improve the quality and reli- One of the most conspicuous changes in the ability of diagnosis. These are discussed in more DSM-5 is the dissociation between “bipolar and details in the following sections. This chapter related disorders” and “depressive disorders”, also provides a detailed overview of biological which are now listed as two separate chapters. In markers that could potentially serve as reliable the current edition of the DSM, the chapter on tools for the diagnosis of MDD and for tailoring bipolar disorder is placed between the chapters therapies that target individual differences in on “schizophrenia/psychotic disorders” and symptoms. “depressive disorders” in support of findings showing that bipolar disorder shares a similar degree of symptomatology and genetic overlap 4.2 Diagnostic and Classification with schizophrenia and depression (Lichtenstein Criteria of MDD in the DSM-5 et al. 2009; Mitchell et al. 2011; Ivleva et al. 2012; Cross-Disorder Group of the Psychiatric 4.2.1 Criteria for MDD Diagnosis Genomics Consortium 2013). However, despite shared pathogenic processes, the degree of neu- The use of reliable and valid diagnostic criteria is robiological and cognitive impairments varies essential for making effective clinical decisions between bipolar disorder and MDD, suggesting and implementing appropriate management strate- that these disorders should be viewed as two sep- gies. Based on evidence from clinical practice and arate continuums, rather than opposite ends of existing epidemiological and neurobiological the same dimension (Cuellar et al. 2005; van der research, the DSM-5 has developed new diagnos- Werf-Eldering et al. 2010). In addition, to reflect tic criteria that provide the standard language by the heterogeneous nature of depression, the which clinicians and researchers communicate DSM-5 has increased the number of categories in about mental disorders (American Psychiatric the “depressive disorders” section, with the addi- Association 2013). This new edition of the DSM, tion of disruptive mood dysregulation disorder, which was published in 2013, marks the first major persistent depressive disorder, and premenstrual overhaul of diagnostic criteria and classifications dysphoric disorder (American Psychiatric used by clinicians and researchers since the Association 2013). Given the high prevalence DSM-IV in 1994 (American Psychiatric rate of these disorders (Tschudin et al. 2010; Association 1994). To meet criteria for MDD in Byers et al. 2012; Copeland et al. 2013), and their the DSM-5, at least five of the following symp- similar and somewhat overlapping symptomatol- toms must be present nearly every day during the ogy with depression (Uher et al. 2014), their same 2-week period: (1) depressed mood, (2) loss inclusion in the DSM-5 will consequently of interest or pleasure, (3) changes in weight or increase the rates of comorbidity of MDD and appetite, (4) insomnia or hypersomnia, (5) psycho- may have major implications for therapeutic motor agitation or retardation, (6) fatigue or loss of decision-making. 4 Diagnosis of Major Depressive Disorders: Clinical and Biological Perspectives 55

4.2.3 Inclusion of Hopelessness toms of MDD were excluded from diagnosis if they were also bereaved within the past 2 months Another amendment proposed by the DSM-5 is to account for the fact that a state of intense grief the inclusion of the word “hopeless” as a subjec- following the loss of a loved one is a normal reactive descriptor of depressed mood (American tion (American Psychiatric Association 1994). Psychiatric Association 2013). A sense of hope- However, diagnosis could be done if the bereave- lessness reflects a negative attribution about a ment lasted more than 2 months and resulted in particular event or even oneself and the belief severe functional and behavioral impairments that nothing could be done to change it. This reminiscent of grief reactions (American small, but potentially important change, will Psychiatric Association 1994). In contrast, the broaden the diagnosis of MDD since individuals DSM-5 has lifted the bereavement exclusion who report feeling hopeless but not sad would be from the diagnostic criteria, primarily based on able to fulfill the mood criterion in the DSM-5. evidence suggesting that depression following The inclusion of hopelessness as an indicator of a bereavement is similar in nature and outcome major depressive episode is bolstered by evi- from non-bereavement-related depression (Zisook dence showing that individuals who struggle with and Kendler 2007; Zisook et al. 2012). Indeed, feelings of hopelessness are more likely to the majority of studies seem to concur with the develop symptoms of clinical depression view that bereavement-related depression is com- (Brothers and Andersen 2009), and show mon, long lasting, recurrent, and characterized by increased vulnerability to suicide (Beck et al. clinical outcomes reminiscent of MDD, includ- 1989, 1990), suicide intent (Wetzel et al. 1980; ing worthlessness, suicidality, and impairments Jaiswal et al. 2016), and suicide ideation (Britton in psychosocial and psychomotor functioning et al. 2008; McCullumsmith et al. 2014). (Zisook et al. 2007). However, despite mounting Hopelessness has also been suggested as a cen- evidence pleading in favor of the removal of the tral dimension of depression insofar as clinically bereavement exclusion, this decision provoked a depressed patients endorse significantly higher lot of criticism among scientists and clinicians. level of hopelessness than patients suffering from Critics have mostly argued that the removal of a variety of other disorders (Greene et al. 1982). the bereavement exclusion will recognize ordi- However, notwithstanding the compelling evi- nary grief as a major depressive episode, result- dence in support of the inclusion of hopelessness ing in inappropriate increases in false-positive in the DSM-5, several investigations see this sub- diagnosis and in the number of prescribed anti- jective descriptor as phenomenologically distinct depressants (Pies 2014). As such, the DSM-5 from a depressed mood (Greene 1989; Beck et al. has added a descriptive guideline to call for cli- 1993; Joiner et al. 2001). As such, the specificity nicians to differentiate between symptoms char- of hopelessness as an indicator of a major depres- acteristic of normal grief and those that are sive episode in the DSM-5 is likely to broaden reminiscent of depressive disorders based on the diagnosis of MDD, but it may also decrease their clinical judgment and experience in patho- its reliability insomuch as hopelessness often physiology (American Psychiatric Association occurs independently of depression. 2013).

4.2.4 Removal of the Bereavement 4.2.5 Dimensional Ratings Exclusion As part of the DSM-5 revision, the introduction One of the most controversial changes proposed of dimensional measures has been proposed as a by the DSM-5 is the removal of the bereavement complement to the current categorical approach exclusion from the diagnostic criteria of MDD of diagnosis (American Psychiatric Association (American Psychiatric Association 2013). In the 2013). Similar to the DSM-IV, DSM-5 encour- DSM-IV, individuals who were exhibiting symp- ages the use of standardized dimensional rating 56 M. Fakhoury scales and self-reporting questionnaires as 2014). As part of a mixed categorical dimen- screening tools to assess the severity of symp- sional approach, a list of uncoded specifiers can toms and to provide clinicians with information now be added in the diagnosis of MDD, includ- relevant for psychiatric diagnosis. In the DSM-5, ing “with anxious distress”, “with mixed fea- symptoms are classified as mild, moderate, or tures”, “with melancholic features”, “with severe, and a direction for a four-level rating of atypical features”, “with mood-congruent psy- new specifiers of MDD is included to allow char- chotic features”, “with mood-incongruent psy- acterization of additional symptoms (Uher et al. chotic features”, “with catatonia”, with 2014). Compared to the classical categorical “peripartum onset”, and “with seasonal pattern” assessment of psychopathology, whereby diag- (American Psychiatric Association 2013). With nosis is based on the presence or absence of respect to the DSM-IV, one major change pro- symptoms, dimensional systems have the poten- posed by the DSM-5 is the addition of the “with tial to more richly explain heterogeneity in clini- anxious distress” descriptive specifier, which was cal settings (Brown and Barlow 2005), and are added to account for the high prevalence of anxi- more likely to serve as a putative predictor of ety symptoms among individuals with depressive antidepressant treatment response (Uher et al. disorders (Lamers et al. 2011; Li et al. 2012). 2012). Such a dimensional approach can be This new addition could have a major impact on applied across several disorders to assess severity clinical practice since individuals with anxious and disaggregate the relevant symptoms, which depression respond poorly to antidepressants could eventually provide a more in-depth under- compared to individuals with nonanxious depres- standing of the pathological profile of patients sion and may therefore require additional treat- and offer a reliable guide for clinicians on future ment care (Fava et al. 2008; Wu et al. 2013). therapeutic strategies. However, despite having Second, the “with mixed features” specifier was greater explanatory power, the dimensional anal- introduced in the DSM-5 to replace the DSM-IV ysis of symptoms may offer lower clinical utility entity of a mixed episode of bipolar disorder and since most decisions in clinical practice are to account for specific treatment requirements for purely categorical, involving a yes-or-no charac- depressed individuals with mixed symptoms ter (Uher et al. 2012, 2014). Careful clinical (Parker 2014). Finally, the “postpartum onset” judgment is therefore needed to determine at specifier of the DSM-IV has been expanded to which stage dimensional measures are best intro- “peripartum onset” in the DSM-5, which may duced into the categorical diagnostic system and now be applied if the depressive episode takes how they could be used to effectively guide the place during pregnancy or within 4 weeks of treatment process. child birth (Parker 2014). This change will help improve the detection of depressive symptoms during the perinatal period and will serve as a 4.2.6 Specifiers of MDD prevention tool toward postpartum depression, which could lead to multiple negative effects for The number of specifiers in the DSM-5 has been both mothers and children if left untreated. increased to reflect the existence of phenomeno- logical variants of MDD and to define a more homogeneous subgrouping of individuals with 4.3 Biological Markers in MDD the disorder (American Psychiatric Association 2013). The expansion of descriptive specifiers for A biological marker, or biomarker, is an objective the diagnosis of depressive disorders will help measurement of a normal biological process that convey information relevant to treatment can be used to predict or indicate the presence of decision-making and may also have implications a disease. In MDD, the advantages of having reli- for forensic practice in the context of sentencing, able biomarkers are diverse, ranging from the civil commitment, and child custody (Parker stratification of the disorder according to severity 4 Diagnosis of Major Depressive Disorders: Clinical and Biological Perspectives 57 and symptomatology, the indication of disease for dopamine, the majority of studies thus far prognosis, to the prediction of therapeutic have focused on the role of the dopamine D4 responses (Gururajan et al. 2016). Validated receptor in depression. These studies, however, disease-associated biomarkers are also critical have yielded conflicting results inasmuch as elements of the translational process, enabling the dopamine D4 receptor mRNA expression was direct transition between ethologically valid ani- found elevated in the amygdala (Xiang et al. mal models and human conditions (McGonigle 2008), decreased in lymphocytes (Rocc et al. and Ruggeri 2014). Many different biological 2002), and unaltered in leukocytes (Iacob et al. measures can be used to detect the presence of 2014) of MDD patients compared to healthy depression, including neurotransmitters, proteins, controls. metabolites, and brain activity patterns. The following sections present an overview of the bio- 4.3.1.2 Norepinephrine logical measures that may potentially serve as In light of early evidence showing that inhibition biomarkers in MDD, and discuss key challenges of norepinephrine reuptake contributes to the in their use and application in psychiatry. therapeutic efficacy of several classes of antidepressants (Burrows et al. 1998), substantial and consistent evidence has associated MDD with 4.3.1 Neurotransmitters alterations in norepinephrine signaling. Frequently reported findings include the presence of increased 4.3.1.1 Serotonin and Dopamine density of α2-adrenoceptors (a target of norepi- One of the most established etiological theories nephrine) in the frontal cortex (Callado et al. of depression is the monoamine hypothesis, 1998; Garcia-Sevilla et al. 1999; Valdizan et al. which states that the underlying pathophysiologi- 2010) and temporal cortex (De Paermentier et al. cal basis of the disorder is due to specific deficits 1997) of depressed suicide victims. In addition, in serotonin (5-HT) and catecholamines in the increased α2-adrenoceptor sensitivity (Gonzalez- central nervous system (Delgado 2000; Albert Maeso et al. 2002) and mRNA expression (Escriba et al. 2012). This long-standing hypothesis forms et al. 2004) were found in the frontal cortex of the cornerstone of current therapeutic approaches suicide victims diagnosed with mood disorders. of depression, which primarily use drugs for Subjects with MDD were also shown to exhibit inhibiting the reuptake of neurotransmitters in marked decreases in norepinephrine transporter the brain, like 5-HT and norepinephrine. In sup- binding in the midcaudal portion of the locus coe- port of the monoamine hypothesis of depression, ruleus (Klimek et al. 1999). However, studies studies have reported decreased peripheral levels investigating the density of α2-adrenoceptors in of 5-HT (Maurer-Spurej et al. 2007; Paul-Savoie platelets of MDD patients reported opposite et al. 2011) and its precursor tryptophan (Cowen results, showing either decreases (Maes et al. et al. 1989; Ogawa et al. 2014) in depressed 1999) or increases (Gurguis et al. 1999) in recep- patients. In addition, postmortem analysis of tor density. Despite being contradictory, these brain tissues revealed decreased expression of findings provide strong evidence for the involve- 5-HT1A mRNA in the hippocampus and dorsal ment of α2-adrenoceptors in the pathogenesis of prefrontal cortex (Lopez-Figueroa et al. 2004), depression, and together with evidence from post- and increased level of 5-HT2A receptors in the mortem studies, indicate that alterations in spe- prefrontal cortex (Shelton et al. 2009) of MDD cific aspects of norepinephrine signaling may patients, thus bolstering the view that the seroto- serve as potential biomarkers in MDD. nergic system is dysregulated in depression. Other players of the serotonergic system that are 4.3.1.3 Glutamate and GABA incriminated in MDD include the 5-HT1B and Although the majority of studies investigating the

5-HT2A receptors, as well as the 5-HT membrane neurobiological mechanisms of depression have transporter protein (SERT) (Fakhoury 2016). As focused on monoamines such as serotonin, 58 M. Fakhoury

dopamine, and norepinephrine, evidence also mediating functions important for the survival, points to a role of glutamate and GABA neuro- differentiation, and maintenance of nerve cells. transmission in depressive behaviors. Recent Four neurotrophins are expressed in the mamma- postmortem analyses reveal robust decreases in lian brain, including nerve growth factor (NGF), the expression of several key glutamate receptor brain-derived neurotrophic factor (BDNF), neu- subunits, including the NR2A and NR2B sub- rotrophin-3 (NT-3), and neurotrophin-4 (NT-4) units of NMDA receptors, in the perirhinal and (Huang and Reichardt 2001). Although NGF and prefrontal cortex of MDD patients (Beneyto et al. NT-3 have been implicated in depression (Hock 2007; Feyissa et al. 2009). Consistently, neuro- et al. 2000; Chen et al. 2015; Wysokinski 2016), imaging studies reported downregulation of glu- BDNF has been the most extensively studied tamate in the ventromedial prefrontal cortex of thus far, with the large majority of findings depressed patients (Portella et al. 2011), and reporting decreased level of this neurotrophin in reduced levels of metabotropic glutamate recep- the serum (Karege et al. 2005; Aydemir et al. tor 5 (mGluR5) binding in the prefrontal cortex, 2006; Bocchio-Chiavetto et al. 2010; Ristevska- the cingulate cortex, the insula, the thalamus, and Dimitrovska et al. 2013) and plasma (Kim et al. the hippocampus of individuals with MDD 2007; Lee et al. 2007; Piccinni et al. 2008) of (Deschwanden et al. 2011). Likewise, synaptic depressed individuals; effect that is normalized alterations in GABA neurotransmission have by antidepressant treatments (Shimizu et al. been shown to substantially contribute to MDD’s 2003; Aydemir et al. 2005; Gonul et al. 2005; underlying etiology. The general consensus Yoshimura et al. 2007; Huang et al. 2008). appears to be that GABA concentrations are Notwithstanding the inconsistency reported in downregulated in the plasma (Petty and Schlesser the literature (Serra-Millas et al. 2011; Brunoni 1981; Petty and Sherman 1984; Petty et al. 1992), et al. 2014), the aforementioned studies strongly cerebrospinal fluid (CSF) (Gold et al. 1980; suggest that peripheral levels of BDNF are good Gerner and Hare 1981; Gerner et al. 1984), and candidate biomarkers for MDD and could be brain regions (Honig et al. 1988; Sanacora et al. considered as reliable predictors of antidepres- 1999) of patients with depression, though some sant response. studies reported no differences between depressed Besides neurotrophins, growth factors such as and control individuals (Roy et al. 1991; vascular endothelial growth factor (VEGF) and Godlewska et al. 2015). In addition, reduced pro- fibroblast growth factor (FGF) have also been tein level (Karolewicz et al. 2010) and mRNA implicated in the etiology of depression. expression (Thompson et al. 2009) of glutamic Originally described as an angiogenic mitogen, acid decarboxylase (GAD), the GABA synthesiz- VEGF has been shown to play a crucial role in the ing enzyme, were found in the prefrontal cortex pathophysiology of depression and to act as a and orbitofrontal cortex of MDD patients, respec- mediator of antidepressant actions (Warner- tively, indicating that the development of depres- Schmidt and Duman 2007; Clark-Raymond and sive behaviors may be due to a widespread Halaris 2013). However, studies evaluating the reduction in GABA neurotransmission. levels of VEGF in depressed patients have reported inconsistent findings, showing either increased (Kahl et al. 2009; Lee and Kim 2012) or 4.3.2 Neurotrophins and Other no change (Dome et al. 2009; Kotan et al. 2012) in Growth Factors peripheral levels of this growth factor compared to healthy controls. In another set of studies, Numerous studies have implicated neurotroph- altered gene expression of several FGF transcripts ins and other growth factors in the etiology of was found in the dorsolateral prefrontal cortex depression and in the therapeutic effects of anti- (Evans et al. 2004), locus coeruleus (Bernard depressants. Neurotrophins are a family of pro- et al. 2011), and hippocampus (Gaughran et al. teins that belong to the class of growth factors, 2006) of MDD subjects, suggesting that perturba- 4 Diagnosis of Major Depressive Disorders: Clinical and Biological Perspectives 59 tions of FGF regulation may also serve as a valu- Gururajan et al. 2016) and may potentially be able biomarker of depression. In addition, elevated used to aid in the detection and prediction of level of FGF-2 has been observed in the serum of depressive symptoms. MDD patients (Kahl et al. 2009), pointing to a Glial cell dysregulation, which ultimately role of this growth factor in the pathophysiology leads to increased cytokine production and of depression. Other growth factors that may chronic inflammation, is also believed to con- serve as biomarkers of MDD and a predictor of stitute a prominent pathological feature of antidepressant response include the vascular MDD (Rajkowska and Stockmeier 2013; Rial growth factor (VGF), glial cell line-derived neu- et al. 2015). Postmortem studies have repeat- rotrophic factor (GDNF), insulin-like growth fac- edly reported decreased glial cell density in tor-1 (IGF-1), and nerve growth factor (NGF) cortical regions of depressed patients, includ- (Schmidt et al. 2011; Galvez-Contreras et al. ing the anterior cingulate cortex (Cotter et al. 2016). However, given the numerous discrepan- 2001; Gittins and Harrison 2011), the dorsolat- cies and missing gaps in the literature, further eral prefrontal cortex (Cotter et al. 2002), the investigations with sound methodology are war- subgenual prefrontal cortex (Ongur et al. 1998), ranted to evaluate the reliability of these growth and the orbitofrontal cortex (Rajkowska et al. factors as biomarkers of MDD. 1999). Consistent with these findings, patients with depression were also shown to have a lower density of numerous proteins involved in 4.3.3 Inflammatory Mediators glial cell activation and function within cortical regions, including glial fibrillary acidic protein Several lines of evidence indicate that inflamma- (GFAP) (Si et al. 2004), excitatory amino acid tory mediators, including cytokines and immune transporters 1 and 2 (Miguel-Hidalgo et al. cells, may have a role in the etiology of 2010), aquaporin-4 (Rajkowska and Stockmeier MDD. Clinical studies demonstrate that patients 2013), and connexin 43 (Miguel-Hidalgo et al. with depressive symptoms display increased 2014). peripheral (Kahl et al. 2006; Diniz et al. 2010; Altogether, the aforementioned findings pro- Dowlati et al. 2010) and cerebrospinal (Levine pose that depression is characterized by conspic- et al. 1999; Lindqvist et al. 2009) levels of pro- uous changes in immune and inflammatory inflammatory cytokines, including tumor necro- markers. Although these changes may show great sis factor-alpha (TNF-α), interleukin-1beta potential in helping clinicians make appropriate (IL-1β), and IL-6; effect that can be reversed diagnosis and treatment decisions, their use upon treatment with antidepressants (Basterzi remains limited by the fact that it is still not clear et al. 2005; Himmerich et al. 2010; Hannestad whether the inflammatory response in depressed et al. 2011). Consistent with the notion that ele- patients contributes to the etiology of MDD or vated inflammatory response contributes to the takes place as a consequence of a depressive etiology of depression, inhibition of pro- state. A better understanding of inflammation and inflammatory cytokines using TNF-α antagonists its relationship with the development of depres- (Krishnan et al. 2007; Raison et al. 2013) or sive behaviors is thus of paramount clinical COX-2 selective nonsteroidal anti-inflammatory importance. drugs (Muller et al. 2006; Nery et al. 2008) results in improved symptomatology in patients with depressive symptoms. Alterations in other 4.3.4 Endocrine and Metabolic markers of inflammation and oxidative stress, Markers including C-reactive protein (CRP), superoxide dismutase (SOD), myeloperoxidase (MPO), and The hypothalamic–pituitary–adrenal (HPA) axis, inducible nitric oxide synthase (iNOS), are also a major endocrine system that regulates the phys- found in depressed patients (Lopresti et al. 2014; iological response to stress, is believed to play a 60 M. Fakhoury pivotal role in the pathophysiology of depression level (Dunbar et al. 2008; Lehto et al. 2008), and (Varghese and Brown 2001; Du and Pang 2015). elevated blood pressure (Reiff et al. 2001) show Activity of the HPA axis is governed by the pro- significant and independent associations with duction and release of corticotrophin-releasing depression. Increased waist circumference was hormone (CRH) and arginine vasopressin (AVP) also suggested as a very strong predictor of from the paraventricular nucleus of the hypothal- depressive symptoms (Pulkki-Raback et al. amus, which in turn activate the secretion of 2009), thus urging the need for individuals with adrenocorticotrophic hormone (ACTH) from the abdominal adiposity to consider lifestyle changes, pituitary (Pariante and Lightman 2008). This such as adopting a healthy dietary pattern to pre- results in an increased secretion of glucocorti- vent depression later in life. Consistent with these coids (cortisol in humans and corticosterone in findings, circulating levels of leptin and ghrelin, rodents) from the adrenal cortex, which then which regulate hunger and metabolism, were exert a direct feedback inhibition of the HPA axis found to be differentially regulated in individuals (Pariante and Lightman 2008). Reported findings with depressive behaviors (Kraus et al. 2001; from depressed patients concur with the view that Gecici et al. 2005; Tuncel et al. 2016) and were MDD is associated with an upregulation of the shown to play a role in the mechanisms of actions HPA axis, including elevated levels of cortisol of antidepressants (Schilling et al. 2013; Ozsoy (Vreeburg et al. 2009), CRH (Austin et al. 2003), et al. 2014). Thus, altered metabolic function and AVP (van Londen et al. 1997); effect that is should be routinely assessed in the clinic since it reversed following chronic treatment with antide- could be used as a viable biomarker for decisions pressants (Piwowarska et al. 2009, 2012). pertaining to clinical diagnosis and treatment However, HPA axis activation is not always care in depressed patients. abnormally increased in individuals with MDD (Watson et al. 2002; Van Den Eede et al. 2006) and appears to be differentially regulated in spe- 4.3.5 Neuroimaging-Based Markers cific subtypes of depression (Levitan et al. 2002; Lamers et al. 2013). Notwithstanding the incon- Methods for identifying neuroimaging-based sistency in the existing literature, monitoring the biomarkers over the past few years have shed changes in cortisol and CRF levels, as well as new light on the underlying mechanisms of other HPA axis factors, could prove beneficial in MDD. Notably, techniques such as structural characterization distinct subtypes of MDD and magnetic resonance imaging (MRI), diffusion assessing treatment response to antidepressants. tensor imaging (DTI), functional magnetic reso- Evidence also demonstrates an association nance imaging (fMRI), and positron emission between depressive disorders and metabolic syn- tomography (PET) have allowed for a better drome, the latter being defined by a cluster of understanding of the relationship between symptoms that include increased waist circum- depression and brain structure and function ference, high blood pressure, high glucose level, (Dunlop and Mayberg 2014). One of the most elevated triglycerides, and low high-density lipo- frequently reported findings is reduced hippo- protein (HDL) cholesterol (Foley et al. 2010; campal volume in patients with MDD (Cole Marazziti et al. 2014). The prevalence of meta- et al. 2011), which normalizes after remission bolic syndrome among patients with depression (Ahdidan et al. 2011) or treatment with antide- is markedly higher compared to that of healthy pressants (Malykhin et al. 2010). Other struc- individuals (Heiskanen et al. 2006; Lasic et al. tural changes, including decreased volumetric 2014), suggesting that some individual metabolic asymmetries in the basal ganglia (Shah et al. syndrome components may be indicative and 2002; Lacerda et al. 2003) and smaller volume of predictive of depressive symptoms. Indeed, the orbitofrontal cortex (Bremner et al. 2002), increased waist circumference (Dunbar et al. cingulate cortex (Caetano et al. 2006), and 2008; Zhao et al. 2011), low HDL cholesterol amygdala (von Gunten et al. 2000; Hastings 4 Diagnosis of Major Depressive Disorders: Clinical and Biological Perspectives 61 et al. 2004), were also reported in individuals Conclusion with MDD, thus advocating changes in cortico- The diagnostic criteria of MDD have under- limbic structures as potential diagnostic bio- gone major changes from the DSM-IV to markers for depression. DSM-5. Some of the most significant amend- In addition to the reported structural changes ments include the inclusion of hopelessness as observed in depression, MDD patients show a descriptor of depressed mood, the removal marked impairments in resting and task-evoked of the bereavement exclusion, and the intro- activation of several brain regions. For instance, duction of new dimensional measures and task-based fMRI studies in depressed patients specifiers. Notwithstanding the major revi- reported aberrant activation of numerous struc- sions made by the DSM-5, the latter has been tures within the cortico-limbic system, including largely criticized for being based on pragmatic increased activation of the amygdala (Mingtian judgments rather than scientific evidence. et al. 2012; Ruhe et al. 2012), decreased activa- Among some of the controversial issues sur- tion of the prefrontal and cingulate cortex (Ruhe rounding the new set of diagnostic criteria, et al. 2012), and increased activation of the insula critics have argued that the introduction of (Surguladze et al. 2010) in response to facial mixed features and the removal of the bereave- stimuli. Depressed patients also exhibit decreased ment exclusion may lead to misdiagnosis of activation of the right hippocampal and left para- MDD with a resultant increase in the number hippocampal gyrus during recollection memory of prescribed antidepressants (Koukopoulos trials, implicating abnormalities in memory et al. 2013; Pies 2014). Caution should there- retrieval processes in MDD (Milne et al. 2012). fore be taken when making a diagnosis of Similarly, resting-state fMRI studies have MDD. Decisions made by clinicians should revealed the presence of aberrant patterns of not only rely on the DSM-5 criteria but also on effective connectivity among cortical, limbic, their prior experience and knowledge of and paralimbic structures (Greicius et al. 2007; psychopathology. Hamilton et al. 2011), implicating abnormalities Over the past few years, tremendous efforts of the default-mode functional connectivity in the have also been made toward the identification etiology of depression. Last but not least are PET of potential biological markers that could aid measures of neural activity revealing multiple in the diagnosis of MDD and serve as predictor abnormalities in glucose metabolism and/or of antidepressant response. Some of the fre- regional blood flow in cortical-limbic structures quently reported findings include abnormali- (Drevets et al. 1997) and in limbic structures ties in neurotransmitter systems, such as those (Neumeister et al. 2006) of individuals with for 5-HT, dopamine, norepinephrine, gluta- MDD. mate and GABA, and alterations in the levels Taken together, findings collected over the of growth factors, such as BDNF, VEGF, and past few years have consistently shown that FGF. Evidence also indicates the presence of MDD is characterized by specific patterns of conspicuous changes in the levels of inflam- structural and functional abnormalities in cortico- matory, endocrine, and metabolic markers, and limbic regions. These abnormalities, if suffi- the presence of structural and functional abnor- ciently important to be detectable by malities in specific cortico-limbic regions of neuroimaging tools, may have the potential to depressed patients. Dysregulations of these translate into robust clinical biomarkers for the biological markers, if sufficiently important, diagnosis of depression. Neuroimaging-based may constitute reliable indicators of depres- biomarkers could also be reliably used to predict sive behaviors and even serve to predict pretreatment outcome (Drysdale et al. 2017), stratify dispositions to MDD. However, future patients into distinct clinical subgroups (Drysdale studies are needed to indicate whether these et al. 2017), and might even serve to detect pre- changes constitute a direct cause of depres- dispositions to MDD. sion or a compensatory mechanism for spe- 62 M. Fakhoury

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Ayla Arslan

5.1 Introduction initial pharmacotherapy regimen, for example (Krishnan and Nestler 2010). Also, existing treat- Depression is a brain disease deriving from the ments are neither optimally effective nor without complex interplay of genes and environment. adverse effects (Goodwin 2008). For instance, According to World Health Organization, it is a side effects of selective serotonin reuptake inhib- common mental disorder affecting more than 300 itors (SSRI), one of the most prescribed antide- million people worldwide and major contributor pressant drug (AD), are prominent (Price et al. to the overall global burden of disease (WHO, 2009). Moreover, patients diagnosed as Depression Fact Sheet, 2017). depressive but unresponsive to AD treatment or Despite its devastating impact on quality of more difficult to treat have higher probability of life, the neurobiological mechanism of depres- bipolar disorder (BPD) diagnosis (Li et al. 2012). sion is not fully understood. Thus, diagnosis of So, problems for the differential diagnosis of depression is grounded on clinical guidelines. depression and other psychiatric conditions exist. These guidelines such as Diagnostic and Figure 5.1 summarizes the problems associated Statistical Manual of Mental Disorders (DSM- with clinical classification of depression. V) or International Classification of Diseases One way to address these problems is the use (ICD-10) lack biological validity, despite being of biological markers rather than relying on clini- clinically reliable. cal soft signs and symptoms for the classification The classification criteria of the DSM-V or of depression. This in turn would certainly guide ICD-10 involve clinical signs, symptoms, and better disease diagnosis. Besides, the discovery course of illness causing patients with different of relevant biomarkers would help predict the phenotypes to be diagnosed in the same way and risk for developing a disorder as well as its course to receive same pharmacotherapy. Consequently, and treatment outcome. Are there such two third of the patients, diagnosed with major biomarkers? depressive disorder (MDD), do not respond to But, before that, what is a biomarker exactly? According to Webster’s New World Medical Dictionary, a biomarker is defined as “a biologic A. Arslan Genetics and Bioengineering Program, Faculty feature that can be used to measure the presence of Engineering and Natural Sciences, International or progress of disease or the effects of treatment”. University of Sarajevo, Hrasnička cesta br. 15, For psychiatric conditions, this sounds very Ilidža, Sarajevo 71210, Bosnia and Herzegovina ambitious yet challenging. e-mail: [email protected]

Psychiatrists would like to know if a specific 5.2 Neuroimaging: A Window drug is going to treat depression or if a person to the Black Box with depression is in danger of committing suicide. Thus, a biomarker is expected to give the Imaging of brain (or neuroimaging) was unthink- opportunity to evaluate drug response and dis- able until the late nineteenth century, when the ease risk based on biological data. Addressing discovery of X-rays has opened a window to this the former, such a biomarker can be named as black box. Since then, different types of neuroim- treatment-selection biomarker (TSB) which is aging techniques have been increasingly used for defined as a biological moderator that can be the studies of brain structure and function such as measured before treatment to guide selection of positron emission tomography or magnetic reso- the optimal treatment for patients (McGrath nance imaging (Box 5.1). et al. 2013). Also, a biomarker for psychiatric condition is expected to assist better diagnosis, providing opportunity to classify the disease and Box 5.1: What Is Neuroimaging? its subtypes precisely. Neuroimaging corresponds to a range of This type of biomarker can be named as noninvasive methodologies such as mag- “diagnostic biomarker”. Another group of bio- netic resonance imaging (MRI) or positron markers can be used to identify the utility of an emission tomography (PET) to obtain, iden- ongoing intervention early in the course of ill- tify, analyse, and interpret the images of ness, thus decreasing the time required to deter- brain structure and functionality. mine treatment outcome. In this chapter, we will examine the potential of neuroimaging derived data as biomarkers to be used in the diagnosis and treatment of depression (Fig. 5.2 Positron emission tomography (PET) is a type shows examples for candidate neuroimaging of neuroimaging, which can be used to identify biomarkers). resting-state metabolic features as well as density

Lack of differential diagnosis due to overlapping symptoms that cut across the disease boundaries Diagnosis Measuring disease severity remains unrecognized in ordinary practice

Pharmacotherapy is not as effective as desired Side effects Treatment Unresponsiveness Long time is required for the drug response

Clinical symptom based definition of depression Research interferes with top down biological research

Fig. 5.1 Current problems associated with classification of depression 5 Application of Neuroimaging in the Diagnosis and Treatment of Depression 71

Diagnostic Biomarker Treatment Selection Biomarker (TBS) Prognostic (Predictive) Biomarkers Measurements that can be used to Measurements obtained before Measurements that can be used to distinguish between different states of treatment used to decide on the predict the outcome or course of an illness and health. treatment options illness

• fMRI patterns of connectivity in limbic • Hippocampal volume3 • Midbrain glucose metabolism as 1 5 and fronto-striatal networks • Metabolism of subcallosal cingulate4 potential remission biomarker • Combined gray matter and white matter features in the structural MRI scans2

Fig. 5.2 Types of depression biomarkers discussed in the prefrontal cortex, sgACC subgenual anterior cingulate chapter and examples for candidate neuroimaging bio- cortex, VMPFC ventromedial prefrontal cortex. 1Drysdale markers. fMRI functional magnetic resonance imaging, et al. (2017), 2Sankar et al. (2016), 3Fu et al. (2013), MRI magnetic resonance imaging, DFN default mode net- 4McGrath et al. (2014) work, OFC orbital frontal cortex, DLPFC dorsolateral of neurotransmitter receptors and neurotransmit- imaging of white matter (WM) pathways ter transporters. Using radioactive tracers and (reviewed by O’Donnell and Westin 2011). WM ligands, a PET scan, can show how the brain and pathways are bundles of axons connecting the its tissues are working. As the late 1970s have brain parts by commissural tracts like the corpus witnessed the increase in the development of callosum and by association tracts like the arcu- radioactive tracers for brain, many human studies ate fasciculus. These features can be assessed by of PET have been conducted. The first examples several methodologies of DTI: (1) diffusion of such studies involve the imaging of regional property of the white matter such as fractional amino-acid metabolism or drug kinetics in brain anisotropy (FA) or mean diffusivity (MD), (2) 3D tumours (Bergstorm et al. 1983; Diksic et al. geometrical models of fibre paths derived from 1984) or neurotransmitter function (Garnett et al. tractography, and (3) connectivity matrices of 1983) followed by many others. brain connection networks (Arslan 2018). Magnetic resonance imaging (MRI) can be Thus, DTI can identify microstructural WM used to determine volume of different brain abnormalities with high resolution enabling the regions such as hippocampus and amygdala. The characterization of WM tracts related to critical MRI measurements, then, can be used to deter- brain regions implicated in emotion and cogni- mine individual differences in these structures tion. Moreover, it can address the genetic effects and their correlation with the biological parame- on the WM structures. The twin or sibling studies ters such as genetic variations and/or disease of brain asymmetry and development (Jahanshad states. MRI utilizes a strong oscillation of mag- et al. 2010; Chiang et al. 2011) or studies analys- netic field to make exogenously added contrast ing the individual differences of white matter agents (or endogenous atoms such as hydrogen) tracts (Schotten et al. 2011) have shed light on to emit radio waves. The radio waves are then the dissection of these effects on the WM param- used to generate two- and three-dimensional eters. Conversely, DTI is a valuable tool for the images of the brain in vivo. determination of white matter integrity and den- The diffusion tensor imaging (DTI) was first sity as measures of structural connectivity. proposed in the 1990s for use in magnetic reso- Also, by combining DTI with functional mag- nance imaging (MRI) (Basser et al. 1994a, b). In netic resonance imaging (fMRI), a neuroimaging principle, DTI measures a specific direction of method that reflects states of brain metabolic water diffusion by gradients of magnetic field activity in the resting state or during a specific generated by MRI. A repetition of this process in neural task as blood oxygenation level-dependent multiple directions is used to derive a 3D diffu- (BOLD) contrast, the model of connectivity sion model called the tensor, estimated for the (connectome) can be studied (reviewed by 72 A. Arslan

Structural Analysis Functional Analysis Molecular Analysis DTI and MRI fMRI PET

Structural connectivity Neural activation pattern Metabolic activity Volumetric measurements Functional connectivity Receptor density Effective Connectivity

Fig. 5.3 Summary of neuroimaging methods described in the present study

Glasser and Rilling 2008; Schotten et al. 2011). locked-in patients. For psychiatric conditions As ultrahigh magnetic fields increase the BOLD including depressive disorders, this is yet to be sensitivity (Uğurbil 2012), fMRI studies are established for routine clinical applications; increasingly used to measure neural activity in a however, neuroimaging in collaboration with specific brain region during a cognitive or emo- other fields holds a strong potential for this goal. tional task. Elaborating on this, functional con- In fact, there is a tremendous progress in molec- nectivity analysis is used to examine neural ular and cellular mechanisms underlying neural activation patterns in coordinated temporal pat- function and plasticity, but translation of this terns of activity across multiple regions (func- knowledge to clinical practice was not very fruit- tional connectivity MRI [fcMRI]) (Fox and ful, either. Thus, it was argued that clinical psy- Raichle 2007). Moreover, effective connectivity chiatry did not benefit from genomic revolution is an approach of fMRI, which identifies a cause as desired (Arslan 2015). and effect relationship to determine how one part One way to address this “bottleneck” is to of the brain regulates activity in another during a accelerate the screening of reliable biomarkers, specific task of emotion or cognition (Arslan which can link neuroscience research with clini- 2018). cal studies. Put it together, a good repertoire of Because of these increasing capabilities, neu- biomarkers is not only needed to address prob- roimaging is widely used to probe neurobiologi- lems of disease classification, personal pharma- cal characteristics in almost every field of cotherapy, and preventative medicine but also for neuroscience (Patel et al. 2016) despite contro- better research climate. Thus, neuroimaging versies (Vul et al. 2009). Since the first functional studies (Fig. 5.3) are particularly critical in this brain mapping of human subjects in the early context as there is a huge potential in line with 1990s (Belliveau et al. 1991; Ogawa et al. 1992), the advancements in the field. Here we will for example, the number of research articles pub- describe this in terms of PET, MRI, DTI, fMRI, lished in NCBI PubMed relevant to) fMRI hit to the promises, and the challenges. 27,995 papers in between January 1, 2016, and January 1, 2017. Why is it so? The appeal of neuroimaging lies behind the 5.3 The Depressed Brain irresistible idea of decoding the activation patterns and algorithms of the brain to sense, per- Neuroimaging can shed light on how dysfunction ceive, and respond to the world during health in specific brain structures and circuits might and disease. However, the outcomes were below underlie depression. Accordingly, many studies the expectations: At present, utilization of neu- attempted to identify molecules, regions and cir- roimaging biomarkers for clinical practice is cuits involved in this process. Two circuitries are restricted to neurological conditions such as pre- reported as associated with depression and other surgical evaluation of epilepsy, differential diag- mood disorders most consistently: The serotoner- nosis of coma, and brain-computer interfaces for gic circuitry centred on amygdala and differ- 5 Application of Neuroimaging in the Diagnosis and Treatment of Depression 73 ent medial prefrontal cortical regions, and the association of several brain regions with MDD circuitry centred on the ventral striatum and including bilateral insula, left lentiform nucleus medial prefrontal cortex (Phillips et al. 2015). The putamen, and extranuclear, right caudate, and former circuitry is involved in the modulation of cingulate gyri, which show a significant decreased implicit emotion regulation, and the latter is a metabolism in patients with MDD, whereas right dopamine-regulated reward circuit. It is suggested thalamus pulvinar and declive of posterior lobe that different dimensions of depression symptoms and left culmen of vermis in anterior lobe have might be linked to abnormalities in these circuit- significantly higher metabolic activity in MDD ries thus can serve as biomarkers for treatment patients (Su et al. 2014). selection. For example, abnormalities in the One of the first systematic, well-controlled implicit emotion regulation circuitry may cause studies to identify the first potential biomarker poor affect and anxiety, while abnormalities in that distinguishes between treatment responses reward circuitry may cause indifference and anhe- was published not so long ago (McGrath et al. donia (Pizzagalli 2011; Keedwell et al. 2005). 2013). The group first measured glucose metabo- One of the mediators of implicit emotion reg- lism of the brains of 82 treatment-resistant ulation is thought to be serotonergic transmission depressed patients using PET scans. Then, they particularly in the amygdala and medial prefron- randomly assigned the patients to two different tal cortical regions (Phillips et al. 2015). treatment groups. While one group received the Addressing this, PET studies reported differences SSRI escitalopram for 12 weeks, the other group in the levels of serotonin receptors (5-HT1A and received 16 sessions of cognitive behavioural

5-HT2A) between healthy people and patients therapy (CBT) over the same period. Results with , MDD (Drevets et al. 1999; Meyer et al. show that the rate of glucose metabolism in the 2003); Sargent et al. 2000; Savitz and Drevets right anterior insula—which is related to 2009; Smith and Jakobsen 2009). Patients of depression-relevant behaviours such as emotional major depressive disorder (MDD), who have self-awareness and decision-making—predicted high levels of pessimism, show an elevation in the treatment response. The patients who have

5-HT2A receptor levels (Bhagwagar et al. 2006; higher rate of insula glucose metabolism than the Meyer et al. 2003), and patients with major average metabolism rate for the whole brain depressive episode show a reduction in 5-HT1A responded to pharmacotherapy, whereas those receptors (Drevets et al. 1999; Sargent et al. who did not respond showed a below-average 2000). Also, 5-HT1A density was determined by insula metabolism rate. Moreover, MDD patients using the PET tracer [carbonyl-C- who fail to achieve remission as a result of CBT 11]-WAY-100635, a selective 5-HT1A antagonist or escitalopram, either alone or in combination, in a study of 50 patients with MDD (34 female, showed a distinct brain metabolic pattern com- 16 male) and 57 healthy controls (32 female, 25 pared to patients who achieve remission (McGrath male). Results show that 5-HT1A density of male et al. 2014): Metabolism of subcallosal cingu- subjects diagnosed with MDD was significantly late—the portion of the cingulum that lies ventral higher across 13 brain regions compared with to the corpus callosum including Brodmann area male controls (p < 0.0001), suggesting that 25 and parts of 24 and 32—was significantly 5-HT1A density could be a biomarker for depres- higher in non-remitters. Besides, increased activ- sion in males (Kaufman et al. 2015). ity of superior temporal sulcus—the sulcus infe- In particular, several studies analysed the met- rior to the lateral fissure and separating the abolic features of MDD by PET. Given that glu- superior temporal gyrus from the middle temporal cose is the major substrate for brain metabolism, gyrus in the temporal lobe—was also associated studies of glucose metabolism using with no responsiveness to two treatments. In a 2(18F)-fluoro-2-deoxy-d-glucose (FDG) by PET follow-up study, metabolism of the right part of (FDG PET) have been conducted. For example, a the anterior insula, the cortical region folded meta-analysis (Su et al. 2014) confirmed the in the depth of the lateral sulcus, has been 74 A. Arslan tested as treatment predictor for psychotherapy in with controls (Campbell and MacQueen 2004). 30 escitalopram-treated non-remitters who took Particularly, according to a meta-analysis, struc- combination treatment. Results show that patients tural MRI studies show that there is an association whose added treatment matched the anterior between larger hippocampal and cingulate vol- insula metabolism-indicated treatment remitted ume with remission response to AD treatment more often than anterior insula metabolism- (Chi et al. 2015). Volumes of the left middle fron- mismatched patients (Dunlop et al. 2015). Other tal and the right angular gyri have been reported clinically relative studies compare two pharmaco- as reliable predictors for no remitters to AD treat- therapy options. For example, some studies ment (Korgaonkar et al. 2014). reported the predictors between two classes of Also, some findings of structural measurements antidepressant response, but the results, to date, may lead to differential diagnostics. For example, have been difficult to interpret and apply clini- when compared with patients of bipolar disorder, cally (Little et al. 2005; Wagner et al. 2010; Frodl patients of MDD are differentiated by larger cor- et al. 2011). Nevertheless, a study of meta-analysis pus callosum and smaller hippocampus and basal (Fu et al. 2013) focusing on functional and struc- ganglia. On the other hand, there is also an overlap tural neuroimaging studies of pharmacological between the brains of MDD and BD patients: and psychological therapies confirmed several larger lateral ventricle and subcortical grey matter brain regions within a fronto-striatal-limbic net- when compared with healthy controls. work which can predict treatment outcome. One of the subjects of structural neuroimaging, the cortical thickness, is of great interest in both normal development and psychiatric disorders 5.4 The Structural Degenerate (Fischl and Dale 2000) and may offer some other opportunities for neuroimaging of depression. Regarding depression perhaps one basic question is to ask if there is any structural difference between a healthy brain and a depressed brain. If so, can it be 5.5 Measuring Neural Activity measured precisely by structural MRI? As reviewed by Kempton et al. (2011), accu- Measurement of neural activity in distinct brain mulating studies of structural MRI show that regions may be considered as another neuroim- MDD is linked to larger lateral ventricle, larger aging methodology useful to predict treatment cerebrospinal fluid volume, and smaller volumes response. Indeed, such measurements as done by of the basal ganglia, thalamus, hippocampus, fron- functional MRI indicate an important role for tal lobe, orbitofrontal cortex, and gyrus rectus. the amygdala for this purpose (Phillips et al. Neuroimaging studies of these structures 2015). For example, one study reported that report associations between structural variants to greater pretreatment amygdala activity predicted treatment response. Among these, it was proposed better outcome for cognitive behavioural therapy that the ACC and hippocampus may provide an (CBT) (Siegle et al. 2006), while the opposite estimate of response to treatment (Vakili et al. was found for the outcome of ketamine treat- 2000). Many other studies suggest that hippocam- ment (Salvadore et al. 2009). pus may be used to predict treatment outcome Other brain regions such as the prefrontal cor- (Frodl et al. 2008; MacQueen et al. 2008; tex (PFC) or ACC have also been studied. For Lorenzetti et al. 2009; Fu et al. 2013). Especially, example, a lower pretreatment activity in the ven- individuals during depressive episodes are associ- trolateral prefrontal cortex during an emotional ated with smaller volume of hippocampus com- task was associated with better response to either pared to individuals during remission. This is well fluoxetine or venlafaxine in depressed subjects supported by meta-analysis approach showing (Light et al. 2011). A lower baseline activity in that depressed patients had significantly decreased the dorsal anterior cingulate cortex was associ- left and right hippocampal volumes compared ated with an improved clinical outcome with an 5 Application of Neuroimaging in the Diagnosis and Treatment of Depression 75

8-week treatment with fluoxetine was reported characterized by increased fatigue. These areas by one study (Walsh et al. 2007). are involved in motivation and incentive-salience Indeed, accumulating evidence strongly sug- evaluation. On the other hand, connectivity gests the activity of ACC as a predictor of a clini- involved in reward processing, adaptive motor cal response to antidepressant medication or control, and action initiation, i.e. thalamic and other treatments (Ebert et al. 1991; Wu et al. fronto-striatal pathways, was especially promi- 1999; Mayberg 1997) For example, a meta- nent in type 3 and type 4, related to increased analysis suggest that ACC activity has also been anhedonia and psychomotor retardation. These positively related to a variety of treatment four subtypes of depression were also associated responses, including antidepressant pharmaco- with differences in treatment outcome. therapy and experimental treatment strategies, Conversely these data suggest that measures such as sleep deprivation suggesting that ACC of activity in the ACC, medial prefrontal cortex, response can be used as a general predictor across and amygdala may suggest guidance for treat- different treatment types (Pizzagalli 2011). ment selection between CBT and pharmacother- Another meta-analysis focusing on fMRI and apy as well as between different options of PET studies reports that increased ACC activity pharmacotherapy. Moreover patterns of connec- extending into the orbitofrontal cortex and decreased tivity in limbic and fronto-striatal networks may baseline activation of right striatum and anterior be used to classify depression subtypes. However insula in acutely depressed patients can predict clin- more studies are required. ical response to AD or CBT (Fu et al. 2013). Some other studies focus on the classification of depression by functional neuroimaging. One fMRI 5.6 The Connectivity Problem study (Fu et al. 2008) addressed the pattern of brain activity during the neural processing of sad facial Studies focusing of structural connectivity show expressions, which correctly classified up to 84% that patients with MDD is consistently associated of patients (p < 0.0001). Moreover, this classifica- with a decreased fractional anisotropy in the tion of patients’ clinical response at baseline, prior white matter fascicles connecting the prefrontal to the initiation of treatment, appears to be predic- cortex within cortical (frontal, temporal, and tive for treatment response (Fu et al. 2008). occipital lobes) and subcortical areas (amygdala One recent paper (Drysdale et al. 2017) has and hippocampus) (Liao et al. 2013). Moreover, flustered this year, bringing us inspiring news that one study reports that lower frontal fractional depression can be subdivided in to biological anisotropy is associated with sertraline response types, i.e. “biotypes” (Williams 2017). fMRI in late-life depression, for example (Taylor et al. scans of more than 1100 patients with clinical 2008). Are these features specific to MDD or depression and healthy individuals revealed that common in other depression subtypes or other patients with depression can be divided into four psychiatric conditions? This is crucial to identify subtypes based on distinct patterns of connectiv- the prognostic and diagnostic potential of DTI ity in limbic and fronto-striatal networks and dif- measurements. The current evidences require ferent clinical symptoms (Drysdale et al. 2017). further investigation of this matter as the number For instance, a finding for the reduction in the of studies and sample sizes are very small. For frontoamygdala connectivity, a network involved example, the study of Liao et al. (2013) included in the regulation of fear and reappraisal of nega- 11 studies with a total sample size of 231 patients tive emotional stimuli, led to the differentiation with MDD and 261 comparison participants. depression subtypes which was most severe in Thus, more studies with standardized patient types 1 and 4. These subtypes are associated with groups with increased sample sizes are required. symptoms of increased anxiety. Reduced connec- On the other hand, studies of structural and tivity in anterior cingulate and orbitofrontal areas, functional analysis of MDD are increasing (Qin were most severe in types 1 and 2, which were et al. 2014; Korgaonkar et al. 2014; Lai and Wu 76 A. Arslan

2014; Song et al. 2014; Colle et al. 2016; Choi 5.7 Clinical Trials et al. 2016; Won et al. 2016; Grieve et al. 2016; Myung et al. 2016; Tatham et al. 2017; Tymofiyeva The proposition of depression models especially et al. 2017; Petrovska et al. 2017; Repple et al. by PET scans (Mayberg 1997, 2009) was one of 2017; Takeuchi et al. 2017; Chen et al. 2017; the important contributions to our understanding Connolly et al. 2017). Especially, studies of com- of depression as these depression network mod- bined analysis of WM connectivity, antidepressant els can be used to optimize the antidepressant response, and/or genetic variation are taking atten- effect of treatment to more precisely target net- tion as candidates of biomarkers for MDD. One works relevant in depression, for example. study, suggests FA measures of the stria terminalis Addressing these several clinical trials is already and cingulate portion of the cingulate bundle (CgC) on the way. as prognostic biomarker to identify nonremission As neuroimaging studies converge on founda- to drug therapy (Grieve et al. 2016). Greater speci- tions of neural connections between the cingulate, ficity for escitalopram and sertraline response has internal capsule, and other regions of the brain been found in the identification nonremitting MDD associated with MDD (Dyster et al. 2016), surgi- patients, which may help managing the drug ther- cal approaches such as deep brain stimulation apy of depression. Also, resting-state functional (DBS) or cingulotomy (Banks et al. 2015) get connectivity of the amygdala has been linked to facilitation for planning and refining or predicting longitudinal changes in depression severity in ado- outcomes in psychiatric neurosurgery. For lescent depression (Connolly et al. 2017). instance, a clinical trial (NCT003670032) is Another study reported an association between designed to assess the feasibility of stimulation of polymorphisms in the genes encoding for the subgenual cingulate white matter (Cg25WM) 5-HTTLPR and BDNF and uncinate fasciculus using implantable deep brain stimulation (DBS) connectivity and antidepressant treatment for the treatment-refractory major depression. response in MDD (Tatham et al. 2017). Other dif- Other targets for DBS under investigation for fusion MRI studies showed a positive relation- clinical potential are trial for lateral to the ventral ship between the fractional anisotropy of the tegmental area in the midbrain (NCT01095263). cingulum bundle and remission. White matter An ongoing clinical trial (NCT019847101) signal hyperintensities were also found as predic- involves the patients of treatment-resistance tive for remission rates (Chi et al. 2015). depression, which will be implanted by the “brain Many other studies reported potential neuro- radio” system in the subcallosal cingulate cortex to imaging biomarker that could identify the out- stimulate that area with electricity, to reset the comes of remission and treatment failure to AD regulation of the network. This effect, as supported treatment or CBT. For instance, an fMRI study by previous experimentation, is expected to result published recently reports the resting-state func- in a significant antidepressant response. The study tional connectivity analysis to determine any is also aiming to record patients over 3 years, potential biomarker as predictor for outcomes of while they receive electric stimulation. The record- remission and treatment failure to CBT and AD ings will be correlated with the primary clinical treatment (Dunlop et al. 2017). Results show that response which altogether helps understand neu- the resting-state functional connectivity of the robiology of depression and the antidepressant left anterior ventrolateral prefrontal cortex/insula, response. the dorsal midbrain, and the left ventromedial prefrontal cortex with the subcallosal cingulate Conclusion cortex is differentially associated with outcomes A scan of a depressed brain often shows a pat- of CBT and AD treatment. Thus, resting-state tern of increased neural activity in amygdala, a activity in these areas in the future may serve as a brain region involved in fear and emotional criterion for the type of first-line treatment that response and decreased neural activity in the will most likely lead to remission. regions of prefrontal cortex which is involved 5 Application of Neuroimaging in the Diagnosis and Treatment of Depression 77

in executive control. Accumulation of such (RDoC), classification framework for research neuroimaging findings leads to the proposition on mental disorders (Insel et al. 2010), will of molecular, structural, and functional brain increasingly contribute standardization of neu- states, which may be used for diagnosis or pre- roimaging studies. Other initiatives such as the diction of treatment outcome (Crane et al. Consortium for Reliability and Reproducibility 2017). Among these, limbic-cortical circuit- (CoRR), aiming to establish test-retest reli- ries have been identified as the key brain net- ability as a minimum standard, will trigger work that may guide treatment of depression. development of new methodologies for func- Thus, in this chapter, studies addressing these tional connectomics (Zuo et al. 2014). links have been presented such as hippocam- In parallel, there is growing evidence that pal and cingulate volume as the predictor of opportunities of better data quality of neuroim- AD response (Chi et al. 2015), activity of aging are increasing. For example, one study amygdala as a predictor of CBT response (Glasser et al. 2016) by using the information (Siegle et al. 2006), and activity of ACC as a derived from structural and functional MRI predictor of a clinical response to antidepres- data mapped the 180 areas per brain hemi- sant medication or other treatments (Wu et al. sphere—more than twice the number previ- 1999; Mayberg 1997; Pizzagalli 2011). Several ously known. This in turn suggests a better clinical trials, targeting these and other associ- analysis of individual variations in brain corti- ated regions were described (see also Sect. cal architecture, functionality, connectivity, 5.7). In addition, whole brain neuroimaging and topography for better understanding of measures and pattern classification methods neurobiology, personalized and predictive were underlined as they may aid diagnosis and treatment, and prevention of mental disorders prognosis. Especially limbic and fronto-striatal (Trivedi et al. 2016). Moreover, another study network-based classification (Drysdale et al. reported the use of a radioligand of synaptic 2017) seems promising (see also Sect. 5.5). vesicle glycoprotein for (PET) to quantify syn- On the other hand, neuroimaging and its aptic density in living human brains (Finnema utility for clinics and especially for depression et al. 2016). This brings the possibility to per- are still a relatively new field with its own form an in vivo synaptic quantification which intrinsic problems such as reproducibility, could aid the diagnosis of disease associated inconsistency, and validity. For example, neu- with synaptogenesis and synapse loss. roimaging studies especially functional neuro- In summary, the continuous progress imaging with “puzzlingly high correlations” described so far, together with well-coordi- or “entirely spurious correlations” were highly nated standardized, better planned neuroim- criticized (Vul et al. 2009; Bennett et al. 2009). aging studies, will help produce better Sirotin and Das (2009) claimed that consistent data which will contribute our, so “Anticipatory haemodynamic signals in sen- far limited, knowledge of depression leading sory cortex not predicted by local neuronal to the identification of biomarkers for person- activity” suggesting that the BOLD signals of alized, prognostic, predictive, and preventa- functional MRI (fMRI) can arise without any tive medicine. measurable neuronal activity, despite objec- tions (Handwerker and Bandettini 2011; Kleinschmidt and Müller 2010). References Thus, more analysis with well-coordinated standardized, better planned neuroimaging Arslan A. Genes, brains, and behavior: imaging genetics studies with increased sample size and accu- for neuropsychiatric disorders. J Neuropsychiatry Clin rate analytics is required. Yet, the field is devel- Neurosci. 2015;27(2):81–92. oping rapidly (Dubin et al. 2017). For example, Arslan A. Imaging genetics of schizophrenia in the post-GWAS era. Prog Neuropsychopharmacol Biol initiatives like Research Domain Criteria Psychiatry. 2018;80(Pt B):155–65. 78 A. Arslan

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Shinichi Tokuno

6.1 Introduction problematic because the information can vary owing to a variety of factors. Recently, voice The diagnosis of depression is ordinarily con- screenings for stress and depression have been ducted by a psychiatrist using an interview. reported. Methods involving the screening of However, when screening an extremely large voices offer advantages, such as the lack of a population for stress or depression, it is impossi- requirement for special equipment, low running ble for a psychiatrist or clinical psychologist to cost, as well as the possibility for remote proce- conduct an interview with each and every sub- dures. This paper discusses the potential for ject. Therefore, the method commonly applied in screening voices to monitor stress and depression. such cases involves screening using a self- assessment questionnaire, which leads to an interview with a psychiatrist or a clinical psy- 6.1.1 Depression and Voice chologist. A self-assessment questionnaire, however, is based on a subjective self-assessment by The occurrence of atypical characteristics in the the subject, and, as such, it has a tendency for quality of the voices of depression patients has significant bias. Therefore, what is expected is been observed clinically for a considerable screening based on objective indicators by bio- amount of time (Newman and Mather 1938; markers. In recent years, extensive studies have Cobb et al. 1943; Moses 1954). Much effort has been conducted on biomarkers relating to stress been devoted to subjectively categorizing such and depression; nevertheless, none of them have characteristics (Darby 1981; Darby et al. 1984). reached the practical level, yet tests conducted on On the other hand, attempts have also been made blood and saliva generally tend to offer more reli- to objectively evaluate the voice of depression able information on the subject; however, these patients. Hargreaves and his associates attempted tests are invasive and involve cost consideration to perform a spectral analysis of the voices of issues, as special equipment and reagents are depression patients (Hargreaves et al. 1965). required to perform such measurements. Weintraub discovered that depression patients Physiological methods are less invasive but are tend to speak slowly (Weintraub and Aronson 1967), while Szabadi and colleagues proposed that this slow speech was affected by the pause S. Tokuno time (Szabadi et al. 1976). Almost concurrently, Department of Verbal Analysis of Pathophysiology, most of studies were attempted based on the fun- Graduate School of Medicine, The University damental frequency of voice (F0), and many find- of Tokyo, Tokyo, Japan e-mail: [email protected] ings were based on comparisons of average

© Springer Nature Singapore Pte Ltd. 2018 83 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_6 84 S. Tokuno values of the F0 (Newman and Mather 1938; tion) is difficult for all types of emotions. For that Tolkmitt et al. 1982); however, Darby and Hollien reason, prosodic rules are often employed in compared the variance of F0 instead (Darby and addition to formant analysis in recent years. In Hollien 1977). More detailed F0 analyses started the same era, Mitsuyoshi developed a technology in the second half of the 1980s (Nilsonne et al. for identifying emotions by using only F0 analy- 1988; Scherer 1987). Nilsonne and her associates sis, which is a prosodic feature value. provided a detailed introduction to a method that The expression of emotion is inhibited by uses a computer program to analyze F0. Scherer depression. The manifestation of depression, sor- conducted an analysis of the voice of depression row, or loss of joy daily for 2 weeks is considered patients using a voice characteristic referred to as as the standard for diagnosis for depression, “jitter” which is frequency fluctuation and “shim- according to the Diagnostic and Statistical mer” which is amplitude fluctuation and discov- Manual of Mental Disorders, Fourth Edition, ered that the jitter was higher in the voice of Text Revision (DSM-IV-TR). We therefore con- depression patients. Another report indicated that sidered that deriving an objective index for a voice characteristic referred to as the harmonic- depression must be possible by capturing emo- to-noise ratio (HNR), used to evaluate hoarseness tional changes (Mitsuyoshi 2015). of voice, was greater in individuals with depression (Low et al. 2011). Analyses have been conducted on the formant frequency, defined by the 6.2 Voice Emotion Recognition resonance formed when the vibration of the vocal cord passes through the vocal tract (Flint et al. 6.2.1 Sensibility Technology 1993; Cummins et al. 2011). The shimmer, jitter, and HNR are feature quantities considered funda- Our system is based on the emotion recognition mental to sound analysis, and various studies are technology (sensibility technology, ST; AGI Inc., currently being conducted using software capable Tokyo, Japan) developed by Mitsuyoshi and his of analyzing several thousand feature quantities associates (Mitsuyoshi 2002), who focused on F0 (Eyben et al. 2010). An attempt has also been changes during conversation and selected the F0 made to identify ailments based on machine learn- variation parameters in a voice labeled for emo- ing and deep learning by using large numbers of tions. They then extended that to many F0 varia- feature quantities (Maxhuni et al. 2016). tion parameters, which were labeled for emotions. The labeling of emotions in voices consisted of the four emotions of joy, sorrow, anger, and calm- 6.1.2 Emotion and Voice ness, as well as a fifth aspect, excitement. The labeling of a voice for F0 was conducted using Efforts to estimate and scale the emotions of peo- voice in which judgment of emotion and excite- ple based on their voice began approximately in ment by speaker, listener, and third party matches. the 1990s, when the evaluation of depression ST determines in real time what percentage of based on voices became popular (Cahn 1990; each emotion and excitement parameter is con- Murray and Arnott 1995). Evaluations of emo- tained in the voice by the parameter of F0-labeled tions were conducted primarily using formant emotion (Mitsuyoshi et al. 2006, 2007). analysis (Cahn 1990; Murray and Arnott 1995; According to fMRI studies, emotions deter- Burkhardt and Sendlmeier 2000). This may be mined with ST have been reported to almost because research on speech and languages coincide with emotional activities of the brain. In became popular and software development this research, conversations conducted with test advanced. The analysis of the formant region is subjects during fMRI measurements confirmed strongly affected by the vocal tract and indicates that the activities of the amygdaloid corpus of the voluntary emotional changes. Capturing more right hemisphere, the bottom of the forehead (in primitive involuntary components (rapid emo- the vicinity of BA12), and the prefrontal cortex, 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression 85 which are emotional region of the brain, coin- 6.3 From Emotional Recognition cided (Mitsuyoshi et al. 2011). to Pathologic Analysis In Japan, ST is no longer limited to the entertainment domain, portable games, and smart- 6.3.1 Development phone applications but is also being utilized in of Psycho-Analyzer industries such as call centers. Currently, implementation development on automobiles and A program (psycho-analyzer; AGI Inc.) that pro- robots is progressing. vides a prototype for determining the extent of stress based on the stress indices (joy, sorrow, anger, calmness, and excitement) derived by ST 6.2.2 Emotional Changes was prepared (the relevant paper is currently Due to Stress being drafted). The research defined an algorithm for quantifying the intensity of the emotional We conducted a verification test to determine state recognized by ST based on the characteris- whether emotional changes due to stress can be tics of mood disorders which is defined by the captured using ST (Tokuno et al. 2011). The DSM-IV-TR. In other words, the emotional char- voices of nine individuals who were dispatched acteristics of the voice, which were derived by overseas with disaster duties were acquired. voice emotion analysis, were calculated as vocal Those who worked in a stress-full environment affect displays (VADs). Based on the emotional for a long time showed a tendency that joy indices derived by ST, the low VAD (VAD-L), decreased and sorrow increased as compared which indicates negative emotional states, and with those who worked in a similar environment the high VAD (VAD-H), which indicates positive for a short time (Fig. 6.1). However, significant emotional states, were calculated. These were individual differences were observed in emo- then used to derive the scale of the VAD ratio tional changes due to stress, and it was concluded (VAD-R). First, the algorithm for calculating that a detection of depression solely based on a VAD-L focuses on the excite parameter of ST comparison of emotions is difficult. On the other and classified roughly according to the value of hand, a discovery that confirmed the correlation excite. Next, VAD-L was determined with the between emotions derived by ST and GHQ-30 focus on anger and joy. The algorithm for calcu- scores was made by another study (Nakamura lating VAD-H was classified roughly according et al. 2015). This research indicated that there to the value of excite similarly; then, VAD-L was was correlation between the emotional index of determined with the focus on sorrow and calm- anger and the GHQ-30 scores, as well as between ness. The VAD-R value was defined as the ratio the index of excitement and suicidal ideation and of VAD-L to VAD-L. The application of this depression, which scored at the lower scales of method to the nine individuals described earlier the GHQ-30. An investigation of the correlation obtained a result that indicated that the individu- between the amount of change of voice emo- als who remained in the disaster area for longer tional indicators and GHQ score on two different periods of time had greater VAD-L and VAD-R time examinations indicated a correlation of the and lower VAD-H in comparison to those who amount of change in the emotional index with remained in the area for shorter periods of time. that in the GHQ-30 scores, while the amount of change in the emotional index of joy exhibited correlation with that in “general disorder trends,” 6.3.2 Overcoming Reporting Bias “physical conditions,” and “social activity disorders,” which score at the lower scales of the We conducted an evaluation of individuals on a GHQ-30. Based on these findings, mental health greater scale than this prototype (psycho- state screening through voice emotion recogni- analyzer) (Tokuno et al. 2014). Psychological tion was considered possible. tests consisting of self-assessment questionnaires 86 S. Tokuno

Joy Sorrow 10 10

8 8

6 6

4 4

2 2

0 0 Short G Long G Short G Long G

Anger Calm 10 10

8 8

6 6

4 4

2 2

0 0 Short G Long G Short G Long G

Excite 10

0 Short G Long G

Fig. 6.1 Emotional change due to stress. Those who increased as compared with those who worked in a similar worked in a stress-full environment for a long time environment for a short period (Tokuno et al. 2011) showed a tendency that joy decreased and sorrow

(GHQ-30 (Goldberg and Blackwell 1970); K10 the Great East Japan Earthquake. Two hundred (Kessler et al. 2002); IES-R (Weiss 2004); CES-D and twenty-five individuals who were determined (Radloff 1977); eC-SSRS (Mundt et al. 2010, to be abnormal in even one of the five psycho- 2013)) and voice stress evaluations were con- logical tests and consented to an interview were ducted on 444 employees of the Japan Self- categorized by a single specialist (a specialist that Defense Forces (JSDF) who were assigned is unique to JSDF, equivalent to a clinical psy- ordinary routine duties and 1004 employees of chologist) into two groups: one in need interven- JSDF dispatched on emergency duties following tion (medical treatment or counseling required) 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression 87 and one under observation. The voice-based subconscious undervaluation or overvaluation by stress evaluation was then compared with the the test subjects. Its detection rate has been results of the interviews. The emotional analysis reported to be lower within organizations with revealed that all emotions of joy, anger, and sor- established hierarchy, such as fire departments, row were observed to have declined in the mem- police departments, or military organizations bers of the group needing intervention. (Hoge et al. 2004; Perrin et al. 2007; McLay et al. Furthermore, a comparison with the findings 2008). Resistance, prejudice, and discrimination from the GHQ-30, which demonstrated the high- against mental health issues or insecurity about est sensitivity among all self-assessment ques- repercussions in their professional careers can be tionnaires, indicated approximately the same reasons that cause such undervaluation in self- level of sensitivity in determining the level of assessment screening (Hoge et al. 2004). Our depression, whereas in terms of specificity, the study suggested that by combining self-written results did not compare with those of the GHQ- questionnaires and evaluations by voice, it would 30 (Table 6.1). The voice-based evaluation be possible to pick up patients who could not be assessed that two participants were highly screened with self-contained questionnaire alone stressed, although they exhibited no problems due to reporting bias. according to the GHQ-30; however, during the interview, they were immediately diagnosed with serious conditions that required urgent medical 6.4 Monitoring System treatment. In other words, the voice-based evaluation allowed the prevention of the reporting bias 6.4.1 Development of MIMOSYS that occurs with self-assessment questionnaires (Fig. 6.2). The reporting bias is a conscious or The voice-based stress evaluation with the psycho- analyzer obtained favorable sensitivity but was not Table 6.1 The comparison between voice analysis and satisfactory with regard to specificity. It also self-assessment questionnaires involved other issues, such as deference in the Need results between males and females. To overcome intervention such issues, we developed a new program and an Voice analysis + − application for smartphones to facilitate the use of VAD- 50=< 26 162 188 Sensitivity, the program. This application is called MIMOSYS L 50> 3 34 37 0.897; (Mind Monitoring System; PST Inc.) (Tokuno Specificity, 29 196 2015a, b; Omiya 2016; Omiya et al. 2016). 0.173; Positive predictive Excitement, anger, and joy were used to calcu- value, 0.138; late VAD-L, with the psycho-analyzer. However, Negative MIMOSYS first calculates an index referred to as predictive “vivacity” for joy, which tends to be greater for value, 0.919 females, and sorrow, which tends to be greater Need for males, while the index referred to as “relax- intervention Self-assessment ation” was similarly calculated for calmness and questionnaires + − excitement. This was followed by the calculation GHQ- 7=< 27 123 150 Sensitivity, of the index “vitality,” which represents the state 30 7> 2 73 75 0.931; Specificity, of the mind based on vivacity and relaxation 29 196 0.372; (Shinohara et al. 2015; Mitsuyoshi 2016) Positive (Fig. 6.3). By conducting such dual-level calcula- predictive value, 0.180; tions, we successfully eliminated the difference Negative between males and females (Fig. 6.4). The vital- predictive ity index is an index characterizing a positive value, 0.973 emotional state, and, as such, it decreases owing 88 S. Tokuno

GHQ-30 Depressive Score by Voice 30 100

25 80 20 60 15 40 10

5 20

0 0 Intervention Follow up Intervention Follow up

Fig. 6.2 Emotional change due to stress. Self-assessment uation. Two were judged to be normal in GHQ-30 and psychological tests and stress assessments by voice were high stress was judged in voice. They were judged to be a conducted on 444 SDF personnel who are in constant serious case requiring medical treatment immediately at operation and 1004 SDF personnel dispatched during the the interview. We thought that the reporting bias could be Great East Japan Earthquake. Among them, for 225 peo- overcome by voice evaluation (Tokuno et al. 2014: ple who approved clinical psychologists’ interview, we Revised from presentation slide) compared the result of GHQ-30 with the voice stress eval-

Emotion Recognition Mind Monitoring

Joy Activity Mental Anger Vivacity Vitality Sorrow Calm Relax Exite

Fig. 6.3 Vitality and mental activity in MIMOSYS. In of vivacity and relaxation, we calculated the index called MIMSYS (Mind Monitoring System), in order to elimi- vitality as an indicator of the condition of the mind. nate gender differences, we first calculated vivacity index Furthermore, we devised an index called mental activity, from joy that tends to be higher in women and sorrow that which is an index that adds the moving average of vitality tends to be higher in men and similarly calculated indices and the variation of that period (Mitsuyoshi 2016: of relaxation from calm and excite. Then, from the values Presentation slide) to stress reactions or a depressed state. Based on vitality distributions of depression patients and previous data (Tokuno 2016), the sensitivity of healthy individuals was investigated. In this pilot the vitality index was confirmed to be similar to study, when multiple measurements of an indi- that of VAD-L. However, no difference was vidual subject were obtained, it became evident observed in terms of specificity from that of that the vitality index of depression patients had VAD-L. Therefore, the difference between the lower values, whereas that of healthy individuals 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression 89

VAD-L Vitality 1 1 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 Female Male Female Male

Fig. 6.4 Gender difference in VAD-L and vitality. We compare VAD-L and vitality with 38 male and female each. Vitality succeeded in excluding gender differences by calculating in two steps was distributed over a wide range, with occasion- tends to manifest emotions more readily, there ally very high and very low values. We proposed are often occasions where the speaker becomes an index referred to as “mental activity,” which hesitant, not knowing what to talk about. We considers the average change of vitality and its adopted the automatic recording system for voice variation within a given period; we consider this conversations from telephone calls, which can be distribution difference to correspond to the dif- used without the user becoming conscious of the ference between depression patients and healthy process. This decision was made because we individuals. A period of 2 weeks was adopted as believe that a system that does not require any the average period of transition, as indicated by special operation on the part of the user would be the DSM-IV-TR. The mental activity index indi- more likely used for longer periods of time. cates the trend of vitality and its implementation Actually, it has been confirmed that the automatic allows the distinction between healthy individu- recording of conversations facilitates the acquisi- als and depression patients with sufficient sensi- tion of data over a longer period more than the tivity and based on specificity (Tokuno 2016). manual recording of prescribed text (Hagiwara Vitality may be considered as an instantaneous et al. 2016a, b). The application MIMOSYS index on the time when the voice is recorded, starts automatically when a telephone is used to while mental activity can be considered a make or receive a call and records only the voice medium- to long-range index. Using these indi- of the user. Voice analysis is performed after the ces together can describe the current mental state call has been terminated and the results are dis- of an individual. played to the user. Once the analysis has been Subsequently, we produced a smartphone completed, the voice recording is deleted auto- application to make this technology available for matically. Previous results can also be viewed by general use by a wide range of people. Methods operating the application. To easily illustrate the for capturing voice using a smartphone include levels of vitality and mental activity, the vitality the automatic recording of voices from a index is displayed on a meter, while mental activ- conversation conducted during an ordinary tele- ity is shown in a symbolic image with five stages phone call, as well as the recording of voices by (Fig. 6.5). The vitality and the mental activity manually starting an application. In manual levels are only displayed for each measurement, recordings, methods for recording freely spoken but it is also possible to present the chronological speech and the subject reading a prescribed text changes of both indices in a graph. A review on are also available. Although freely spoken speech the graph is expected to help provide insight 90 S. Tokuno

Vitality Mental Activity

Fig. 6.5 Screen display of MIMOSYS. For ease of image, vitality is displayed with a meter, and mental activity is displayed in a symbolic five-level image regarding changes and trends to illustrate the Earthquake occurred during the course of this behavioral transformations of the user (Tokuno research, and a small number of studies were con- 2015a, b; Omiya 2016; Omiya et al. 2016). ducted before and after the earthquake. A comparison of such results for the seismic epicenter and the surrounding areas indicated different 6.4.2 Medical Verification changes. Although no significant changes were of MIMOSYS confirmed before and after the earthquake in other areas, regions that sustained damages from the We released the application to the general public Great East Japan Earthquake 5 years ago were to verify the effectiveness of MIMOSYS. The confirmed to have experienced changes that dif- number of downloads reached 3400 in a year and fered from those observed in any other areas. half since the release, and approximately 1000 Since no other investigations have been con- users are currently using the application. Since ducted, this is purely a speculation; however, the use of the application began, a self-assessment these changes may portray psychological changes, questionnaire (Beck Depression Inventory, BDI) such as PTSD (Tokuno et al. 2016) (Fig. 6.7). evaluation has been conducted every 3 months We compared speech evaluation with blood (Beck 1961; Beck et al. 1961). Various results biomarkers in another study. We have reported were obtained from the analysis of 1 year after that during military training conducted in an starting the research. For instance, vitality and extremely stressful environment, there is a mental activity were both lower in females than in decline in the brain-derived neurotrophic factor males; in other words, a higher depression ten- (BDNF) and the vascular endothelial growth fac- dency was confirmed for females than for males tor in the blood (Suzuki et al. 2014). Subsequently, (Fig. 6.6). The same trend was indicated by the an investigation conducted in approximately the concurrent BDI, and this result is believed to be same environment confirmed that the vitality accurate considering that there are more female scores obtained from the BDNF and MIMOSYS than with male depression patients in Japan. It and the GHQ-30 changed with the same trends also became evident that vitality and mental activ- (Tokuno 2016). ity were influenced by age, income, and even the An industrial hygiene survey derived a weak extent of obesity (Tokuno 2016). The Kumamoto correlation based on a voice-based evaluation of 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression 91

Histogram of Vitality and Mental Activity 9000 140

8000 Female 120 Female 7000 Male 100 Male 6000 ersations v 5000 80

4000 60 3000 40 2000

Number of Subject s 20 1000 Number of Con 0 0 0510 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95100 0510 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Vitality Mental Activity

Categories of Beck Depression Inventory (BDI) Score

Normal Female Mild mood disturbance Borderline clinical depression Moderate depression Male Severe depression Extreme depression

0% 20%40% 60%80% 100%

Fig. 6.6 Comparison between female and male in be more depressed. The same trend is also shown in BDI MIMOSYS analysis. Female are lower than male in both which was done at the same time (Tokuno 2016: presenta- vitality and mental activity. In other words, female tend to tion poster)

0.9 Mental Activity 0.8

0.7

0.6

0.5

0.4

0.3 Vitality 0: Pre 0.2 012012012012012012012012012 1: 0-5 days after Chugoku Chugoku Tohoku Tohoku Kyushu Kyushu 2: 6-10 days after Kanto Chubu Kinki Shikoku Shikoku (West) (East) (Others) (Centor) (West) (East) n=6n=7 n=142 n=28 n=22 n=16 n=4n=7 n=4

Fig. 6.7 Psychological impact of Kumamoto Earthquake. recovery was seen. In a little remote area from the epicen- There is a big earthquake in Kumamoto, the west part of ter, it was mutated to gradually depressive tendency after Japan, thus we investigate the effect of the disaster on the the earthquake. In areas affected by the disaster in the mind of residence. In the comparison of before and after Great East Japan Earthquake 5 years ago, tendency to earthquake, different reaction depending on the region has gradually become high was observed after the earthquake. been observed. The largest swing areas which close to the It might be affected by flashback of post-traumatic stress epicenter, initially, the mind health score is inclined to disorder (PTSD). In other areas, there was no particularly depressive tendency strongly, then it tends to be somewhat significant change (Tokuno 2016: presentation poster) 92 S. Tokuno the BDI score when comparisons were made at ** P<0.01 9 ordinary businesses using utmost care to ensure that no reporting bias was involved (Hagiwara 8 et al. 2016a, b). In some reported cases, the results of continuous monitoring with MIMOSYS 7 led to referrals of patients to industrial physicians Vitality Score (Miyazaki 2016). Continuous monitoring using 6

MIMOSYS can detect depression states that are erage Pre Post caused by stress originating from changes in the Av 5 environment associated with work, and it has 1-12 13≤ been confirmed that this can be effective in Number of Sessions implementing countermeasures against early res- Fig. 6.8 Determining the effect of stress resilience pro- ignations from work (the relevant paper is cur- gram by voice. We invited 100 SDF personnel to partici- rently being prepared). pate in the stress resilience program developed by the This system is also useful for determining the Japan Self-Defense Force and measured its effect. The effectiveness of medical interventions, and we course is 15 min per week, 5 days a week, 50 days in total. Members who participated in this course more than 13 have reported that it can also be used to deter- times showed improvement in vitality before and after the mine the efficiency of a stress resilience program course in members who participated 13 times or more (Shinohara et al. 2015; Miyazaki 2016). We implemented the stress resilience program developed by the JSDF for 100 volunteers from the of codings were compared to investigate the JSDF and measured its effect. The program con- impact of coding. These confirmed a sufficient sisted of a course of 15-min sessions 5 days every correlation between the analysis results before week for a total of 50 days. After participation in and after the coding and verified that the impact the course, a decline in the GHQ-30 was observed of coding is not very strong (the relevant paper is in personnel that participated in 13 or more ses- currently being drafted). This suggests that anal- sions (Tokuno et al. 2013). Additionally, an ysis can be performed on either the initiator or improvement in vitality was observed in person- the receiver of a telephone call. In other words, in nel who participated in 13 or more sessions cases where medical treatments are provided (Shinohara et al. 2015) (Fig. 6.8). A variety of remotely and interviews are conducted via tele- data is currently being collected to ensure that phone lines, the voice of the patient can be ana- depression screenings become more reliable and lyzed by the provider of the medical treatment. to verify the possibility of judgment of treatment This means that the same level of service can be effect by depression. provided even to patients that do not own a smartphone.

6.4.3 Engineering Verification of MIMOSYS 6.5 Remaining Challenges

Various engineering verification studies have also 6.5.1 Verification on Nonlanguage been conducted to expand the range of applica- Dependence tions of MIMOSYS. For example, voice is coded for transmissions over telephone lines. The cod- Our technology utilizes F0 and, as such, it is theo- ing includes irreversible processes focusing on retically independent of language. Since almost all the reproduction of voices that are easier to com- existing studies were conducted in Japan, no evi- prehend, which incorporates the aural character- dence of language independence exists. We there- istics of people. The analysis results of a variety fore recruited research collaborators overseas to 6 Pathophysiological Voice Analysis for Diagnosis and Monitoring of Depression 93 start joint studies for verification using multiple for the purpose of diagnosing depression. languages. Thus far, the verification has begun Parkinson’s disease and dementia are such for a limited number of languages, and we plan to examples. These ailments have overlapping increase the number of partners for joint studies symptoms in their early stages and differentia- in the future. tion can be delayed in some occasions. Additionally, MIMOSYS is affected by ailments that modify voice quality. This means that the 6.5.2 Differentiation of Depression analysis results are influenced by changes in voice quality that can occur owing to ailments MIMOSYS is a technology based on emotion that cause vocal disorders in the otolaryngologi- recognition and detects the suppression of emo- cal region or paralysis due to brain infarction, as tional manifestations due to depression. It was well as recurrent nerve paralysis. Furthermore, therefore not possible to differentiate healthy people tend to manifest less emotion as they lose individuals that were feeling unhealthy from resilience when an ailment is contracted, even if those that were in a state of depression or suffer- the ailment is different from psychological dis- ing from depression based on vitality. For this eases. A large number of ailments can coexist reason, an index referred to as “mind activity” with depression, and it is difficult to determine if was conceived by considering the continued dis- the decline in vitality or mental activity that is appearance of joy and persistence of sorrow over related to such ailments is due to the associated longer periods. However, this method has diffi- depression or the deterioration of the underlying culty in distinguishing a variety of mood disor- ailment. Furthermore, voice features that are ders. In other words, while MIMOSYS is useful characteristic to each ailment must be identified for observing the progress of rough screening or without relying on emotions to resolve such already diagnosed depression, including the issues. We are continuing our search for charac- effectiveness of treatments, it is however not pos- teristics of voices that are peculiar for such ail- sible to use mind activity to differentiate between ments and feel that we have had some solid major unipolar depression and bipolar depres- results for a number of ailments. However, fur- sion. Naturally, it would be possible to diagnose ther research must be conducted to obtain satis- a patient with bipolar disorder by follow-up factory results. observation. However, it would be more desirable to differentiate such disorders, for which treat- Conclusion ments differ, as soon as possible. We introduced voice screening and monitor- During the development of MIMOSYS, we ing technologies used at our laboratory for have been conducting research intended to dis- stress, depression states, and depression. cover feature quantities that are peculiar in cer- Based on the existing findings of our research, tain disorders directly from voices and without in February 2017, a business in the area of indus- relying on emotions. We are approaching a trial hygiene launched a service using our sys- breakthrough in discovering candidates for such tem. Similar activities are expanding throughout characteristics (Shinohara et al. 2016) and plan to the world and services are expected to be imple- report on the findings in the near future. mented in a variety of forms. Although a large number of issues still remain, we hope that research in this field will 6.5.3 Differentiation from Other continue to progress in the future. Ailments Acknowledgments I appreciate Shunji Mitsuyoshi, Shuji Shinohara, Mitsuteru Nakamura, Masakazu Besides the differentiation between major Higuchi, Yasuhiro Omiya, and Naoki Hagiwara. They are depression and bipolar depression, there are a my team and each working on research with original ideas large number of ailments that must be excluded and outstanding skills. 94 S. Tokuno

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Troy K. Chow, Sidney Kennedy, and Sakina J. Rizvi

7.1 Introduction This chapter will provide an update on the current literature of anhedonia in the context of Major depressive disorder (MDD) currently MDD. Specifically, this chapter will highlight the remains one of the leading causes of global dis- neurobiology, measurement and treatment of this ability and has significant personal, societal and core symptom of MDD. economic burden (Lam et al. 2016; World Health Traditionally, conceptualizations of anhedonia Organization 2017). MDD can be defined by a have focused on the consummatory aspect of myriad of symptoms; however, at least one of pleasure; however, this simplified definition leads two core symptoms must be present. The first of to difficulties in the precise measurement and these core symptoms, “a low mood or a feeling of study of anhedonia (Rizvi et al. 2016). Increasing sadness” is a defining symptom of MDD for neuroscientific evidence suggests anhedonia is a many. The second of these symptoms is the pres- more multi-faceted construct that involves inter- ence of anhedonia, historically characterized as a est, anticipation, motivation, effort, expectation “loss of pleasure”. More recently, anhedonia has and consummatory pleasure (Rizvi et al. 2016; received increased recognition due its potential Treadway and Zald 2011). In line with this, there contribution to the prediction of MDD diagnosis, has been an emphasis towards refining the con- treatment response and remission (McMakin struct of anhedonia and to integrate the underly- et al. 2012; Rawal et al. 2013; Uher et al. 2012). ing neurocircuitry involved in the processing of rewarding stimuli. Ultimately, any deficit in the neural processing of reward could lead to the T.K. Chow clinical symptom of anhedonia. Arthur Sommer Rotenberg Suicide and Depression Studies Unit, St. Michael’s Hospital, Toronto, ON, Canada Institute of Medical Sciences, University of Toronto, 7.2 Reward Processing Models Toronto, ON, Canada S. Kennedy • S.J. Rizvi (*) Reward processing models describe the facets of Arthur Sommer Rotenberg Suicide and Depression reward-seeking behaviour and their interactions. Studies Unit, St. Michael’s Hospital, One conceptualization of reward processing is Toronto, ON, Canada the Positive Valence System (PVS) from the Institute of Medical Sciences, University of Toronto, Research Domain Criteria (RDoC), a National Toronto, ON, Canada Institute of Mental Health framework for bio- Department of Psychiatry, University of Toronto, marker research in mental disorders (Insel et al. Toronto, ON, Canada 2010). The goal of RDoC is to utilize a dimen- e-mail: [email protected]

© Springer Nature Singapore Pte Ltd. 2018 99 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_7 100 T.K. Chow et al. sional approach across “units of analysis” (genes, to obtain the reward. Motivation describes the brain circuits, self-reports) to evaluate causes of initial energy expenditure to obtain a reward, and mental illness rather than a single predictor in effort describes the sustained energy expenditure. isolation (Hess et al. 2016; Vengeliene et al. In other words, motivation is required to start the 2017). The PVS is not a model of reward process- process of reward obtainment, and effort is ing, per se, but a suggested starting point for the required to continue this process. constructs pertinent to a reward processing model Outcome following reward can be negative, which include the ability to make a reward- positive (pleasurable) or neutral. Consummatory stimulus association, motivation, effort, expecta- pleasure describes the pleasure experienced by tion and consummatory pleasure. A model based an individual as they directly interact with a stim- on Kring and Barch (2014) has been put forth to ulus. Based on the outcomes from previous depict the associations among these constructs stimulus-reward associations, individuals (Fig. 7.1) (Rizvi et al. 2016). It is important to develop expectations of reward. These expecta- note that, while reward processing is depicted as tions may relate to whether a reward will be pres- a linear process, the facets may act in parallel or ent, the likelihood of attainment and magnitude vary according to the situation. of experienced pleasure or the effort required to Based on the Fig. 7.1 model, the reward pro- obtain it. Reward expectations may influence cess is described as initially building a stimulus- other facets of reward such as the level of antici- reward association, which then leads to interest/ pation experienced or motivation to attain a desire, anticipation, motivation, effort, hedonic reward (Rizvi et al. 2016). In particular, expecta- response and feedback integration. After a tion can also affect the original stimulus-reward reward-stimulus association has been estab- association through feedback integration, which lished, an interest in the rewarding stimulus can is the ability to utilize new information to update then develop. Importantly, interest in reward is existing knowledge of a potential reward. This important to be able to anticipate it or to develop reward learning ability is crucial to maintain a “wanting” for a reward (Rizvi et al. 2016). The accurate expectations and associations of the brain also needs to calculate the energy required stimuli for future encounters. For example, there

Stimulus

Activate Reward Association

Interest Feedback Integration

Expectation

Anticipation Pleasure/liking

Compute Effort

Motivation Expend Effort

Compute Action Plan

Fig. 7.1 Model of reward processing (Modified from Kring and Barch 2014) 7 Anhedonia and Depression 101 may be only certain contexts where a stimulus is prefrontal cortex and ventromedial prefrontal cor- rewarding or a stimulus may no longer be reward- tex are particularly involved in these processes ing at all. In addition, the value one places on a (reviewed in Treadway 2015). In addition, evi- stimulus can vary considerably by several factors dence suggests that once a stimulus has been including the time to attainment and the magni- identified as pleasurable, the anterior cingulate tude of the reward. MDD patients demonstrate cortex (ACC) is a region involved in cost-benefit deficits across these facets (reviewed in Rizvi analysis and effort-related functions required to et al. 2016; Treadway and Zald 2011; Tremblay obtain reward (Salamone et al. 2009; Treadway et al. 2005), although the specific factors and and Zald 2011; Der-Avakian and Markou 2012). conditions that contribute to these deficits need Using this information, the ventromedial PFC further exploration. Understanding the neurobi- (vmPFC) may be responsible for executing the ology associated with the reward facets can help decision to carry out the reward-directed behav- to elucidate this knowledge gap. iour (Grabenhorst and Rolls 2011). Furthermore, the vmPFC, ACC, orbitofrontal cortex and striatum may also be involved in reward processing by 7.3 The Neurobiology monitoring the rewarding properties of a stimulus of Anhedonia (Elliott et al. 2000; Seo and Lee 2007). Neurotransmitter imbalances in reward pro- Understanding the underlying neurobiological cessing have historically focused on the role of underpinnings of MDD is essential to identifying dopamine, due to its high level of expression in subtypes, biomarkers and targeted treatments. the nucleus accumbens (Salamone et al. 2003). Deficits in reward processing have been found to The ventral tegmental area (VTA) is a group of correlate with the clinical symptom of anhedonia dopaminergic neurons which supplies dopamine (reviewed in Rizvi et al. 2016) and the above to other areas in the mesocorticolimbic pathway described reward facets may have shared and dis- including the nucleus accumbens and ventral tinct neurobiological mechanisms. In support of striatum. Reduced dopamine activity can result in this idea, Whitton et al. (2015) reported that sepa- impaired reward function (Malhi and Berk 2007; rate neurobiological pathways may partially gov- Salamone et al. 2003). Exposure to pleasant stim- ern the activity of each reward facet. These uli increases dopamine activity in the ventral pathways are superimposed over brain regions striatum; however, this dopamine activity may be that are primarily in the frontal lobe, although reduced in MDD patients (Dunlop and Nemeroff other regions are also important. 2007). Interestingly, this reduced dopamine The nucleus accumbens has long been activity in the ventral striatum is correlated with acknowledged as the “pleasure centre” of the anhedonia severity, but not necessarily depres- brain and has historically been tied to anhedonia sive symptom severity (Treadway 2015). (Wong et al. 1991). However, we now have a Furthermore, anhedonia was found to correlate deeper understanding of the role of other brain with reduced ventral striatal grey matter, which regions in reward processing, which include the highlights its role in reward function (Sternat and prefrontal cortex (orbitofrontal cortex, ventrome- Katzman 2016). However, preclinical findings dial prefrontal cortex, anterior cingulate cortex), have helped to elucidate the role of dopamine as amygdala, dorsal and ventral striatum and the being more linked to anticipation and motivation insula (reviewed in Der-Avakian and Markou rather than consummatory pleasure (Salamone 2012; Treadway 2015). The prefrontal cortex, in et al. 2003; Schultz 1998). For example, animals particular, is involved in higher cognitive process- with reduced levels of dopamine may still experi- ing of reward, including reward valuation, deci- ence pleasure, but prefer low cost-low reward sion making, context integration and cost-benefit options rather than high cost-high rewards. analysis (Elliott et al. 2000; Grabenhorst and Treadway (2015) also reported that dopamine Rolls 2011). The orbitofrontal cortex, dorsolateral activity in the insula and ventral striatum had 102 T.K. Chow et al.

different effects on effort-based decision making. the nucleus accumbens in healthy controls. Taken Increased dopamine activity in the ventral stria- together, these findings suggest that opioids may tum was correlated with increased effort in a mediate motivation and pleasure responses; how- dose-dependent manner; however, the opposite ever, further studies are needed to confirm its role trend was observed in the insula. in reward processing. While substantial evidence has supported dopa- While anhedonia is a core symptom of MDD, mine’s role in anticipation, expectation, motiva- it is important to recognize that it also plays a sig- tion and effort of reward processing, the role of nificant role in schizophrenia and bipolar disorder other neurotransmitter systems is less clear. (Zhang et al. 2016). Several studies have attempted However, recent studies indicate that dopamine to elucidate the underlying neurobiology of anhe- does not act in isolation and that serotonin, gamma- donia in each of these patient groups (Sharma aminobutyric acid (GABA), glutamate and opi- et al. 2017; Whitton et al. 2015; Zhang et al. oids may play an important role in reward (McCabe 2016). However, a transdiagnostic neurobiologi- et al. 2010; Wassum et al. 2009; Wong et al. 1991). cal profile of anhedonia has yet to be completely Reduced serotonin activity has been implicated in elucidated. In order to identify a common func- the preference for immediate smaller reward than tional connectivity pattern associated with anhe- delayed greater reward in MDD. Some studies donia across disorders, Sharma et al. (2017) have suggested this may be due to increased assessed a sample of MDD, schizophrenia and impulsivity and desire for short-term gratification bipolar disorder patients. The authors performed a (Der-Avakian and Markou 2012). whole-brain resting state analysis and examined GABA is one of the most abundant neu- its relationship with the reward responsivity mea- rotransmitters in the brain and has a variety of sure on the behavioural activation scale (BAS). functions. In the context of reward, GABA has Reduced reward responsivity was associated with demonstrated modulation of dopamine activity a specific pattern of dysconnectivity surrounding and indirect effects on serotonin and noradrener- the nucleus accumbens, which was common to gic activity (Wong et al. 1991). Importantly, some MDD, schizophrenia and bipolar disorder, and neuroimaging studies have identified lowered characterized by hypoconnectivity with the GABA concentrations in the anterior ACC and default mode network (DMN). The DMN is occipital cortex of depressed patients (Gabbay primarily active during internally directed forms et al. 2012; Kugaya et al. 2003; Sanacora et al. of cognition, including memory, prospection and 1999). Interestingly, when depressed patients facets of reward processing (Sharma et al. 2017). were grouped according to the presence of anhe- Some studies have noted that increased connec- donia, only those with anhedonia had reduced tivity in the DMN was related to anhedonia GABA levels (Gabbay et al. 2012). (Hamilton et al. 2011). The specific regions in the Opioids have primarily been studied in the DMN with diminished connections to the nucleus context of pain, although there has been an accumbens included the anterior and dorsal pre- increased interest in opioid receptors in frontal cortex and the posterior cingulate cortex, MDD. The μ-opioid receptors found in the ven- which are heavily involved in reward processing tral tegmental area are implicated in the disinhi- (Sharma et al. 2017). Therefore, it is reasonable to bition of dopamine in the nucleus accumbens expect deficits in reward processing and anhedo- (Johnson and North 1992). Further, μ-opioid nia when hypoconnectivity between the DMN receptors in the amygdala may mediate the evalu- and nucleus accumbens is present. ation of a stimulus’ incentive properties (Wassum In contrast to the hypoconnectivity with the et al. 2009). MDD patients with reduced opioid DMN, the nucleus accumbens was found to dem- activity were prone to lower social motivation onstrate hyperconnectivity with the cingulo- after rejection and lower pleasure during positive opercular network, in particular with the insular interactions (Hsu et al. 2015). This motivation cortex (Sharma et al. 2017). While the role of the was positively correlated with opioid release in insula in reward is unclear, some evidence has 7 Anhedonia and Depression 103 suggested that it is involved with the effort to “first-generation” and “second-generation” ques- acquire rewards (Prevost et al. 2010; Treadway tionnaires to distinguish older versus more contem- 2015). Interestingly, imaging studies have sug- porary scales that have been developed in the last gested that decreased insula activation, as a result decade (Rizvi et al. 2016). of decreased dopamine release, may be associated with the selection of high effort reward 7.4.1.1 First-Generation Scales options (Prevost et al. 2010; Treadway 2015). In The first-generation scales mostly measure summary, several key brain regions and connec- consummatory pleasure, but some include tions have been identified in reward processing, motivational and effort components. The particularly within the prefrontal cortex. It is pos- Snaith-Hamilton Pleasure Scale (SHAPS) is a sible that a neural dysfunction in any aspect of 14-item scale designed to assess hedonic capac- reward processing could lead to the clinical ity and is the current gold standard of anhedonia symptom of anhedonia. measurement in MDD research (Snaith et al. 1995). The SHAPS presents participants with several examples of pleasurable situations that 7.4 Assessment of Anhedonia span the domains of hobbies, social life, sensory experiences and food/drink. The participants are Currently, measurement of anhedonia in clinical instructed to select the degree to which they populations is primarily through self-report would enjoy situations over the past few days. As scales and behavioural tasks. While both tools a measure of state anhedonia, the SHAPS has allow for the assessment of anhedonia, each pro- demonstrated its ability to detect acute changes vides a unique but equally important perspective in anhedonia, including treatment-related on this core symptom. In line with this, Treadway improvements. The scale has demonstrated good and Zald (2011) strongly assert that both mea- divergent and convergent validity in MDD popu- sures should be used in tandem to obtain a more lations. Furthermore, it has been shown to posi- complete understanding of anhedonia. In this tively correlate with closely related measures section, current scales and behavioural tasks will such as quality of life and function. However, the be described, along with their benefits and SHAPS is a measure of consummatory pleasure limitations. and does not probe the other facets of reward processing life effort. In addition, while the items are generalizable across samples (“I would enjoy my 7.4.1 Self-Report Scales favourite meal”), they may not be specific enough to elicit a strong hedonic reaction, thereby limit- MDD patients often display reduced interest in ing the scale’s sensitivity. While the SHAPS con- rewarding stimuli (Uher et al. 2008, 2012); tinues to demonstrate its strength in the therefore, self-report scales are particularly use- assessment of consummatory pleasure, its use in ful since they are able to directly assess anhe- tandem with other measures of anhedonia should donic symptoms (Kringelbach et al. 2012; Rizvi be considered. et al. 2016). The measurement of the explicit A similar measure of anhedonia is the Fawcett- components of anhedonia is particularly impor- Clark Pleasure Capacity Scale (FCPCS), which tant due to the subjective nature of reward behav- includes 36 items (Fawcett et al. 1983). Like the iour. Furthermore, specific activities that are SHAPS, the FCPCS solely assesses consumma- perceived as rewarding and the motivation to tory pleasure on a scale between extreme displea- obtain rewards vary between each patient. sure to extreme pleasure. The FCPCS assesses Therefore, self-report scales should ideally be pleasure across several domains including social generalizable across cultures and individuals. activities, sensory experiences and the sense of For the purposes of this chapter, current self- mastery of difficult tasks. Like the SHAPS, the report scales of anhedonia will be grouped into FCPCS has demonstrated good convergent and 104 T.K. Chow et al. divergent reliability and as a measure of state The Temporal Experience of Pleasure Scale anhedonia is capable of measuring acute changes (TEPS) was developed by Gard et al. (2006). in anhedonia due to treatment (Clark et al. 1984; Importantly, the TEPS was developed with two Leventhal et al. 2006). However, the FCPCS suf- subscales that measure anticipatory and consum- fers from a lack of generalizability due to several matory pleasure separately. In particular, the items possessing high cultural bias. Despite this, anticipatory items encompass reward responsive- the FCPCS has been validated in MDD popula- ness and imagery, while the consummatory items tions, and the items possess high internal consis- focus on appreciation of positive stimuli. The tency reliability (Leventhal et al. 2006). items are measured on a 6-point Likert scale Finally, the last two scales, the Revised which range from “very false for me” to “very Chapman Physical Anhedonia Scale (CPAS) and true for me”. Selected items focus on physical the Chapman Social Anhedonia Scale (CSAS), anhedonia as the authors believed it would pro- are designed to measure various facets of reward vide results that are more homogeneous and including motivation, effort and consummatory interpretable. Despite attempts at designing the pleasure in the context of physical anhedonia and TEPS to be more generalizable, some items are social anhedonia, respectively (Chapman et al. not applicable to all populations, such as “the 1976). Several criticisms of the CPAS and CSAS sound of crackling wood in the fireplace is very as measures of anhedonia in MDD have arisen relaxing”. While the convergent and discrimina- due to its design. Both scales were developed for tory validity have demonstrated that the subscales use in schizophrenia and thus have several items are distinct, the anticipatory subscale had low that are not applicable to MDD populations. internal consistency reliability. Furthermore, the Further, some items are not related to anhedonia, TEPS has only been validated in bipolar, schizo- such as “I have often felt uncomfortable when phrenia and opioid-dependent groups with lim- my friends touch me”. With the large number of ited studies in MDD populations (Gard et al. items for each scale, 61 on the CPAS and 40 on 2007; Garfield et al. 2016; Tso et al. 2014). Taken the CSAS, there is limited use in clinical settings. together, the TEPS may require additional valida- Furthermore, the construct and discriminant tion studies to confirm the reliability of its psy- validity of the scales have been questioned, and chometric properties and its use in MDD. some have asserted that the items are outdated The Anticipatory and Consummatory (Leventhal et al. 2006). Both scales use a binary Interpersonal Pleasure Scale (ACIPS) is a 17-item true or false answer format which hinders a more scale designed to measure social anhedonia in sensitive assessment of anhedonia. In contrast to schizophrenia and address the limitations of the the SHAPS and FCPCS, the CPAS and CSAS are CSAS (Gooding and Pflum 2014). The ACIPS measures of trait anhedonia as opposed to state uses a 6-point Likert scale as opposed to a binary anhedonia. Despite this, both measures can detect outcome. The ACIPS also includes subscales for changes in anhedonia (Leventhal et al. 2006). the anticipatory and consummatory facets of reward; however, factor analysis did not reveal 7.4.1.2 Second-Generation Scales distinct subscales. Nevertheless, when both the With the increased focus on expanding the con- CSAS and ACIPS were assessed against the struct of anhedonia beyond consummatory plea- TEPS, the ACIPS demonstrated better correlation sure, there has been recent development of with the TEPS subscales than the CSAS. Finally, anhedonia scales to reflect these changes and to despite being developed as a substitute to the address the limitations of the “first-generation” CSAS in schizophrenia, the ACIPS has not been scales. These new scales are designed to measure validated in this population. On a similar note, various facets of reward function in order to cap- the ACIPS has not been validated in MDD. Further ture a more complete understanding of anhedonia validation studies are required to assess its utility (reviewed in Rizvi et al. 2016). in several psychiatric populations and to deter- 7 Anhedonia and Depression 105 mine whether their measures of anticipation and this may not be the case. Several lines of evi- consummatory pleasure are distinct constructs. dence suggest that these experiences, while Lastly, the Dimensional Anhedonia Rating often conscious, may include an unconscious Scale (DARS) is the most recently developed component. Kringelbach et al. (2012) asserts scale by Rizvi et al. (2015). The DARS consists that at times, we may be poor at identifying our of 17-items on a 5-point Likert scale and was current emotional states. Further, he suggests designed to specifically assess anhedonia in that this may lead to an unawareness of what MDD patients. In order to increase the generaliz- motivates us, why we take interest or what ability of the scale, participants are asked to fill in brings us pleasure. Several studies have sug- personal activities or experiences they perceive gested that reward learning often occurs implic- as enjoyable across the domains of hobbies, itly. A study by Pessiglione et al. (2008) utilized social activities, food/drink and sensory experi- a behavioural task which presented healthy par- ences. With the highly subjective nature of ticipants with two cues, one associated with a rewarding experiences, this feature may allow for monetary reward and another associated with a a more sensitive measurement of anhedonia. “punishment”. As the task progressed, partici- While increasing generalizability, the DARS is pants were more prone to selecting the cues designed to maintain specificity by having a spe- associated with a reward without their aware- cific set of items for each domain assessed. ness, supporting the occurrence of implicit Within each of these domains, items to probe reward processing. Where self-reports can pro- interest, motivation, effort and consummatory vide great explicit information, behavioural pleasure are measured based on how the respon- tasks can tap into both the conscious and uncon- dent feels “now”. This measurement of state scious and as such are valuable objective mea- anhedonia has the benefit of increased sensitivity sures in the study of anhedonia. during assessment of treatment response. In contrast to the other “second-generation measures”, 7.4.2.1 Reward Association the reliability and validity of the DARS has been The ability to develop an association between a tested in a MDD population and demonstrated stimulus and reward is primarily assessed using good convergent validity with the SHAPS. The reward response bias tasks, which are based on DARS may also be useful in predicting subtypes signal detection theory (Henriques and Davidson as results from the validation study demonstrated 2000; Pizzagalli et al. 2005). Specifically, these its ability to predict treatment-resistant status tasks measure the level of “response bias”, which over the SHAPS in MDD patients. While promis- is the tendency to select the stimuli associated ing, further research into the use of the DARS is with greater rewards. In general, these tasks required to assess its test-retest viability and its involve the presentation of two or more different use in the study of the neurobiology of stimuli with specific reward contingencies, which anhedonia. can vary. Stimuli can range and include verbal or non-verbal cues. One stimulus may be neutral or associated with a punishment, or all stimuli can 7.4.2 Behavioural Tasks be associated with reward but vary in terms of frequency and/or magnitude. Oftentimes, the par- Self-report scales provide direct insight into ticipants are not informed of the specific reward experiences of anhedonia and have demon- contingencies. These tasks assess the ability of strated important utility in clinical settings; individuals to discriminate between stimuli however, they possess several limitations. While according to their rewarding properties. During many consider rewarding experiences and its behavioural tasks that assess stimulus-reward associated pleasures, motivations, interests and association, healthy individuals display a bias anticipation, an entirely conscious experience, towards rewarding stimuli (Pechtel et al. 2013). 106 T.K. Chow et al.

However, several studies have noted that this bias 7.4.2.4 Expectation is reduced in depressed individuals, which sug- Prediction error tasks assess brain activity associ- gests an impaired ability to form this association ated with changes in dopaminergic activity in the (Henriques and Davidson 2000; Pechtel et al. ventral striatum in response to outcomes that are 2013; Pizzagalli et al. 2008). different than expected (Schultz 1998; reviewed in Rizvi et al. 2016; Schultz 2013). Outcomes 7.4.2.2 Reward Valuation that are better than predicted are associated with Several factors may influence the value of a an increased burst of dopamine. In contrast, there reward, such as the size and time required to is a decrease in dopamine signaling when the out- obtain it (Green et al. 1997). Delay discounting come is worse than predicted. No changes in tasks manipulate these variables to assess how activity occur when the result is accurately pre- they affect the value one places on a reward dicted. Many variations of the task have been cre- (Kirby et al. 1999). Delay discounting describes ated, but they all involve having participants learn the situation where the value of a reward drops a certain reward contingency, which changes and as the time to obtain the reward increases (Green results in a greater or lesser reward than expected et al. 1997). Most delay discounting tasks have (Forbes et al. 2009; Kumar et al. 2008; reviewed been developed with monetary rewards which in Rizvi et al. 2016). Cohen et al. (2009) devel- may vary in size or may be fixed (Kirby et al. oped a prediction error task which was composed 1999; Pulcu et al. 2014; Richards et al. 1999). of two phases: a learning phase and a choosing The more immediate reward is always associ- phase. In the learning phase, one of two stimuli is ated with a smaller size. MDD patients often presented at one time to allow the participants to display greater discounting effects than healthy learn their reward contingencies. The “safe” controls and value immediate rewards more stimulus is rewarded 100% of the time, whereas highly despite being offered a larger, albeit rela- the “risky” stimulus has a chance of loss or gain. tively delayed reward, suggesting differences in Once completed, the participants begin the reward valuation (Dombrovski et al. 2012; choosing phase where they are presented with Pulcu et al. 2014). both stimuli and are asked to select one. MDD patients demonstrate reduced prediction error 7.4.2.3 Anticipation signal compared to healthy controls. There is also Several reward tasks designed to probe the other some evidence to suggest that MDD and schizo- facets of reward are often modified in order to phrenia patients have dysfunction in shared as measure anticipation (Knutson et al. 2008; well as disparate brain regions during prediction reviewed in Rizvi et al. 2016). These tasks are error tasks. commonly used in a neuroimaging environment. Changes in brain activity prior to the participant 7.4.2.5 Motivation obtaining the reward are used as measures of Motivation can be assessed using a cued- anticipation (Knutson et al. 2008; Kumar et al. reinforcement reaction time task which assesses 2014). The monetary incentive delay task was reaction time speed (Chase et al. 2010; Cools designed to distinguish anticipatory and consum- et al. 2005; reviewed in Rizvi et al. 2016). Cools matory facets of reward processing (Knutson et al. (2005) developed this task in order to assess et al. 2008). This task is composed of three trial the impact of reduced serotonin levels on motiva- types, a reward trial, punishment trial and notion. During the task, three circles are presented, incentive trial. Each trial is composed of an with one arranged in a different orientation. The incentive cue, target stimulus and then a feed- goal is to select the “out-of-place” circle as fast back. The goal is to press the correct button asso- as possible, with faster responses rewarding more ciated with the trial type once the target stimulus points. Prior to each trial, a coloured rectangle has been presented to increase win money or to will be presented which will signify the probabil- avoid losing money. ity of receiving a reward. MDD participants tend 7 Anhedonia and Depression 107 to be less affected by motivational cues, thus will Learning may occur through positive feedback or respond with lower reaction times than healthy negative feedback. For example, participants controls (Treadway 2015). may obtain more correct answers by focusing on positive feedback or by avoiding negative feed- 7.4.2.6 Effort back. MDD patients are more hypersensitive to Effort to obtain a reward is necessary for reward negative feedback and will often switch their decision making via a cost-benefit analysis. selection to the incorrect stimulus too soon Consequently, Treadway et al. (2012) developed (Thomson 2015). In line with this, Murphy et al. the effort-expenditure for rewards task to deter- (2003) demonstrated that MDD patients are more mine the effect of probability and reward size on likely to view a potentially rewarding stimulus as effort-based decision making. This task is com- non-rewarding shortly after any negative associa- posed of two trial types, “easy” and “hard”. Prior tion of the stimulus’ rewarding properties is to the start of the trial, the probability of receiv- received. ing the reward upon successful completion and In summary, behavioural tasks can evaluate size of the reward is listed for each trial type. The various aspects of reward processing including goal of each trial is to press a button several times response bias and learning. Importantly, most to fill a metre in a certain period. The time limit, tasks use monetary reward, instead of primary finger selection and number of button presses rewards (e.g. food, social reward). Levels of required depend on the trial type. Prior to each monetary reward may also be too small to elicit a trial, participants are to select either the low strong reward response. Future research should reward and low-cost “easy” trial or the high/low evaluate different types of reward in the above reward and high-cost “hard” trial. This was done described paradigms. in a limited amount of time to ensure that selection was based on effort calculations. As noted in several studies, MDD patients expend less effort 7.5 Treatment of Anhedonia to obtain rewards (Prevost et al. 2010; Salamone et al. 2003; Treadway et al. 2009). Treadway Currently, there are many treatment options et al. (2012) also reported that anhedonia severity available for MDD; however, the prevalence of was negatively correlated with willingness to treatment-resistant depression remains signifi- expend effort, especially when there was a low cantly high (Kennedy et al. 2016; Lam et al. probability of a reward. 2016). The inadequacy of current treatment options are highlighted in the Sequenced 7.4.2.7 Feedback Integration Treatment Alternatives to Relieve Depression Several probabilistic reversal learning tasks have (STAR*D) study (Warden et al. 2007). In this been developed to assess the effect feedback has study of over 3000 patients, participants initially on reward learning (Hasler et al. 2009; Murphy received a first-line antidepressant. If the patient et al. 2003; Taylor Tavares et al. 2008). These failed to achieve remission, they received an tasks always include the presentation of two additional antidepressant. By the fourth treat- stimuli simultaneously, both with an equal prob- ment step, 30% of patients failed to achieve ability of being associated with a reward. The remission (Warden et al. 2007). Currently, the first stimulus a participant selects will subse- serotonin and norepinephrine systems remain the quently be associated with a high probability of primary target of first-line antidepressants reward in future trials. Participants are told to (Kennedy et al. 2016). Most of these first-line select the stimulus most associated with reward treatments are selective serotonin reuptake inhib- despite any potential reward losses that may itors (SSRIs) and serotonin and norepinephrine arise. However, participants are also told that the reuptake inhibitors (SNRIs). Since dopamine and rules may reverse with the other stimulus being other neurotransmitters play a significant role in more rewarded and to then select this one. the reward system (McCabe et al. 2010; Wassum 108 T.K. Chow et al. et al. 2009; Wong et al. 1991; reviewed in Rizvi 143 patients were given agomelatine, and anhe- et al. 2016), this has important implications in donia was assessed using the SHAPS. Gargoloff MDD treatment since conventional antidepres- and colleagues reported a significant decrease in sants do not significantly target these systems. anhedonia as early as 1 week of treatment. There has been substantial evidence linking Interestingly, patients who were also on concom- anhedonia to poor treatment outcomes, including itant treatments demonstrated a delayed improve- treatment resistance (Malhi and Berk 2007; ment in anhedonia. The authors suggested that Malhi et al. 2005; Rizvi et al. 2014a, b; Souery the increase in serotonin levels by SSRIs may et al. 1999). This suggests that targeting the dopa- dampen the activity of norepinephrine and dopamine or other systems involved in anhedonia may mine, reducing their ability to improve anhedo- benefit MDD treatment. Despite being a core nia. Finally, the authors also performed a separate symptom, there are not a significant amount of analysis which compared changes in anhedonia studies conducted on the effects of antidepres- between patients experiencing their first episode sants on anhedonia. to those who are experiencing recurrent episodes. While SSRIs have demonstrated effectiveness Both groups demonstrated similar reductions in in the treatment of MDD, they have been reported anhedonia. to induce emotional blunting effects (McCabe In response to the high failure rate of first-line et al. 2009). Healthy controls treated with citalo- antidepressant monotherapy, there has been an pram had lowered emotional responses to aver- increase use of adjunctive pharmacotherapy to sive and rewarding stimuli which indicate that target specific neurotransmitter systems, which SSRIs can impact emotional range (McCabe include stimulants (e.g. methylphenidate, dextro- et al. 2009). Interestingly, when participants were amphetamine) (Kennedy et al. 2016). Rizvi et al. treated with the noradrenergic antidepressant (2014a) conducted a secondary analysis of reboxetine, they demonstrated greater response osmotic-release oral system methylphenidate to rewarding stimuli and decreased response to (OROS-MPH) to determine whether early symp- aversive stimuli (McCabe et al. 2010). tomatic improvements in apathy/anhedonia pre- Norepinephrine is associated with increased dicted increased likelihood of treatment response attention and is synthesized from dopamine compared to placebo. Using the Apathy (McCabe et al. 2010). Further, preclinical studies Evaluation Scale (AES), the authors determined in mice have demonstrated that SNRIs may be that early improvements in apathy predicted effective in minimizing the emotional blunting increased likelihood of treatment response only effects of serotonin while retaining its antide- in the active drug group and not the placebo pressant activity (Dekeyne et al. 2002). While group. These results support the notion that a per- promising, further studies are required to confirm sonalized treatment approach may be beneficial whether SNRIs are more favourable than SSRIs to alleviate specific symptoms experienced by a in the treatment of anhedonia. patient, including anhedonia. Agomelatine, a melatonergic antidepressant, Deep brain stimulation (DBS) is a neurosurgi- has demonstrated efficacy in depressioncal procedure that has recently been adapted for (Kennedy and Rizvi 2010). In addition to action use in MDD treatment and was originally used on the melatonin system, agomelatine disinhibits for the treatment of pain and movement disorders the release of norepinephrine and dopamine by (Kennedy and Giacobbe 2007). Certain brain acting as a 5-HT2c receptor antagonist. areas associated with reward have been selected Demyttenaere et al. (2013) demonstrated that as potential targets of DBS treatment in agomelatine treatment had a greater reduction in MDD. 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Seung-Gul Kang, Heon-Jeong Lee, Leen Kim, and John Weyl Winkelman

8.1 Introduction rapid eye movement (REM) density and decreased delta sleep ratio (Wichniak et al. 2013). Depressive disorders are prevalent psychiatric ill- Primary sleep disorders such as obstructive nesses, and major depressive disorder (MDD) sleep apnea (OSA) and restless legs syndrome has a lifetime prevalence of 10–15% worldwide (RLS) are also common in depression. There are (Ferrari et al. 2013). Depression is a serious ill- several possibilities for such comorbidities: (1) ness, which produces psychological distress, depression comorbid with a primary sleep disor- impairs quality of life, decreases productivity, der; (2) depression-like symptoms caused by a worsens other medical conditions, and can result primary sleep disorder; and (3) sleep-wake dis- in suicide (Gelenberg 2010). turbances, similar to those in a primary sleep dis- Sleep-wake disturbances such as insomnia order, that occur as side effects of medication and hypersomnia frequently develop during the including antidepressants. Therefore, the differ- course of depression. Such disturbances not only ential diagnosis and management of these are symptoms but also are important diagnostic conditions should be carried out carefully. This criteria for depression. In addition, sleep-wake article will also discuss the clinical treatment symptoms are associated with the biological options available for sleep-wake disturbances mechanism of depression and might be a biologi- that are comorbid with depression. cal marker for the onset, treatment response, and relapse of depression. The typical sleep structure changes that accompany depression are increased 8.2 Sleep Changes in Depression

8.2.1 Sleep-Wake Symptoms, S.-G. Kang (*) Polysomnography (PSG), Department of Psychiatry, Gil Medical Center, and Sleep College of Medicine, Gachon University, Incheon, South Korea Electroencephalography e-mail: [email protected] (EEG) Findings in Depression H.-J. Lee • L. Kim Department of Psychiatry, Korea University Medical Sleep-wake disturbances are consistent symp- Center, Korean University College of Medicine, toms associated with MDD; sleep disturbances Seoul, South Korea are reported by 60–90% of MDD patients (Abad J.W. Winkelman and Guilleminault 2005). Two-thirds of depressed Departments of Psychiatry and Neurology, patients suffer from insomnia, including initial Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA insomnia, sleep maintenance difficulty, and

terminal insomnia, while approximately 15% NREM sleep regulation. Glutamate interacts complain of hypersomnia. The relationship with cholinergic neurons and increases the activ- between sleep disturbances and depressive symp- ity of the reticular system, which is related to the toms is bidirectional since depressive episodes onset of REM sleep (Peterson and Benca 2008). can precede poor sleep and vice versa. Glutamate neurotransmission is also involved in Depressed patients complain of shallow the thalamocortical generation of sleep EEG sleep, and they show changes in their sleep struc- oscillations during NREM sleep (Pace-Schott ture. The most common findings in the polysom- and Hobson 2002; Peterson and Benca 2008). nographs of patients with depression are the Dysregulation of the hypothalamic-pituitary- following: (1) prolongation of sleep latency, adrenocortical (HPA) system has also been noted early morning awakening, reduced total sleep as a cause of depression and its sleep distur- time, and disruption of sleep maintenance, which bances. Abnormally increased activity of the includes increased waking after sleep onset and HPA system has been suggested as one of the decreased sleep efficiency; (2) REM sleep dis- core mechanisms in the pathogenesis of depres- turbances, which present as shortened REM sion (Holsboer 2000). In depression, there are sleep latency, increased REM density (frequency changes in corticotropin (adrenocorticotropic of rapid eye movements), and an increased pro- hormone—ACTH) activity, cortisol secretion, portion of REM sleep; (3) slow-wave sleep and corticotropin-releasing hormone, and thus (SWS) disturbances, which manifest as corticosteroid receptor signaling is altered decreased non-REM stage 3 (N3) and delta accordingly. This overactivity of the HPA axis activity (especially in the first 100 min of sleep) may in turn cause sleep EEG changes and (Palagini et al. 2013; Steiger and Kimura 2010; increased arousal, poor sleep, and promotion of Wichniak et al. 2000). REM sleep (Vgontzas and Chrousos 2002). The sleep disturbances in depression such as decreased SWS are also attributed to impairment 8.2.2 Biological Mechanisms of the homeostatic process S (Borbely 1987). The of Sleep Disturbances illness-related neurobiological changes and in Depression decreased daytime activity due to depression may lower the level of process S (Borbely 1987). Several hypotheses have been proposed regard- Some studies have proposed roles for genetic ing the sleep disturbances and the changes in polymorphisms and specific brain regions in REM sleep that often accompany depression. depression and insomnia. CLOCK genes, the One hypothesis is derived from neurotransmitters monoamine oxidase A gene, and the serotonin such as acetylcholine and glutamate having been transporter gene have been suggested to influence reported to be involved in this mechanism. sleep patterns and to be related to the etiology of Cholinergic (REM-on) dominance over mono- MDD and the treatment response to light therapy aminergic (REM-off) activity is one of the puta- and antidepressants (Benedetti et al. 2003; tive core mechanisms for the disinhibition of Bunney and Potkin 2008; Hu et al. 2007; Serretti REM sleep in depression (Jouvet 1972; McCarley et al. 2005). The lateral habenula, which is 1982) since cholinergic-adrenergic balance is located adjacent to the medial dorsal thalamus, is thought to play a crucial role in the etiology of also considered to be involved in the regulation depression and mania (Janowsky et al. 1972). of mood and sleep. Stimulation of the lateral This theory is further supported by a report that habenula inhibits the activity of serotonergic and the suppression of REM sleep is related to the dopaminergic neurons of the brainstem, and improvement of depression during antidepressant hyperactivity of the lateral habenula may cause treatments that enhance monoaminergic neuro- the decreased motor activity and REM sleep transmission (Vogel et al. 1990). Glutamate is changes that are characteristic of MDD (Aizawa also known to be linked to depression and REM/ et al. 2013). 8 Sleep and Sleep Disorders in Depression 115

8.3 What Does Sleep depression (Steiger and Kimura 2010), given that Disturbance Mean REM sleep measures were found not to change in Depression? between depressive episodes and remission periods (Wichniak et al. 2013). Studies have also 8.3.1 Effect of Insomnia and Sleep reported that the sensitivity of REM density as an Disturbances on the indicator for monoaminergic/cholinergic dys- Treatment Course function could be improved by using cholinergic of Depression REM sleep induction tests. Depressive patients and subjects at high risk of mood disorders Sleep disturbances and insomnia are commonly showed REM sleep changes after receiving cho- encountered during the course of depression. linergic agents such as RS 86 or arecoline (Gillin Conversely, however, sleep disturbances can et al. 1991; Riemann and Berger 1992). affect the symptoms and course of depression. Interestingly, it is common clinical knowledge MDD develops three times more often in insom- that sleep disturbances differ among depression niacs than in individuals with healthy sleep pat- subtypes. As indicated in the diagnostic criteria terns (Johnson et al. 2006). In addition, depressive for depression, seasonal affective disorder and patients with sleep disturbances show more sui- atypical depression are characterized by hyper- cidality, severe depressive symptoms, and refrac- somnia, while melancholic depression is charac- toriness to treatment for depression (Peterson and terized by terminal insomnia (American Benca 2008). From a therapeutic standpoint, Psychiatric Association 2000; Murphy and sleep deprivation is considered one of the most Peterson 2015). Therefore, the characteristics of rapid therapies for depressive patients, although sleep disturbances might be helpful in subtyping the treatment effect is temporary (Wichniak et al. depression. 2013). Moreover, suppression of REM sleep is considered to be related to the improvement of depression during antidepressant treatment 8.3.3 Sleep as a Biomarker (Vogel et al. 1990). Synchronization of the circa- for Treatment Response dian rhythm in depression has also been reported and the Relapse of Depression as a necessary prerequisite for better recovery from depression (Hajak and Landgrebe 2010). Sleep disturbances and PSG findings could be biomarkers not only for depression onset but also for treatment response and relapse. Persistent 8.3.2 Sleep as a Biomarker insomnia is a strong predictor of future relapse, for Depression even without current mood symptoms (Benca and Peterson 2008). Residual hypersomnia is Sleep disturbances and related PSG findings have also known to be associated with an increased been recognized as biomarkers for depression. A risk of relapse of depression (Kaplan and Harvey meta-analysis reported that patients with insom- 2009). Abnormal PSG measures have been nia without depression have twice as high a risk regarded as a biomarker, which suggests the of developing incident depression as individuals advantage of a biological treatment over a psy- without sleep problems (Baglioni et al. 2011). In chological approach, since 3/4 of nonresponders an earlier study, subjects at high risk of depres- to psychotherapy went into remission after sub- sion (i.e., healthy first-degree relatives of patients sequent pharmacotherapy (Thase et al. 1997). with mood disorders) showed an abnormally Since a change in REM density is the most increased REM density and decreased SWS replicated finding, this could be a valuable bio- amount (Lauer et al. 1995). In addition to this, marker for treatment outcome or recurrence changes in sleep parameters have been consid- (Wichniak et al. 2013). High REM density after ered trait markers rather than state markers for 1 week of paroxetine treatment has been related 116 S.-G. Kang et al. to non-response after 6 weeks (Murck et al. activity, to irregular activity patterns, and to the 2003). In addition, increased REM density and effect of medication such as antidepressants. In decreased total sleep time at 2–4 weeks of absti- this case, the refractoriness of depression to treat- nence from alcohol predicted relapse during the ment becomes worse (Schroder and O'Hara first 3 months in depressed alcoholic patients 2005). Some also hold the idea that OSA and (Clark et al. 1998). One study suggested that MDD share a common etiology. An imaging REM activity and density in participants with study has shown that the hypoxemia from OSA depression are correlated with remission and has an impact on mood symptoms (Kamba et al. recovery and that quantitative measurement of 1997), and the reverse mechanism is that reduced rapid eye movements provides a better correlate serotonin levels in depression lead to loss of mus- of treatment response than do quantitative sleep cle tone of the upper airway dilator muscles and EEG measures (Buysse et al. 2001). could contribute to the development of OSA Slow-wave activity (SWA) in the delta fre- (Lipford et al. 2016). quency band of an EEG during sleep has also RLS is also a common neurological disease and been reported to be related to treatment response. a distressing sleep disorder. Its core symptoms are An increase in SWA has been reported to be cor- restlessness in the legs and an urge to move the related with treatment response to clomipramine legs. According to published studies, 26% of (Kupfer et al. 1989). A low delta ratio and less patients with unipolar depression show RLS symp- delta EEG activity at baseline and remission have toms, and the odds ratio of RLS symptoms was also been found to be related to depression recur- found to be 1.64 in adults with depression (Foley rence after the discontinuation of antidepressants et al. 2004; Picchietti and Winkelman 2005). The (Buysse et al. 1997; Kupfer et al. 1990). Spectral comorbidity of RLS with depression could be analysis has shown that the delta sleep ratio based attributed to dopamine hypofunction. Decreased on quantitative EEG is a stronger predictor of the dopamine function is one of the most frequently recurrence of depressive episodes than is REM proposed etiologies of RLS and could also induce latency (Kupfer et al. 1990). depression (Picchietti and Winkelman 2005). On the other hand, antidepressants could underlie the increased prevalence of RLS and periodic limb 8.4 Comorbid Primary Sleep movements during sleep (PLMS) in depressed Disorders Other than patients (Picchietti and Winkelman 2005). Insomnia REM sleep behavior disorder (RBD) is commonly caused by antidepressants during the course In depression, primary sleep disorders other than of pharmacotherapy of depression, especially in insomnia are also common. In some cases, the older people. Probable RBD is significantly associ- primary sleep disorder may cause depression or ated with depression, and the odds ratio of depres- has depression-like symptoms. Therefore, in the sion in RBD was found to be 2.99 (Mahlknecht case of atypical depression, more attention should et al. 2015). Participants who take antidepressants be paid to differential diagnosis. have also been found to have greater EMG activity Depression is common in patients with OSA. in the submentalis muscle during REM than do In one study, the odds ratio of MDD in patients controls, and dream enactment symptoms have with OSA was 2.4 in male subjects and 5.2 in been found to develop in up to 6% of subjects tak- female subjects (Wheaton et al. 2012). OSA can ing antidepressants (Ju et al. 2011; Teman et al. induce depression-like symptoms such as fatigue, 2009; Winkelman and James 2004). hypersomnolence, difficulty concentrating, and Hypersomnia and hypersomnolence some- lack of energy (Schroder and O'Hara 2005). The times appear in depression. In some cases, these converse is also true, in that OSA occurs fre- symptoms are more prominent than depressive quently in depression (Reynolds et al. 1985), symptoms, so it is necessary to differentiate this which may due to weight gain caused by decreased condition from sleep-wake disorders such as 8 Sleep and Sleep Disorders in Depression 117 narcolepsy. Depression may be accompanied by (Wichniak et al. 2012). Agomelatine is an agonist narcolepsy. The cause of narcolepsy with cata- of the melatonin MT1 and MT2 receptors and has plexy is known to be hypocretin deficiency, and antagonistic action on the serotonin 5-HT2C hypocretin projections may be involved in mood receptor. Agomelatine is also known to improve regulation, given that the hypocretin neural cir- sleep measurements such as sleep efficiency and cuit projects broadly to the locus ceruleus, raphe SWS and not to change the latency or duration of nucleus, and limbic area (Dauvilliers et al. REM sleep (Quera-Salva et al. 2010). 2013). According to an epidemiological study, In chronic use of antidepressants, the afore- 19.2% of narcoleptic patients have MDD, while mentioned acute effect on sleep and sleep struc- 6.4% of the general population have MDD ture is alleviated, and beneficial effects on sleep (Ohayon 2013). such as increased sleep continuity and amount of SWS can occur as the depressive symptoms are relieved and daytime activity is increased (Wilson 8.5 Treatment of Sleep and Argyropoulos 2005). In addition, even non- Disturbances in Depression sedating antidepressants might play a role in improving subjective sleep symptoms by reliev- 8.5.1 Pharmacotherapy ing tension, anxiety, worry, and cognitive distor- tion about sleep, which are common in patients Antidepressants have diverse effects on sleep and with chronic insomnia (Nowell et al. 1999). sleep structure. In fact, in depression, the struc- However, studies have shown that during mainte- ture and other parameters of sleep usually change nance therapy with activating antidepressants, more by antidepressants than do subjective sleep- 30–40% of patients may continue to experience wake symptoms (Wichniak et al. 2013). insomnia (Iovieno et al. 2011). In this case, Antidepressant use acutely and strongly sup- monotherapy with sedative antidepressants (e.g., presses REM sleep. In particular, antidepressants trazodone and mirtazapine) or combination ther- that block serotonin reuptake have a strong effect apy with low-dose sedative antidepressants and on REM sleep (Wilson and Argyropoulos 2005). SSRIs might be useful (Jindal et al. 2003; Jindal However, antidepressants can have a variety of and Thase 2004; Wichniak et al. 2012). However, effects on sleep depending on the type. Tricyclic little controlled evidence supports the long-term antidepressants (TCAs, e.g., amitriptyline and usage of sedative antidepressants (e.g., mirtazap- doxepin), noradrenergic and specific serotonergic ine, trimipramine, and amitriptyline) for insom- antidepressants (NaSSAs, e.g., mirtazapine), and nia symptoms (Kurian et al. 2009), and side serotonin receptor 5-HT2 antagonists and reup- effects such as excessive sedation and weight take inhibitors (SARIs, e.g., trazodone) are seda- gain should be considered. Antidepressants also tive antidepressants, and they induce sleep exert various potentially harmful effects on sleep through antagonistic action on the serotonergic by inducing (or aggravating) RLS symptoms,

5-HT2A and histamine H1 receptors (Wichniak PLMS, weight gain and related sleep apnea risk, et al. 2013). On the other hand, antidepressants and RBD symptoms. that increase noradrenergic and dopaminergic Although combination pharmacotherapy neurotransmission are classified as activating using hypnotics such as zolpidem, zaleplon, antidepressants. Serotonin and norepinephrine eszopiclone, or benzodiazepines with antidepres- reuptake inhibitors (SNRIs, e.g., venlafaxine and sants may improve the patient’s sleep, daytime duloxetine) and norepinephrine and dopamine functioning, and quality of life (Franzen and reuptake inhibitors (NDRIs, e.g., bupropion) are Buysse 2008), clinicians should carefully con- representative activating antidepressants. Selective sider the risks of dependence and tolerance to serotonin reuptake inhibitors (SSRIs, e.g., fluox- hypnotics (Murphy and Peterson 2015). In addi- etine) can also induce sleep disruption through tion, benzodiazepines are shown to attenuate the activation of serotonin 5-HT2 receptors slow-wave activity and to enhance sleep spindles 118 S.-G. Kang et al.

(Achermann and Borbely 1987), and non- CBT-I elements include distraction techniques, benzodiazepine hypnotics such as zolpidem and cognitive restructuring, and paradoxical inten- zopiclone show similar unfavorable effects on tion. Cognitive restructuring addresses the sleep EEG, though the clinical implications of patient’s negative and dysfunctional beliefs about these findings are unclear (Landolt et al. 2000). sleep. Paradoxical intention consists of reducing Patients with depression who are suffering worry about negative effects due to poor sleep by from serious hypersomnia or hypersomnolence staying awake intentionally at night (Perlis et al. could be candidates for the use of modafinil or 2010). There are several different relaxation ther- psychostimulants if the symptoms persist after apies, including progressive muscle relaxation treatment of any primary sleep disorders such as therapy and diaphragmatic breathing (Perlis et al. OSA (Peterson and Benca 2008). 2010). Some patients with depression fail to adhere to CBT-I because of motivational deficits, avoid- 8.5.2 Cognitive Behavioral Therapy ance, and automatic negative thoughts. In addi- for Insomnia (CBT-I) tion, insomnia patients with depression have worse sleep hygiene, more mental arousal at bed- CBT-I is the treatment of choice for chronic time, and more dysfunctional beliefs about sleep insomnia, and it is also effective for the treatment than do insomnia patients without depression of insomnia comorbid with depression (Espie (Carney et al. 2007). Therefore, it is recom- 1999). In one study, when CBT-I was combined mended that CBT-I therapy also include the ele- with escitalopram, greater remission from both ments of CBT for depression in the depressive insomnia and depressive symptoms was achieved population (Haynes 2015). Cognitive behavioral than with escitalopram alone (Manber et al. social rhythm therapy (CBSRT), which was 2008). According to another study, patients who designed to improve mood and sleep by stabiliz- were treated with brief behavioral therapy for ing social rhythms and changing dysfunctional insomnia in addition to antidepressant therapy bed associations, might be useful for insomnia showed greater improvements in sleep quality patients with depression or post-traumatic stress and depression, and they showed greater remis- disorder (Haynes 2015; Haynes et al. 2016). sion of depression after 8 weeks than did a treatment group receiving only antidepressants (Watanabe et al. 2011). Moreover, several studies 8.5.3 Sleep Deprivation and Light have shown that CBT-I is efficacious in insomnia Therapy patients with depression, as well as in those without depression (Edinger et al. 2009; Hamoen Sleep deprivation is the fastest-acting treatment et al. 2014). for depression and has comparable short-term Sleep restriction therapy and stimulus control efficacy to antidepressants. According to a meta- therapy are two core behavioral treatment com- analysis, total sleep deprivation led to a transient ponents of CBT-I. Sleep restriction, which is a improvement in mood in 50–60% of depressive typical treatment component of CBT-I, consists patients (Wu and Bunney 1990). Partial sleep of curtailing the amount of time in bed to the total deprivation also produced mild to moderate subjective sleep time of insomnia patients. improvements in depression scores (Benedetti Stimulus control techniques, which constitute and Colombo 2011) that persisted longer than another important treatment component, are those from total sleep deprivation, although the intended to reduce the conditioned arousal or therapeutic effect was rather weak (Giedke and performance anxiety related to sleep at night. To Schwarzler 2002). Regardless, the effect of sleep reassociate the bed with sleep, patients should go deprivation is not sustained, and the effect is lost to bed only when sleepy and get out of bed when after recovery sleep. Although the clinical effi- unable to sleep (Bootzin et al. 2010). Other cacy has not yet been established, the effects of 8 Sleep and Sleep Disorders in Depression 119 combination therapy consisting of light therapy American Psychiatric Association. Diagnostic criteria in the morning and sleep deprivation might be from DSM-IV-TR. Washington: American Psychiatric Association; 2000. stronger and longer lasting (Murphy and Peterson Baglioni C, Battagliese G, Feige B, Spiegelhalder K, 2015). This combination therapy may have a sim- Nissen C, Voderholzer U, et al. Insomnia as a predic- ilar effect to sleep time restriction, especially for tor of depression: a meta-analytic evaluation of lon- depressive patients with insomnia who spend a gitudinal epidemiological studies. J Affect Disord. 2011;135:10–9. long time in bed owing to decreased motivation Benca RM, Peterson MJ. Insomnia and depression. Sleep and energy. Med. 2008;9(Suppl 1):S3–9. Benedetti F, Colombo C. Sleep deprivation in mood disorders. Neuropsychobiology. 2011;64:141–51. Conclusion Benedetti F, Colombo C, Serretti A, Lorenzi C, Pontiggia Sleep-wake disturbances not only are preva- A, Barbini B, et al. Antidepressant effects of light ther- lent symptoms of depression but also are a apy combined with sleep deprivation are influenced biological marker for depression. Primary by a functional polymorphism within the promoter sleep disorders such as OSA, RLS, and RBD of the serotonin transporter gene. Biol Psychiatry. 2003;54:687–92. are also prevalent in depression. During Bootzin RR, Smith LJ, Franzen PL, Shapiro SL. Stimulus depression, the sleep structure frequently control therapy. In: Sateia DJ, Buysse DJ, editors. changes because of the depression itself and Insomnia: diagnosis and treatment. London: Informa the medications that are prescribed for depres- Healthcare; 2010. p. 268–76. Borbely AA. The S-deficiency hypothesis of depression. Antidepressants can have a variety of sion and the two-process model of sleep regulation. effects on sleep depending on their mecha- Pharmacopsychiatry. 1987;20:23–9. nism and characteristics. To treat insomnia Bunney JN, Potkin SG. Circadian abnormalities, molecu- associated with depression, antidepressants, lar clock genes and chronobiological treatments in depression. Br Med Bull. 2008;86:23–32. hypnotics, and CBT-I can be used effectively. Buysse DJ, Frank E, Lowe KK, Cherry CR, Kupfer For depressed patients with persistent insom- DJ. Electroencephalographic sleep correlates of epi- nia, monotherapy with sedative antidepres- sode and vulnerability to recurrence in depression. sants (e.g., trazodone or mirtazapine) or Biol Psychiatry. 1997;41:406–18. Buysse DJ, Hall M, Begley A, Cherry CR, Houck PR, combination therapy with low-dose sedative Land S, et al. Sleep and treatment response in depres- antidepressants and SSRIs might be useful. sion: new findings using power spectral analysis. CBT-I, which is the treatment of choice for Psychiatry Res. 2001;103:51–67. chronic insomnia, is also effective for the Carney CE, Edinger JD, Manber R, Garson C, Segal ZV. Beliefs about sleep in disorders characterized treatment of insomnia comorbid with by sleep and mood disturbance. J Psychosom Res. depression. 2007;62:179–88. Clark CP, Gillin JC, Golshan S, Demodena A, Smith TL, Danowski S, et al. 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Pierre A. Geoffroy and Sunthavy Yeim

9.1 Introduction present with remission (Rush et al. 2006). In this context, new treatment options are necessary and Major depressive disorder (MDD) affects more highly expected. than 5% of the general population with a lifetime Treatments acting on sleep and circadian prevalence about 14% (Waraich et al. 2004). This rhythms are promising antidepressant treatments. is such a leading public health problem that MDD Indeed, such treatments may relieve numerous is ranked as the second worldwide cause of dis- sleep homeostasis abnormalities and circadian ability, associating decreased quality of life and rhythm disruptions that are observed from the an increased mortality (Ferrari et al. 2013; molecular to the behavioral level in MDD Whiteford et al. 2013). “Traditional” treatments (McClung 2011, 2013). Some of the characteris- for MDD are antidepressant drugs and psychotic symptoms reported in MDD are delayed sleep therapies. Unfortunately, remission rates are low onset, non-restful sleep, early-morning waken- despite good adherence of patients and the wide ing, daytime fatigue, and blunting or reversal of range of existing antidepressant drugs. For the normal morning peaks in subjective energy, instance, the large STAR-D study observed that mood, and alertness (Hickie and Rogers 2011). only one out of three patients respond to the first- These symptoms may persist during remitted line antidepressant treatment, and, after four lines phases and are associated with depressive recur- of treatments, only 67% of all patients manage to rences but also a poor global functioning, a

P.A. Geoffroy (*) S. Yeim Inserm, U1144, Paris, France Inserm, U1144, Paris, France Université Paris Descartes, UMR-S 1144, Université Paris Descartes, UMR-S 1144, Paris, France Paris, France Université Paris Diderot, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, France UMR-S 1144, Paris, France AP-HP, GH Saint-Louis—Lariboisière—F. Widal, AP-HP, GH Saint-Louis—Lariboisière—F. Widal, Pôle de Psychiatrie et de Médecine Addictologique, Pôle de Psychiatrie et de Médecine Addictologique, Paris, France Paris, France Fondation FondaMental, Créteil, France Neurosciences Department, Hôpital Fernand Widal, Paris, France e-mail: [email protected]

© Springer Nature Singapore Pte Ltd. 2018 123 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_9 124 P.A. Geoffroy and S. Yeim decrease quality of life, and an increased risk of observed that morning exposures with BLT metabolic syndrome (Sylvia et al. 2012; Kaplan (inducing phase advance of circadian rhythms) is et al. 2011; Jackson et al. 2003). Thus chrono- more efficient in reducing depressive symptoms therapies that aimed to (re)synchronize and stabi- than evening BLT (inducing phase delay) (Sack lize biological rhythms (including sleep/wake et al. 1990). Moreover, this action on circadian patterns), such as bright light therapy, melatonin rhythms of phase advance may not be the sole and its agonists, sleep deprivation, and social explanation of its antidepressant efficacy, as rhythm therapies, may be useful treatments in phase advance has not consistently been corre- MDD (Germain and Kupfer 2008). lated with therapeutic response (Lewy et al. 2006; Skene and Arendt 2006; Burgess et al. 2004). BLT seems to also directly act on monoaminergic 9.2 Bright Light Therapy transmissions. Indeed, it has been demonstrated that a quick serotonin and catecholamine deple- 9.2.1 Why Use Bright Light Therapy tion may reverse antidepressant effects of BLT in in MDD? SAD (Neumeister et al. 1998). So BLT seems to have both an indirect action on MDD symptoms First, we should remind that bright light therapy by a resynchronization of circadian rhythms and (BLT), also named phototherapy, is the first-line a direct action on monoaminergic dysfunctions. treatment for MDD with seasonal patterns. Its effi- A recent meta-analysis of randomized con- cacy is well demonstrated and equivalent to typical trolled trials (RCTs) confirmed that BLT is effec- antidepressants like selective serotonin reuptake tive in treating seasonal MDD with a comparable inhibitors (SSRIs) (Nussbaumer et al. 2015). BLT effect size to antidepressant pharmacotherapies (8 is thus the cornerstone treatment of seasonal affec- studies, effect size = 0.84, 95% confidence inter- tive disorders (SAD). Interestingly, it has been val = 0.60–1.08) (Golden et al. 2005) but also in recently demonstrated that BLT may also be useful treating in nonseasonal MDD (3 studies, effect in nonseasonal MDD. Indeed, BLT appeared effi- size = 0.53, 95% CI = 0.18–0.89). Moreover, cacious and well tolerated in the treatment of dawn simulation appears also effective in sea- adults with nonseasonal MDD, of moderate to sonal MDD (5 studies, effect size = 0.73, 95% severe intensity, with an effect size equal or supe- CI = 0.37–1.08) (Golden et al. 2005). Nevertheless, rior to SSRIs (Golden et al. 2005; Lam et al. 2016). this meta-analysis does not inform about the uni- First evidence of BLT efficacy comes from a polar or bipolar profile of patients included. case series recently published in 1984 by However, some specificities linked to bipolar dis- Rosenthal and colleagues (Rosenthal et al. 1984). orders (BD), such as the manic switch, warrant Artificial bright light appeared more effective evidence-based therapeutic guidelines and so than dim light but also showed the effects of deserve more studies in BD (Geoffroy et al. lengthening the photoperiod (defined as the 2015b). Finally, in MDD, the combination of BLT length of light period during a night/day cycle) and SSRIs may be superior to both monotherapies and suppressing the melatonin secretion (i.e., the (Lam et al. 2016), and BLT antidepressant effects sleep hormone that may have a depressive role) appeared sooner in seasonal (1–2 weeks) than in (Rosenthal et al. 1984). The antidepressant effect nonseasonal (4 weeks) MDD (Lam et al. 2016). of BLT may come from its action on serotoninergic and catecholaminergic systems but also via an action on circadian rhythms by advancing the 9.2.2 How to Treat with Bright Light phase when using BLT in the morning (Lam et al. Therapy? 1996; Neumeister et al. 1998; Lewy et al. 1987). These actions lead to a resynchronization of cir- The BLT use a device that produces a fluorescent cadian rhythms and restore monoaminergic dys- light between 2000 and 10,000 lux and must have functions (Lewy et al. 2006). Indeed, it has been an ultraviolet filter to protect retina (Sohn and 9 Chronobiology and Treatment in Depression 125

Lam 2004). There are several kinds of BLT How often and how long? The therapeutic devices available, and a particular attention is response to BLT is generally quick (1–2 weeks), needed to the quality of the device (international especially in seasonal MDD. BLT should be medical norms like 93/42/CEE). Standard BLT daily used and the treatment should include a and dawn simulation devices have well demon- minimum of 4-day exposure to at least 3000 lux strated their efficacy (Golden et al. 2005). The in 1 h (or 1500 lux in 2 h) (Golden et al. 2005). light intensity to use for antidepressant effects It should be noted that a relapse can occur depend on the length exposition. A similar effect quickly upon discontinuation of BLT, and it is is recognized for the following expositions: 2 h at therefore advisable in these cases to continue 2000 lux, 1 h at 5000 lux, and 30 min at 10,000 BLT exposition until the period of natural remis- lux (Tam et al. 1995). For a maximal exposition sion in the situation of seasonal MDD. A strat- at 10,000 lux for 30 min, the BLT device should egy for introducing preventive BLT is also be placed at 30 cm from the subject and at eye indicated for the following year during the at- level (Terman and Terman 2005). The goal is for risk period. retina photoreceptors to benefit from a direct What are the side effects of BLT? Possible exposition to BLT. side effects of light therapy include headache, When using BLT? It is well demonstrated that eye fatigue, nausea, and restlessness (Levitt et al. a morning exposure is the most effective in MDD 1993; Labbate et al. 1994; Terman and Terman (Sohn and Lam 2004). Indeed, the antidepressant 1999). Furthermore, there does not seem to be effect of BLT is demonstrated to be potentiated any retinal toxicity associated with luminother- by early-morning administration in circadian apy (Gallin et al. 1995). It is also well established, time, optimally about 8.5 h after melatonin onset as previously mentioned, that BLT, like pharma- or 2.5 h after the sleep midpoint (Terman et al. cological antidepressants, can induce manic 2001). For instance, a BLT exposition 7.5–9.5 h switch in patients with BD or at risk to BD after melatonin onset allows to double the antide- (Kantor et al. 1991; Chan et al. 1994). The most pressant response in comparison to an exposition important strategy in BD is thus to use BLT only 9.5–11 h after this melatonin onset (remission with a mood stabilizer at therapeutic dosage, as rates of 80% and 40% respectively) (Terman for all antidepressants, especially in patients with et al. 2001). Also, these scientific data may be BD I subtype (Sohn and Lam 2004; Golden et al. difficult to translate in clinical practice with such 2005). Regarding the type mood stabilizers, there precision. Nevertheless, the Composite Scale of are no solid data, but lithium seems to have a par- Morningness (CSM) (Greenwood 1994; Caci ticular efficacy in reducing seasonal depressive et al. 2000) or the questionnaire of Horne and symptoms (Sakamoto et al. 1995; Faedda et al. Ostberg (1976)), for instance, may be used in 1993). Another therapeutic adaptation in BD may clinical practice to adapt the schedule of exposi- be to shift the schedule of exposure to light ther- tion to BLT. Indeed, it has been observed that the apy, for example, at midday, in case of tachypsy- total score from these scales is correlated to the chia, logorrhea, increased energy and activities, nocturnal melatonin secretion (Terman and irritability, or aggressiveness (Sit et al. 2007; Terman 2005). In routine, it is possible to pro- Leibenluft et al. 1995). Finally, BLT may precipi- pose the use of BLT directly when the subject tate or aggravate suicidal thoughts sporadically wakes up at fixed time. Lastly, in patients with (Praschak-Rieder et al. 1997) but appears to have BD, it should be safer to avoid too early exposi- a protective antisuicidal effect in the majority of tions to diminish the risk of manic switch patients (Lam et al. 2000) both in unipolar (Geoffroy et al. 2015b; Sit et al. 2007). For at-risk (Sahlem et al. 2014) and bipolar patients subjects, a midday exposition (noon) should be (Benedetti et al. 2014). the start of the BLT, and then exposures may be Table 9.1 summarizes some of these guide- advanced in the situation of antidepressant inef- lines for using BLT in seasonal or nonseasonal ficacy (Terman and Terman 2005). MDD. 126 P.A. Geoffroy and S. Yeim

Table 9.1 Utilization of bright light therapy (BLT) in seasonal or nonseasonal depression Bright light therapy in seasonal or nonseasonal depression Therapeutic light flux 2000–10,000 lux Light devices Bright light or dawn simulators Time/lux 30 min—10,000 lux or 2 h—2000 lux or 1 h—5000 lux If bipolar disorder: increase gradually starting with 15 min Position Lamp at eye level Distance of about 30 cm Direct exposure Frequency Daily 7 days a week Time of the day Morning (when get up) Fixed hours If bipolar disorder: begin at midday, with progressively advanced schedule if ineffectiveness (Avoid schedules too early to prevent the manic switch) Time to response From 1 to 2 weeks Treatment duration Until reduction of depressive symptoms or until the period of natural remission if relapse at the stop (if seasonal depression) Prevention BLT a few weeks before the usual seasonal depressive relapse Preventing manic switch If bipolar disorder: BLT only with a mood stabilizer Monitoring side effects Headache, eyestrain, nausea, agitation, and manic switch

9.3 Melatonin dopaminergic, and noradrenergic neurotransmitters regulate mood and follow circadian rhythms 9.3.1 Melatonin Physiology in their secretion, catabolism, and expression of and Effects their receptors (Milhiet et al. 2014). The synthesis of melatonin in the pineal gland derives also Melatonin is considered as the “sleep hormone” directly from the catabolism of serotonin because it promotes sleep (as it lowers central (Takahashi et al. 2008). This synthesis of melato- temperature and alertness) and is secreted at nin from serotonin is regulated and synchronized night by the pineal gland, following circadian by suprachiasmatic nuclei (SCN), which are the rhythms, in response to day/night cycles central “pacemaker” of circadian rhythms (Claustrat et al. 2005; Claustrat 2009). In addi- (Takahashi et al. 2008). It has also been observed tion, melatonin, even at the small physiological that serotonin metabolites, such as tryptophan or dose, may lead to phase advance or delay (e.g., 5-hydroxyindoleacetic acid (5-HIAA), exhibit advance or delay of sleep/wake cycles) depend- circadian fluctuations in their concentration ing on when it is administered in relation to its (Kennedy et al. 2002). Indeed, tryptophan shows response curve—i.e., before or after the central an increase in overnight rates and a decrease at temperature dip (Lewy et al. 2006). Melatonin, or midday (Kennedy et al. 2002). It has also been its agonists, binds to its specific melatonergic demonstrated that therapeutic doses (well above receptors (MT1 and MT2). Melatonin acts, at the physiological doses) of melatonin result in the molecular level, by stabilizing the circadian inhibition of serotonin reuptake in platelets rhythms of the neurotransmitter systems involved (Valevski et al. 1995). In addition, dopamine has in the pathophysiology of depression and sleep/ a major role in circadian rhythms, especially in wake cycles (Anderson et al. 2016). Serotonergic, the retina as a chemical messenger of adaptations 9 Chronobiology and Treatment in Depression 127 to light (Witkovsky 2004). During this process, effects (Kopp et al. 1999). This contrasts with the amacrine cells of the retina release dopamine data in humans which tends rather to show that which activates in return the dopaminergic recep- melatonin in monotherapy does not appear to be tors located throughout the retina (Witkovsky sufficiently effective in MDD (Carman et al. 2004). The noradrenergic neurotransmission is 1976), even if this is associated with improved also involved in these processes. Indeed, the sleep and stabilization of sleep/wake rhythms maximum concentrations of melatonin and its (Dalton et al. 2000). However, melatonin mono- enzyme arylalkylamine N-acetyltransferase therapy demonstrated efficacy in the treatment of (AANAT) are related to changes in the beta- MDD when a phase delay syndrome is associated adrenergic receptor activity of the pineal gland (Rahman et al. 2010). In addition, the use of mel- (Yocca et al. 1983), where the noradrenaline atonin as an adjunctive treatment to traditional appears necessary to synthesize the melatonin antidepressant strategies appears to potentiate the secreted by the pineal gland (Simonneaux and effect of these antidepressants effectively (Wirz- Ribelayga 2003). Justice 2009). Same observations are made for In conclusion, melatonin levels and its circa- melatonin agonists, which improve sleep quality, dian secretion, through serotonergic, dopaminer- are effective treatment of insomnia and phase gic, and noradrenergic systems, are directly delay syndrome (Lemoine et al. 2007; Roth et al. involved in the regulation of mood via the retino- 2006; Rajaratnam et al. 2009; Reynolds et al. hypothalamic-pineal tract. 2005). In the bipolar MDD, melatonin and its agonists also appear to be useful as adjuvant antidepressant therapies when there is a complaint of 9.3.2 Why Melatonin May Be Useful insomnia or a phase delay syndrome (Geoffroy in Depression? et al. 2015a). Agomelatine has a special place in these anti- Interestingly, the exogenous melatonin has shown depressant strategies as, in addition to being a efficacy in (1) treating chronic insomnia with selective melatonin receptor agonist (MT1 and modest efficacy (Buscemi et al. 2005; Ferracioli- MT2), it acts as a serotonin receptor antagonist Oda et al. 2013); (2) treating phase delay syn- (5-HT2B and 5-HT2C) (Millan et al. 2003). drome, where it is part of the therapeutic Agomelatine, at doses of 25–50 mg, demon- recommendations (van Geijlswijk et al. 2010); strated a chronobiotic effect (almost similar to and (3) improving sleep quality on a set of objec- melatonin) but also clinically significant antide- tive parameters such as sleep latency and total pressant and anxiolytic effects in humans (Hickie sleep time (Ferracioli-Oda et al. 2013). Melatonin and Rogers 2011; Dubovsky and Warren 2009; also showed an interest in psychiatry as an de Bodinat et al. 2010; Lôo et al. 2002). A recent adjunctive treatment for children with autism meta-analysis confirmed these effects by analyz- spectrum disorders to improve sleep and behav- ing 20 published and unpublished studies demon- ioral disturbances (Rossignol and Frye 2011; strating that agomelatine in MDD treatment is Doyen et al. 2011; Cortesi et al. 2010). Finally, more effective than placebo and equivalent to melatonin appears useful in remitted BD (euthy- other pharmacological antidepressants (Taylor mic) to prevent mood relapse when a complaint et al. 2014). This antidepressant effect of agomel- of insomnia, poor quality of sleep, or phase delay atine appears to be sustained over the long term. syndrome is associated (Geoffroy et al. 2015a). However, it should be highlighted that there are But is melatonin effective as an antidepres- few studies with often weak methodological sant? The scientific data are less robust here, at qualities (Guaiana et al. 2013). Agomelatine least in monotherapy use on mood symptoms. appears to have less side effects than conventional Nevertheless, melatonin has shown antidepres- pharmacological antidepressants because it does sant properties in animals (Rogers et al. 2003), as not stimulate the 5HT-2A serotonergic receptor, well as a decrease in chronic stress-related side which is responsible for sexual dysfunction and 128 P.A. Geoffroy and S. Yeim gastrointestinal disturbances. However, it is episode in elder patients (Wehr 1990; Wu and important to note that there is a possible hepato- Bunney 1990; Cole and Muller 1976; Leibenluft toxicity of agomelatine (Gahr et al. 2013, 2014). and Wehr 1992; Wirz-Justice and Van den This hepatotoxicity resulted in the abandonment Hoofdakker 1999; Parry et al. 2000). Predictors of its use in the United States. of clinical response to sleep deprivation have In conclusion, melatonin has (at least) an been identified and appear to be similar to the interest as an adjuvant treatment for unipolar or predictive clinical and biological clues of a good bipolar MDD when there are sleep disorders (in response to antidepressant treatments. They particular insomnia) or a phase delay syndrome. include the presence of high daytime mood vari- Agomelatine also induces a resynchronization of ability (Haug 1992), “endogenous” type of circadian rhythms and an improvement in sleep depression (Vogel et al. 1975) (i.e., absence of parameters, with an antidepressant effect equiva- identified triggering factor, but this endogenous lent to other pharmacological antidepressants. characteristic is no longer used: studies have Also the possible hepatotoxicity of agomelatine shown that no clinical or para-clinical marker requires close monitoring. actually differentiates “endogenous” depressions from “exogenous” depressions), an abnormal response to the dexamethasone test (King et al. 9.4 Sleep Deprivation 1982), or decreased levels of inflammatory markers (Francesco Benedetti et al. 2002). Underlying As BLT, sleep deprivation or more commonly genetic variations also contribute to this response called “wake therapy” is part of chronobiological variability to sleep deprivation (Benedetti et al. interventions that are not used yet in clinical 1999b, 2010). practice. Currently, sleep deprivation appears in The only contraindication to sleep deprivation international guidelines for MDD treatments is the existence of underlying epilepsy (Nakken (Ravindran and da Silva 2013; Ravindran et al. et al. 2005). Furthermore, patients having this 2009) as an alternative treatment, in combination therapy should generally undergo a particularly with the recommended pharmacological thera- careful medical examination; stress sometimes pies and psychotherapies. While it may seem felt before or during this therapy may indeed be paradoxical to prevent a patient from sleeping at risk of decompensating of chronic diseases, during a major depressive episode, this therapy is especially cardiovascular. Precautions regarding one of the most interesting chronobiological certain activities (e.g., such as driving) are also to interventions for practitioners, and its immediate be taken into account (risk of excessive daytime antidepressant effect has now been recognized sleepiness caused by sleep deprivation). for over 30 years (Schulte 1959; Wehr et al. 1979; One of the main obstacles to the implementa- Wirz-Justice and Terman 2012). tion of this therapy in current clinical practice is Sleep deprivation is indicated in the treatment probably the short and ephemeral nature of the of MDD. This therapy consists in keeping the improvement: 80% of patients’ relapse after patient awake for periods ranging from 3 to 4 h in sleeping the next night or even after naps during the second part of the night (partial deprivation) the night of sleep deprivation (Svestka 2008). In to more than 40 h (total deprivation) (Giedke order to limit the risk of relapse and extend this et al. 2003). This method has shown surprising ephemeral antidepressant effect, several strate- positive results with rapid mood improvement (in gies have been proposed (Monteleone et al. 24–48 h) in 50–60% of patients in a MDD, inde- 2011). The one that appears to be the more effi- pendently of the subtype of depression (Benedetti cient is the sleep phase advance method. This et al. 2007). Sleep deprivation has shown an treatment involves advancing bedtime at 5 p.m. interest in MDD among unipolar disorder, bipo- in the afternoon, after a complete deprivation of lar disorder, postpartum depressive episode, sleep, and then keep advancing progressively schizoaffective disorder, or in major depressive bedtime 1 h per day (6 p.m., then 7 p.m., etc.), 9 Chronobiology and Treatment in Depression 129 this over a total duration of 7 days. This method unipolar disorders, but such results are also found would prevent relapse in 60–80% of patients who with bipolar depressions. For patients with BD, responded to sleep deprivation (Vollmann and the switch rates to (hypo)manic episodes were Berger 1993; Riemann et al. 1996; Albert et al. not greater than those observed with antidepres- 1998; Benedetti et al. 2001a). Moreover, the sants (Colombo et al. 2000). Overall, chronobio- phase advance over a period of 3 days, more sim- logical interventions seem to be even more ple in clinical practice, would be as effective as a appropriate for these patients with BD. We know period of 7 days (Voderholzer et al. 2003). indeed that anomalies of the circadian rhythms Another strategy was to consider sleep depriva- constitute a fundamental component of the disor- tion as a sequential treatment but with inconsis- der (Bellivier et al. 2015). Benedetti et al. showed tent results. A cycle would be defined as each a significant efficacy in bipolar depression of the period of sleep deprivation followed by restarting combination of sleep deprivation, phase advance, sleep. This treatment was carried out from one to and concomitant lithium treatment (Benedetti six cycles over a period of about 4 weeks (Wirz- et al. 2001a, 2014), as well as encouraging results Justice 2003). for the combination of sleep deprivation with There is also growing evidence in the litera- light therapy (Benedetti et al. 2005). The recent ture of the interest of combining sleep depriva- study by Wu et al. (2009) included a sample of 49 tion with drug therapy. Two open studies have bipolar patients treated with mood stabilizers and shown that the combination of antidepressant antidepressants in combination of three sequences therapy with antidepressant therapy was more of chronobiological treatments (sleep depriva- effective than treatment alone (Caliyurt and tion, light therapy, and phase advance). Patients Guducu 2005; Wiegand et al. 2001). Reynolds showed a more rapid and sustained improvement et al. showed that sleep deprivation was more (decreasing depression scores) than patients effective than selective serotonin reuptake inhibi- treated with drug treatments alone on Day 2 of tors and the combination of both (Reynolds et al. the procedure and up to 7 weeks. Finally, a study 2005). Some randomized studies are also in favor suggests a link between chronotype and antide- of the positive impact of this association: the pressant effect of sleep deprivation: in healthy addition of treatments such as lithium salts volunteers, sleep deprivation would be beneficial (Szuba et al. 1994; Benedetti et al. 2001a, 2014) in subjects with a vesperal profile (so-called eve- or the 5-HT1A pindolol antagonist (Smeraldi ning/night owls), whereas it would be rather del- et al. 1999) would allow to maintain this antide- eterious in terms of mood for those said morning pressant effect of sleep deprivation. Its associa- type (Selvi et al. 2007). This result seems inter- tion with non-pharmacological therapies such as esting to take into account in the case of euthy- morning BLT, without or with concomitant phar- mic bipolar patients, who, as we know, present macological treatment (see Sect. 9.6), would also their own circadian characteristics compared to have shown positive results in maintaining this healthy subjects, with a chronotype rather of the antidepressant effect (Neumeister et al. 1996; vesperal type (Giglio et al. 2010). Up to date, we Colombo et al. 2000; Loving et al. 2002; do not have long-term studies, since patients Echizenya et al. 2013). A randomized study also already have major difficulties in tolerating even suggested the combination of partial sleep depri- partial sleep deprivation. The effect of this ther- vation with repetitive transcranial magnetic stim- apy has also been evaluated in acute thymic epi- ulation (rTMS) and showed maintenance of the sodes, but we do not yet know what the benefit antidepressant effect of sleep deprivation at would be for periods of remission. The data in 4 days in the group with active rTMS terms of security also remain insufficient. (Eichhammer et al. 2002). This finding was not Thus, according to current scientific data, replicated in a recent study (Kreuzer et al. 2012). treatment with sleep deprivation shows a level 2 Most studies have shown rapid and sustained of evidence, as an adjunct treatment, in the acute thymic improvement in patients with MDD in management of MDD characterized by mild to 130 P.A. Geoffroy and S. Yeim moderate intensity, and some data are in favor of 9.5.1 Interpersonal and Social its benefit in MDD with seasonal pattern, as well Rhythm Therapy (IPSRT) as depressive episodes in ante- and postpartum. The guidelines recommend it only as a third line Interpersonal and social rhythm therapy (IPSRT) of treatment, because of practical difficulties and was developed by Ellen Frank 15 years ago tolerability in the medium and long term (Wirz- (Frank et al. 2000). This approach is based on Justice and Terman 2012; Echizenya et al. 2013; some preliminary scientific evidence, including Ravindran and da Silva 2013). Nevertheless, it the already well-established efficacy of interper- seems important to emphasize that non- sonal therapies (TIP) for depressive episodes in pharmacological therapies such as BLT and unipolar disorder (Cuijpers et al. 2014), as well sleep deprivation have strong advantages as as in circadian rhythm anomalies in patients with adjuvants, in terms of flexibility and patient bipolar disorders (Murray and Harvey 2010). acceptability. The side effects reported remain This type of intervention particularly targets the rare, and minimal, and can be controlled by sim- regulation and stability of social and circadian ple and close monitoring. These therapeutic rhythms (control of daily routines and sleep) and strategies also have the advantage of their rapid integrates a behavioral approach as well as strate- delay in action and can make it possible to con- gies for managing interpersonal relationships and siderably reduce the length of hospitalization stressful life events (Swartz et al. 2009). and thus cost. IPSRT includes three types of interventions, Future studies are needed to identify factors of interpersonal therapy, social rhythm therapy, and individual variability in response to this therapy psychoeducation, with a focus on accepting long- (age, gender, light sensitivity, severity of the dis- term pathology. It begins with the principles of order, sleep characteristics such as sleep quality interpersonal therapy and its modalities. It is con- and architecture) and the most effective modali- tracted and limited in time and allows to work on ties of application (right time of intervention in the links between life events, interpersonal rela- the course of the disorder, combinations of treat- tionships, social rhythms, and depressive symp- ments, etc.). toms. IPSRT comprises three phases: an initial phase, an intermediate phase, and a final phase (Bottai et al. 2010). 9.5 Psychotherapies Focused The initial phase should be started as soon as on Circadian Rhythms possible or even during an acute episode. It sums and Sleep up the course of the disease, biographical elements, to have an overview of his interpersonal To date, there is a large body of scientific evi- relationships and the different life events that dence highlighting the value of psychotherapies have marked the patient’s journey. It is also a in combination with pharmacological treatments time for initiating measures of psychoeducation, in depressive episodes management (Vieta et al. with informations given about bipolar disorder, 2009). They all have common goals, including its symptoms, comorbidities, as well as the treat- improved adherence, acceptance of the disease, ments. The assessment of the patient’s circadian and overall a better quality of life for patients. and social rhythms is also carried out with evalu- Several types of psychosocial therapies exist, and ation of synchronizers and desynchronizers (sub- they differentiate by their underlying theoretical stance abuse, jet lag, work, and family models, their modalities, and their delay in the obligations). This evaluation is based on a tool course of the disorder (during an acute episode or called the Social Rhythm Metric (SRM), which in a period of euthymia). Nevertheless, the stabi- can be compared to a valuable weekly agenda for lization of social rhythms is part of most psycho- the patient and the psychiatrist. This way, it is social interventions’ objectives used in mood possible to collect important informations on a disorders. weekly basis: time of day, time of first contact 9 Chronobiology and Treatment in Depression 131 with a person, time of first activity, and mood and sion. Two controlled studies (Frank et al. 2007, level of energy, self-assessed by the patient. Life 2008) followed, confirming the interest of IPRST events are also specified. This tool has the advan- and proposing a comprehensive good practice tage of allowing the patient to appropriate this manual for IPRST in bipolar disorder (Frank evaluation phase and to promote the awareness of 2005). the disorder and of his own rhythms. A recent randomized controlled study also The intermediate phase has several objectives: showed efficacy of IPRST combined with phar- to work on the acceptance of the disease, the macological treatment in a 49 younger group of organization of social rhythms, and interpersonal patients with BD (aged 15–36 years and mostly therapy (problem-solving, evaluation of interper- with bipolar I-type disorder): a decrease in sonal dysfunctions). The development of social depressive and manic symptoms was observed rhythms is of particular interest to us and repre- but appeared to be no different from the control sents one of the most important axes of this ther- group of patients receiving another type of spe- apy. The objective is to look with the patient the cialist supportive care, combining psychoeduca- disruptors of daily routines and circadian tion and supportive psychotherapy (Inder et al. rhythms, such as cultural events, vacations, pro- 2015). Finally, some studies (but including small fessional obligations (shift work), family, or the samples) have specifically focused on the effi- use of psychoactive substances. The therapist cacy of IPRST in bipolar depression (Swartz then establishes with the patient achievable et al. 2012; Hoberg et al. 2013). Swartz et al. objectives to regulate his rhythms, such as gradu- were the first to compare IPRST as monotherapy ally adjusting his sleeping/waking schedules, in versus drug therapy (here, quetiapine) as mono- order to ensure a good sleep hygiene. Careful therapy (Swartz et al. 2012). This randomized attention is given about linking social rhythms, pilot study involved a sample of 25 patients with sleep, and mood swings. type II bipolar disorder and did not show any dif- Finally, the final phase takes stock of the ference between the two groups, although both objectives previously established and worked, to had a decrease in depressive symptoms at consider a possible maintenance phase (consoli- 12 weeks of follow-up. All these results, although dation of acquired knowledge and long-term preliminary, suggest the potential benefit of patient support). IPRST on the improvement of depressive symp- Scientific literature supports the efficacy of toms and in the prevention of relapses. Here IPRST in combination with drug therapy for pre- again, additional studies will be essential to iden- vention of depressive relapses, extension of free tify the most effective methods of application of intervals between episodes, and the better overall this therapy (duration, frequency, target popula- functioning of patients who have had these inter- tion of patients who can benefit from it, etc.). ventions (Miklowitz et al. 2007). The randomized trial (Frank et al. 2005) compared a sample of 175 bipolar I-type patients who followed for 9.5.2 Cognitive Behavioral 2 years two types of psychotherapy: first, an Therapies (CBT) acute phase where patients receive IPRST or intensive clinical management (ICM) and then, Common cognitive behavioral therapies (CBT) during the maintenance phase, either the patients have demonstrated their efficacy in combination having the same type of therapy or alternated with drug therapy in the management of mood with the other. This study showed faster remis- disorders. They include psychoeducational sion following a depressive episode in IPRST measures (see Table 9.2), as well as common patients compared to the control group, regard- CBT techniques, particularly targeting dysfunc- less of maintenance therapy. These patients also tional patterns of thinking for each patient, and had a better stabilization of their daily rhythms, problem-solving and stress management strate- correlated with the quality and duration of remis- gies. Whether in the form of short interventions 132 P.A. Geoffroy and S. Yeim

Table 9.2 Tips for good sleep habits – When it’s bedtime: Generally: create a comfortable place and atmosphere for sleeping • Wear comfortable clothing/pajamas • Organize your bed and bedroom in the most pleasant way possible: clean sheets and pillows, comfortable and rather firm mattresses • Aerate your bedroom before bedtime • The ideal room temperature for a good quality of sleep is 18 °C • Regarding baths or showers: avoid the hot bath just before going to bed if it wakes you up (but there is no absolute rule as it can promote falling asleep in others; nevertheless, it makes frequently increased body temperature and does not promote falling asleep) • Noise and light: be sure to isolate yourself as much as possible from noise, from outside light, or from the standby lights of electrical appliances, e.g., laptops, diodes, alarm clocks, television, etc. • Do not allow pets in your room • Dine light and avoid protein foods – When you wake up: • Wake up at a fixed time every day; this promotes good sleep/wake cycles • Get out of bed when you are awake • Do not work in bed • Expose yourself to the light as soon as you are awake. Natural light in summer or artificial light in winter • The body temperature has cooled overnight: Dress, have a breakfast with a hot drink and a hot shower in order to raise the body temperature • Promote physical activity during the day (but avoid sport at the end of the day or in the evening); this improves the quality of sleep

(integrated into daily clinical practice or in a few conditions, including light, noise, and room tem- sessions), or conventional CBT over several perature. A summary of sleep hygiene rules is months, data from the scientific literature support provided in the following table. Control of sleep- a reduction in the recurrence of depressive and related stimuli typically includes four objectives manic episodes, with longer euthymic phases, to be achieved for the patient: (1) use the bed and better social functioning, and better adherence to bedroom only for sleep or sexual activity (do not treatment (Vieta et al. 2009). read or watch TV in bed); (2) go to bed only A more specific approach to insomnia, called when he is sleepy; (3) leave the room if he can’t cognitive behavior therapy for insomnia (CBT-I), fall asleep, and return to bed within 15–20 min has been identified by the American Academy of only if he is sleepy; (4) get up at the same time Sleep Medicine as the first-line treatment in every morning. Other strict measures on time insomnia (Morgenthaler et al. 2006). This ther- spent in bed are also applied. Excessive time apy includes several interventions: a step of psy- spent in bed is indeed a factor in maintenance of choeducation ensuring a good sleep hygiene with sleep disorders and leads to more nocturnal learning to control the stimuli related to sleep, a awakenings and anxious ruminations. A time short sleep deprivation step, and finally specific spent in bed is thus decided with the patient, cognitive and behavioral work, focusing particu- called “sleep window” according to the duration larly on (false) beliefs and perceptions about of sleep per night. The goal is to improve the sleep and its mechanisms (beliefs about optimal sleep efficiency to 85–90%, defined by the total sleep duration, consequences of insomnia, etc.). sleep time divided by the time spent in bed. Sleep hygiene education also includes a briefing The efficacy of CBT-I in insomnia has long time on the effects of caffeine, alcohol or other been well demonstrated in randomized controlled psychoactive substances, as well as physical trials (Hofmann et al. 2012; Morin et al. 2006; exercise, on sleep. Advice is also given on sleep Riemann et al. 2015). It has thus shown an equiva- 9 Chronobiology and Treatment in Depression 133 lent or even greater efficacy to short- and long- bipolar I disorder with psychoeducation (control term pharmacological treatment, with a decrease group) for 8 weeks and with a 6-month evalua- in nocturnal awakenings, a better sleep efficiency, tion (Harvey et al. 2015). The authors proposed a and an improvement in the subjective feeling of CBT-I specific for bipolar disorder (CBTI-BP). It sleep quality. In addition, there is increasing sci- was characterized by the combination of IPSRT entific evidence for its efficacy in the treatment of elements (see above), motivational interviews, sleep disorders in various psychiatric disorders reduction of the duration of sleep to 6.5 h maxi- (mood disorders, addictions, anxiety disorders) mum (in order to limit the risks of mood shift (Soehner et al. 2013; Swanson et al. 2013; Talbot during sleep deprivation), and special attention to et al. 2014; Myers et al. 2011) and nonpsychiatric exposure to light (decreased light and stopping disorders (cancer, chronic pain, HIV infection) stimulating activities 30–60 min before bedtime, (Smith et al. 2005; Kamath et al. 2015). In addi- if necessary light therapy in the morning in case tion, several variants of CBT-I have recently of depressive symptoms). This study showed developed, including shorter therapies (Shimodera encouraging results with improved sleep and et al. 2014; Troxel et al. 2012), electronic versions mood in both groups and for patients in the on the Internet (Babson et al. 2015; Blom et al. CBTI-BP group, higher rates of remission, and 2015; Gosling et al. 2014; Cockayne et al. 2015), especially a lower risk of thymic relapse (relapse or “step-by-step” therapy ranging from more rate of 13.6% versus 42.2% in the control group). autonomous techniques such as personal develop- These preliminary data are in favor of a positive ment to more individualized and personalized impact of CBT on sleep disorders, thymic symp- psychotherapies (Ho et al. 2015; Espie 2009). toms, and the course of mood disorders. However, Regarding MDD, insomnia may be one of the more randomized controlled studies with larger symptoms of an acute episode or be comorbid of samples are needed. These will help in answering a mood disorder. In the case of associated depres- the questions of feasibility and tolerance and to sive symptoms, available studies support the effi- define the place of this therapy in the overall care cacy of CBT-I with improved sleep and mood of the patient with MDD. (Perlis et al. 2000; Taylor et al. 2007; Manber et al. 2008, 2011). The study by Bei et al. suggests a possible role of the chronotype in the 9.6 Combination Strategies response to CBT, vesperal-type patients showing less improvement on depressive symptoms (Bei Four types of chronotherapies have thus been et al. 2015). Finally, very few studies have shown to be effective in the treatment of MDD: focused on the efficacy of CBT-I in bipolar disor- BLT, agomelatine, sleep deprivation, and phase ders (Kaplan and Harvey 2013; Harvey et al. advance. All of them have shown a rapid antide- 2015; Steinan et al. 2014). The Kaplan and col- pressant effect, but for some do not stay on the laborators study showed an improvement in long-term, especially for sleep deprivation and insomnia symptoms and quality of sleep (via phase advance. In addition of these four chrono- subjective measures) after 8 weeks of CBT-I on a therapies, psychoeducation measures focused on sample of 15 bipolar I-type patients (Kaplan and sleep and rhythms are also effective and should Harvey 2013). This improvement was already be proposed. present after the first stage of general psychoedu- First, combining chronotherapies with phar- cation on sleep hygiene. Two patients presented macological antidepressants would allow benefit- symptoms of hypomania after control of environ- ing both from a rapid antidepressant effect (not mental stimuli sessions, as well as two of the five possible with conventional antidepressants with a patients having achieved sleep deprivation, how- typical delay of action of 2–3 weeks) that could ever following an independent life event. Finally, subsequently be maintained by the pharmacologi- Harvey et al. compared 30 patients with bipolar cal treatment already prescribed. BLT combined disorder undergoing CBT-I and 28 patients with with an antidepressant (SSRIs) demonstrated a 134 P.A. Geoffroy and S. Yeim greater synergistic effect than antidepressant The main side effects are daytime sleepiness and monotherapy or BLT alone in seasonal and non- manic switch (Benedetti and Colombo 2011). seasonal unipolar MDD (Loving et al. 2002; Thus, sleep deprivation should only be used in Lam et al. 2016). Sleep deprivation has also BD with close monitoring of side effects. Sleep shown a superior effect when combined with an deprivation has thus been associated with BLT in antidepressant with a long-lasting effect (Loving several studies with promising results when et al. 2002). Its association with different types including individuals with BD nonseasonal MDD of antidepressants has been studied: serotonergic and then associated with lithium and antidepres- antidepressants (Smeraldi et al. 1999; Benedetti sants (Colombo et al. 2000; Loving et al. 2002; et al. 1997; Martiny 2004), noradrenergic Benedetti et al. 2005, 2014). It should be empha- (Shelton and Loosen 1993), serotonergic and sized that the meta-analysis of Tuunainen and noradrenergic (Wirz-Justice et al. 1976; Elsenga collaborators indicated that there was an efficacy and van den Hoofdakker 1982; Kuhs et al. of this bi-chronotherapy only in patients that 1996), and dopaminergic (Benedetti et al. respond first to sleep deprivation (Tuunainen 2001b). However, it is demonstrated that the et al. 2004). risk of manic switch is also increased with these Finally, several studies have shown encourag- two strategies of combination. Thus, if these ing results in favor of the association of sleep strategies are considered, they should be used deprivation followed by a phase advance in with extremely cautious, especially in individu- patients with unipolar MDD (Berger et al. 1997; als with BD (close monitoring or even hospital- Voderholzer et al. 2003) and bipolar MDD in ization). Lithium therapy remains the first-line combination with lithium (Benedetti et al. 2001a; treatment in case of BD but also in the long- Wu et al. 2009). The study of Wu and collabora- term maintenance of the action of chronothera- tors also included a BLT procedure, so the com- pies such as sleep deprivation alone or in bination of the three chronotherapies combination with light therapy and/or phase (tri-chronotherapies) in addition to the lithium advance (see below) (Szuba et al. 1994; treatment. They showed that sleep deprivation Colombo et al. 2000; Benedetti et al. 1999a, supported by BLT and phase advance was supe- 2001a, 2005). Indeed, lithium is a well-known rior in efficacy for improving depressive symp- chronobiologic agent, and its therapeutic action toms compared to pharmacological treatment has been related to its ability to alter circadian alone, as soon as the second day of tri- rhythms, including an improvement of day-to- chronotherapies, with an effect maintained for day rhythmicity (Moreira and Geoffroy 2016; 7 weeks. In this model proposed, the intervention Geoffroy et al. 2016). began with a night of sleep deprivation from A bi-chronotherapy combining sleep depriva- 11 p.m. until 6 p.m. the following day (33 h of tion with BLT demonstrated a synergistic effect awakening). The BLT started the day after the and so can be considered in cases of severe or end of the sleep deprivation session. Exposure to resistant MDD (Benedetti and Colombo 2011). light was during 2 h at 5000 lux per day for The advantage of combining sleep deprivation 3 days. The phase advance began on the first with BLT is also to benefit from a rapid and pow- night after sleep deprivation, with the first night erful antidepressant action in 24–48 h of sleep that started at 6 p.m. (until 1 a.m.), then at 8 p.m. deprivation and to maintain this effect by BLT on the second night (until 3 a.m.), and on the (Neumeister et al. 1996). The team of Benedetti third night at 10 p.m. (until 5 a.m.). and collaborators, pioneers in the therapeutic use These strategies of combination of therapies of sleep deprivation, propose for this combina- thus seem to show interesting results to potentiate tion a schema of a night of total sleep deprivation their effectiveness and facilitate their place in the followed by a night of sleep recovery, this current MDD treatment strategies. repeated three times. Nevertheless, in some Table 9.3 is summarizing the different types of cases partial sleep deprivation may be preferred. interventions and their expected response. 9 Chronobiology and Treatment in Depression 135

Table 9.3 Chronotherapies that are effective in the treatment of major depressive disorders (Adapted and modified from Benedetti et al. 2007) Type of intervention Therapeutic response Monotherapy Latency Duration Bright light therapy A few days Weeks/months Agomelatine Weeks (2 weeks min) Weeks/months Sleep deprivation A few hours Short (just after sleep recovery) Phase advance 1–2 days Tolerance after 2 weeks Combination Latency Duration Bright light therapy + pharmacological treatment A few days Months Sleep deprivation + phase advance A few hours Decreasing efficacy after stopping (1 week) Sleep deprivation + pharmacological treatment A few hours Months Repeated sleep deprivation A few hours Decreasing efficacy after stopping (1 week) Bright light therapy + sleep deprivation + phase A few hours Months advance + pharmacological treatment

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Subin Park and Jin Pyo Hong

10.1 Introduction der (MDD) or borderline personality disorder (Oquendo and Baca-Garcia 2014). This change There is compelling evidence about the strong has been demanded to address suicidal behavior association of depressive disorder with suicidal as a distinct condition of research to identify its behavior and suicidal death. Over 90% of suicide specific psychological and neurobiological victims had at least 1 psychiatric disorder, and in mechanisms and also as an independent treat- particular, about 60% of victims had affective ment option (Aleman and Denys 2014). This disorders including depression (Cavanagh et al. change reflects the perception of suicidal behav- 2003; Henriksson et al. 1993; Robins et al. 1959). ior as an independent clinical disorder from other Given the strong association between suicidal psychiatric disorders. behaviors and depression, it is important to iden- In the same vein, suicidal behavior in depres- tify risk factors for suicidal behaviors in sion may not just be a severe form of depression, depression. given that the severity of depressive symptoms Recently, suicidal behavior disorder has been does not distinguish suicidal and non-suicidal included as an independent clinical diagnostic depressive patients (Malone et al. 1995; Mann entity in Sect. 3 of DSM-5 (American Psychiatric et al. 1999). In addition, although MDD is one of Association 2013). This change is distinctive the strongest risk factors of suicidal behavior from current nosology in which suicidal ideation (Kessler et al. 1999), only a small fraction of and attempts were perceived as the complication people with MDD get engaged in suicidal behav- of psychiatric disorders rather than an indepen- iors: the lifetime suicide risk is estimated about dent disorder and accordingly were included as 3.4% (Blair-West et al. 1999). Then why some one of the symptoms of major depressive disor- depressed patients are engaged in suicidal behavior, while many others are not? To answer this question, distinct predispositions to suicidal behaviors in depression should be understood (Mann 2003). S. Park Department of Research Planning, Mental Health The stress-diathesis model was regarded as Research Institute, National Center for Mental the most widely accepted hypothesis for under- Health, Seoul, South Korea standing suicidal behavior. It describes suicidal J.P. Hong (*) behavior as the interplay between a stressor (e.g., Department of Psychiatry, Sungkyunkwan University an acute psychiatric crisis or a negative life event) School of Medicine, Samsung Medical Center, and an individual vulnerability to suicide, per- Seoul, South Korea e-mail: [email protected] haps resulting from a genetic predisposition and

© Springer Nature Singapore Pte Ltd. 2018 143 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_10 144 S. Park and J.P. Hong epigenetic alterations related to early-life stress- are the key markers for suicidal behaviors in ful events (Salloum 2017). In this part, we will depression. However, this association between review previous research findings about suicidal suicidal behaviors and impulsivity and aggres- disposition among patients with depression. sion may be significant only among younger adults (Conner et al. 2004; Dumais et al. 2005; Perroud et al. 2011). 10.2 Psychological Dispositions This association of impulsive and aggressive traits with suicidal behavior may explain the high Pessimism and hopelessness increase the risk of comorbidity with Cluster B personality disorder suicidal behavior in depression (Beck et al. 1989; and substance abuse among depressive suicide Hawton et al. 2013; Schneider et al. 2001). Beck attempters or completers (Dumais et al. 2005; et al. (1985) noted that only the extent of hope- Mann 2003). Dumais et al. (2005) noted that lessness among other variables predicted the higher impulsivity and aggression among suicide eventual suicide of hospitalized patients with sui- completers with MDD were linked to the comor- cidal ideation after 10 years. This predictive bidity with Cluster B personality disorders and validity of hopelessness was replicated to outpa- alcohol abuse and dependence. Furthermore, tients as well (Beck et al. 1989): more than 90% Brodsky et al. (1997) examined the association of of suicide completers were from a high-risk suicide attempts with specific traits of BPD and group identified by cutoff scores of hopelessness found that impulsivity was the only characteristic 6 years ago, suggesting that hopelessness may be of BPD that was related to the increased number a sensitive indicator of prospective suicide com- of suicide attempts. pletion. In particular, a high level of hopelessness Hostility is another temperament associated remaining even after the remission of depression with suicide attempt (Weissman et al. 1973). was associated with suicide attempts (Hind et al. When comparing temperament traits between 1994). suicide attempters and non-attempters with major Accumulated evidence has shown a greater depression, hostility was strongly associated with level of impulsivity and aggressiveness among suicidal behavior in patients with major depres- suicide attempters or suicide victims (Brent et al. sion (Christodoulou et al. 2016; Paykel and 1994; Dumais et al. 2005; Mann et al. 1999; Dienelt 1971; Pendse et al. 1999) and other psy- Perroud et al. 2011). When comparing suicide chiatric disorders (Brezo et al. 2006; Ferraz et al. attempter and non-attempter among depressed 2013; Michaelis et al. 2004). patients, there was no significant difference in the Cognitive rigidity has been identified as a pre- severity of depression and other general psychiat- dictor for suicidal behaviors in depression ric symptoms between two groups, but suicide (Richard-Devantoy et al. 2012). According to attempters had a higher level of impulsivity both cognitive rigidity hypothesis, mental inflexibility before and after antidepressant treatment evidenced by diminished executive functioning is (Corruble et al. 1999). Impulsivity and aggres- associated with suicide ideation and attempts siveness were the key differences in the compari- among depressed patients (Dombrovski et al. son between suicide completers and living 2008; Keilp et al. 2001; Marzuk et al. 2005; depressed patients as well: the suicide completers Patsiokas et al. 1979). By comparing depressive with MDD had a higher level of lifetime impul- patients with and without suicide attempt history sive and aggressive behaviors compared to living and non-depressive participants, Keilp et al. depressed patients (Dumais et al. 2005). (2001) noted that the discriminating cognitive Furthermore, Stein et al. (1998) found that a high function between suicidal and non-suicidal level of aggressiveness was predictive of repeti- depressed patients was executive functioning, tive suicide attempts, which may increase the risk while general cognitive functioning, such as of suicide completion. This converging evidence memory and attention, discriminated two depres- demonstrates that impulsive and aggressive traits sive groups from non-depressive control group. 10 Suicidal Behavior in Depression: A Severe Form of Depression or a Distinct Psychobiology? 145

The results suggest that suicide lethality in binding (presynaptic in the cortex) were local- depression may be linked with more extensive ized to ventrolateral prefrontal cortex (VLPFC) cognitive impairment than general cognitive (Arango et al. 1995). Considering the involve- impairment of depressive patients. The findings ment of VLPFC in cognitive inhibition, low sero- for suicide attempt were replicated to suicide ide- tonergic input in this area may contribute to an ation as well (Marzuk et al. 2005). Cognitive impaired inhibition of suicidal depressive patients rigidity may hamper generating alternative solu- (Mann 2003). tions for effective problem-solving under stress- Postmortem studies of suicide found abnor- ful situation and, therefore, might cause malities in noradrenergic system among suicide hopelessness that increases their risk for suicidal victims. Increased α2-adrenoceptor densities behavior (Marzuk et al. 2005). The deficits of were found in the locus ceruleus of victims—the executive functioning among suicidal depressive site for brain synthesis of noradrenaline—sug- patients suggest their impairment in the prefron- gesting the decreased noradrenaline level tal cortex (PFC) (Mann 2003). (Ordway et al. 1994b). The inconsistent findings about the changes in tyrosine hydroxylase (TH) showed that TH immunoreactivity either 10.3 Neurochemical Factors increased (Ordway et al. 1994a) or decreased (Biegon and Fieldust 1992). Given that TH Given the reduction of serotonergic function increases to compensate the decreased levels of increases aggressive behavior and impulsivity noradrenaline, increased TH may result from the (Coccaro 1989), serotonin has been linked to the noradrenergic depletion after its increased neurobiological mechanism of suicide (Oquendo release. In addition, increased level of noradrena- et al. 2014). Alteration of serotonin system, spe- line and decreased α-adrenergic binding in the cifically hypofunction of serotonin system, has prefrontal cortex of were found in suicide victims been found in suicide victims (Mann 2003). (Arango et al. 1993). The findings suggest Lower level of 5-HIAA in cerebrospinal fluid noradrenergic overactivity in the cortical region. (CSF), which indicates decreased serotonergic Psychic anxiety is one of the clinical features activity, was related to the incidence of previous associated with suicide in depression (Fawcett suicide attempts among depressed patients (Mann et al. 1990). Taken together, Mann (2003) sug- et al. 1996). Importantly, the alteration was gested that pathological anxiety of suicidal peo- related to suicide attempts, independently of the ple may cause the sensitive sympathetic response history of MDD (Arias et al. 2001; Mann et al. to stressors accompanying an excessive release 2000). In contrast, suicide victims were found to of noradrenaline, which in turn deplete noradren- have increased tryptophan hydroxylase 2, aline function. Then the depletion of noradrena- decreased serotonin transporter binding affinity, line may increase their hopelessness and and increased serotonin concentrations in the pessimism that increase the risk of suicidal brain. These alterations may compensate the behavior. decreased serotonergic activity (Oquendo et al. Owing to its major role in the stress response 2014). In a prospective cohort study, the increased system, the hypothalamic-pituitary-adrenal 5-HT1A autoreceptor binding affinity in the dor- (HPA) axis has been heavily involved in the neu- sal raphe nucleus of patients with depression, robiological mechanism of suicide. Measuring which leads to decreased serotonin firing, pre- hyperactivity of HPA axis with dexamethasone dicted more lethal suicidal behaviors (Oquendo suppression test (DST), in which failure to sup- et al. 2016). In a postmortem study, the changes press cortisol indicates a hyperactive HPA axis, in serotonin in the particular area were found several studies have found associations between among suicide victims: both the increase of DST non-suppression and attempted or com- 5-HT1A receptor binding (postsynaptic in the pleted suicides among depressive patients cortex) and decrease of serotonin transporter (Coryell and Schlesser 1981, 2001; Jokinen and 146 S. Park and J.P. Hong

Nordstrom 2009; Yerevanian et al. 2004). DST urenine pathway may reduce the availability of non-suppression increased the likelihood of tryptophan and thus decrease serotonin synthesis. eventual suicide 14-fold in a 15-year follow-up Sublette et al. (2011) found elevated plasma kyn- study of patients with MDD (Coryell and urenine levels in suicide attempters with MDD, Schlesser 2001). With regard to cortisol levels, a compared to non-attempters with MDD. A more proxy measure for HPA axis activity, both recent study found decreased tryptophan level increased and decreased levels have been associ- and elevated kynurenine/tryptophan ratio in sui- ated with suicide attempts (Mann and Currier cidal adolescents with MDD compared to non- 2007). A recent meta-analysis concluded that suicidal adolescents with MDD and healthy these inconsistent associations may be related to controls (Bradley et al. 2015). age, with elevated levels in samples with a mean Quinolinic acid, one of the main metabolites age under 40 and blunted levels in samples with of kynurenine, is known for its neurotoxic prop- a mean age over 40 (O'Connor et al. 2016). The erty through N-methyl-d-aspartate (NMDA) hyperactivity of HPA may underlie the afore- receptor agonism, leading to glutamatergic neu- mentioned alterations in serotonergic and adren- rotransmission hyperactivation. Kynurenic acid, ergic system and PFC dysfunction (Mann 2002, another main metabolite of kynurenine, is con- 2003). sidered neuroprotective due to its NMDA and alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor antag- 10.4 Neuroinflammation onism (Bryleva and Brundin 2017; Salloum and Kynurenine Pathway 2017). The quinolinic acid levels in the CSF of suicide attempters significantly elevated by Inflammation is thought to contribute to suicidal around 300% of the levels in the CSF of healthy behavior since inflammatory mediators, such as controls (Erhardt et al. 2013). In addition, CSF cytokines, reciprocally interact with the HPA quinolinic acid levels remain significantly ele- axis and serotonin system (Bryleva and Brundin vated by around 150% even after 2 years after a 2017). Elevated pro-inflammatory IL-6 level in suicide attempt (Bay-Richter et al. 2015). The blood and postmortem brain samples were found CSF quinolinic acid/kynurenic acid ratio, referred in suicidal patients compared with non-suicidal to as the neurotoxic ratio, was twofold higher in patients and healthy controls (Black and Miller suicide attempters compared to healthy controls, 2015; Gananca et al. 2016). Inflammation in the suggesting the role of net positive NMDAR ago- brain is characterized by activation of glial cells. nism on suicidal behaviors (Erhardt et al. 2013). In one study, increased microglial priming and These findings are in line with the facts that anti- macrophage recruitment were observed in the suicidal effect is produced by intravenous injec- dorsal anterior cingulate white matter of post- tion of ketamine, an NMDA receptor antagonist mortem brain samples of depressed suicides (Bryleva and Brundin 2017). compared with matched nonpsychiatric deaths (Torres-Platas et al. 2014). Inflammation also causes activation of the 10.5 Genetic Factors kynurenine pathway, the main pathway for the degradation of tryptophan. Pro-inflammatory Results from studies of families, twins, and adop- cytokines such as interferon-r, interleukin-1ß, tion support a substantial genetic component of and IL-6 can induce indoleamine 2,3-dioxygenase suicidality. People who commit or attempt sui- 1 (IDO-1) and tryptophan 2,3-dioxygenase cide have a higher familial history of suicidal acts (TDO), the key enzyme for degradation of trypto- (Brent and Mann 2005). Concordance rates for phan, and thus activate the kynurenine pathway suicide and suicide attempts are higher in mono- (Bryleva and Brundin 2017). Since tryptophan is zygotic twins compared to dizygotic twins a precursor for serotonin, activation of the kyn- (Voracek and Loibl 2007). The biological parents 10 Suicidal Behavior in Depression: A Severe Form of Depression or a Distinct Psychobiology? 147 of adoptees who commit suicide show a higher neurotransmitters including norepinephrine, rate of suicide compared to the biological parents dopamine, and serotonin. Although abnormali- of control adoptees (Voracek 2007). The genetic ties in monoamine neurotransmission have been components of suicidal behavior are estimated to implicated in the molecular pathogenesis of sui- be around 40% (McGuffin et al. 2010). cidal behavior, the meta-analysis on the most The serotonin transporter plays an important extensively studied polymorphism in the pro- role in regulating serotogenic signaling at syn- moter region, uVNTR, did not confirm the asso- apses. The gene of serotonin transporter ciation with suicide attempts in both gender and (SLC6A4) has a common functional polymor- violent suicide attempts (Hung et al. 2012). phism in the promoter region (5-HTTLPR), which consists of long insertion (L) or deletion Conclusion (S) polymorphism. Clayden et al. (2012) con- In this chapter, we reviewed previous research ducted a meta-analysis of 5-HTTLPR and found examining the risk factors of suicidal behav- the significant association for the 5-HTTLPR S iors among depressive patients. Interplay allele and attempted suicide, but not for com- between interconnected neural systems con- pleted suicide. A meta-analysis of the genetic tributes to suicidal behaviors in depression, polymorphisms of the gene coding for trypto- and neurobiological changes in suicidal phan hydroxylase 1 (TPH1), the rate-limiting depression appear to underlie the psychologi- enzyme in the biosynthesis of serotonin, also cal vulnerability of suicidal behavior found the significant association of the polymor- (Fig. 10.1; Mann 2003). phism A218C with attempted suicide, but not Personal state of hopelessness and pessi- with completed suicide (Clayden et al. 2012). In mism predicts future suicide attempt and com- a recent meta-analysis by Gonzalez-Castro et al. pletion of depressive patients. The depletion of (2014), the polymorphisms A218C and A779C noradrenaline may underlie this hopelessness. have been associated with suicidal behavior on Depressive patients with pathological anxiety both Asian and Caucasian populations. For the may respond to stressors overly sensitively, and neuronal isoform of TPH, tryptophan hydroxy- it may cause depletion of noradrenaline after its lase 2 (TPH2), a meta-analysis by Gonzalez- excessive release. Therefore it is plausible that Castro et al. (2014) did not detect any significant severe psychic anxiety might be linked to hope- association with suicidal behavior. In contrast, lessness and pessimism over time, which even- other meta-analytic study by Choong et al. (2014) tually increase the risk of suicide. found the association of two polymorphisms, In addition, impulsive and aggressive rs7305115 and 1386486, with suicidal behavior, behavior has been identified as key predictor although the included studies were highly of repetitive suicide attempts. Impulsive and heterogeneous. aggressive traits of suicidal patients may be The genetic polymorphisms of the gene cod- linked with the hypofunctioning of their sero- ing for catechol-o-methyltransferase (COMT), tonin system. These two traits may also be the key enzyme for degradation of catechol- associated with comorbidities with other psy- amines, were investigated in few meta-analyses chiatric disorders such as BPD that increase (Mirkovic et al. 2016). A meta-analysis by Kia- suicide risk. Keating et al. (2007) found an association Cognitive rigidity may also increase the between the COMT 158Met polymorphism and risk of suicidal behavior, by inhibiting an suicidal behavior, but more recent meta-analytic effective coping to stressors and heightening studies failed to confirm the association (Calati hopeless and pessimistic thinking and emo- et al. 2011; Clayden et al. 2012). tion as the outcome. This impairment in exec- Monoamine oxidase A (MAOA) is a mito- utive functioning may result from dysfunction chondrial outer membrane enzyme that is respon- of PFC, perhaps associated with the altera- sible for the degradation of monoamine tions in serotonergic and adrenergic system. 148 S. Park and J.P. Hong

Tr yptophan Serotonin Hypo-function of Impulsivity & serotonin system aggressiveness TDO/IDO (+) Cytokine

Suicidal Depletion of Hopelessness & Kynurenine HPA noradrenalin pessimism behavior hyperactivity

Cognitive PFC dysfunction Kynurenic Quinolinic rigidity acid acid (−)(+) Neuroplasticity NMDAR Neurotoxicity

Depressive Stressor Vulnerability symptoms

Fig. 10.1 A stress-diathesis model of suicidal behavior ase, HPA hypothalamic-pituitary-adrenal, NMDAR in depression, modified from Mann (2003). TDO trypto- N-methyl-d -aspartate receptor phan 2,3-dioxygenase, IDO indoleamine 2,3-deoxygen-

Depressive patients with the aforementioned Arango V, Ernsberger P, Sved AF, Mann JJ. Quantitative predispositions may be highly vulnerable to sui- autoradiography of α1- and α2-adrenergic receptors in the cerebral cortex of controls and suicide victims. cide risk. Therefore, the assessment and treat- Brain Res. 1993;630(1–2):271–82. ment for suicidal behaviors in depressive patients Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized should carefully consider these predispositions. alterations in pre- and postsynaptic serotonin binding Suicidal behaviors of depressive patients may sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688(1–2):121–33. not be merely severe depressive symptoms. Arias B, Gastó C, Catalán R, Gutiérrez B, Pintor L, Fañanás Notably, suicidal behavior satisfies the criteria L. The 5-HT2A receptor gene 102T/C polymorphism for diagnostic validity and has been demon- is associated with suicidal behavior in depressed strated to be a reliable diagnosis (Oquendo and patients. Am J Med Genet. 2001;105(8):801–4. Bay-Richter C, Linderholm KR, Lim CK, Samuelsson Baca-Garcia 2014). Reconceptualization of sui- M, Traskman-Bendz L, Guillemin GJ, et al. A role for cidal behavior as a distinct disorder may improve inflammatory metabolites as modulators of the gluta- suicide risk screening and detection in clinical mate N-methyl-D-aspartate receptor in depression and practice and also help expand suicide research suicidality. Brain Behav Immun. 2015;43:110–7. Beck AT, Steer RA, Kovacs M, Garrison B. Hopelessness by using a well-defined phenotype. With the and eventual suicide: a 10-year prospective study of advances in molecular genetics and neuroimag- patients hospitalized with suicidal ideation. Am J ing technology, a better understanding of sui- Psychiatr. 1985;142(5):559–63. cidal behavior as a distinct psychobiology is Beck AT, Brown G, Steer RA. Prediction of eventual suicide in psychiatric inpatients by clinical expected in the future. ratings of hopelessness. J Consult Clin Psychol. 1989;57(2):309–10. Biegon A, Fieldust S. Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus of suicide vic- References tims. Synapse. 1992;10(1):79–82. Black C, Miller BJ. Meta-analysis of cytokines and Aleman A, Denys D. A road map for suicide research and chemokines in suicidality: distinguishing sui- prevention. Nature. 2014;509(7501):421–3. cidal versus nonsuicidal patients. Biol Psychiatry. American Psychiatric Association. Diagnostic and statisti- 2015;78(1):28–37. cal manual of mental disorders (DSM-5®). Arlington: Blair-West GW, Cantor CH, Mellsop GW, Eyeson- American Psychiatric Publishing; 2013. Annan ML. Lifetime suicide risk in major depres- 10 Suicidal Behavior in Depression: A Severe Form of Depression or a Distinct Psychobiology? 149

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Sang Won Jeon and Yong-Ku Kim

11.1 Cognitive Impairment vented patients from changing focus easily in Depression (Marazziti et al. 2010). Other studies have reported that processing speed (Nebes et al. 2000), Although reduced concentration is one of the selective attention, response inhibition, executive diagnostic criteria of depression, there are other function (Beats et al. 1996), and episodic memory cognitive impairments in patients with depres- (Austin et al. 1999) were consistently observed sion. Although some patients do not experience areas of cognitive decline in depressed patients. In cognitive decline, most studies reported that a study that utilized functional magnetic reso- depressed patients underperformed on various nance imaging (fMRI), when a depressed patient neurocognitive function tests compared to a con- group and a control group were asked to perform trol group (Zakzanis et al. 1998). Key aspects of the same working memory task, activation of cognitive impairment in depressed patients additional neural circuits was required for the include attention, memory, and psychomotor depressed patient group (Harvey et al. 2005). speed. Although language, perception, and spatial The characteristics of cognitive impairment in perception are typically well maintained in depressed patients are clearer when compared to depressed patients, impairments to these can Alzheimer’s disease (AD), which is a representa- occur due to the secondary effects of lack of con- tive neurocognitive disorder. There are some dis- centration, motivation, or ability to structure tasks tinguishable points between patients with (Mayberg et al. 2002). According to previous depression and patients with AD in terms of cog- studies, consistently observed cognitive issues in nitive impairment (Olin et al. 2002; Steffens and depressed patients were memory deterioration Potter 2008) (Table 11.1). First, depressed due to reduced concentration and reduced execu- patients tend to experience greater subjective tive function due to rigidity of thought that pre- cognitive dysfunction relative to AD patients. Second, cognitive impairment in depressed patients is usually more rapid and mood congruent, while patients with AD experience more S.W. Jeon Department of Psychiatry, Kangbuk Samsung steady and progressive cognitive impairment. Hospital, Sungkyunkwan University School Third, cognitive impairment is more pronounced of Medicine, Seoul, South Korea in effortful jobs among depressed patients, unlike Y.-K. Kim (*) with AD patients, who experience cognitive Department of Psychiatry, College of Medicine, impairment in phasic or gnostic processes or Korea University Ansan Hospital, apraxia. Fourth, information processing speed or Ansan, Gyeonggi-do, South Korea e-mail: [email protected] psychomotor speed is often maintained in AD

Table 11.1 Typical clinical and cognitive presentations of depression versus Alzheimer’s disease Feature Depression Alzheimer’s disease Subjective memory complaints Overestimate level of cognitive Underestimate level of cognitive impairment impairment Rate of cognitive change Acute Insidious Course of cognitive change Mood-congruent fluctuations in Progressive cognitive decline cognition Memory Improvement with repeated exposure; No improvement despite repeated recall improves with retrieval cues exposure; cueing does not help recall performance Aphasia/apraxia/agnosia Uncommon Emergence after memory impairment Information processing speed Slowed Normal in early stage Psychomotor speed Slowed Normal in early stage patients at early stages; a reduction in these based on the observation that the pattern of mem- speeds is more pronounced in depressed patients, ory impairment in depressed patients is similar to even at early stages. Fifth, depressed patients that of patients with prefrontal cortical dysfunc- show much poorer memory function in early tion. In a study that compared patients with pri- stages and recover with repeated assessment; mary depression and patients with neurological retrieval cues are often helpful for recall. disorders (i.e., Parkinson’s disease), the pattern However, AD patients show poor performance, of cognitive impairment was similar. Both groups even with repeated assessment, and retrieval cues had reduced concentration, working memory, are not helpful for recall. psychomotor speed, planning, strategic search- ing, and flexibility of goal-directed thought processes (Flint et al. 1993). 11.2 Model to Explain Cognitive Impairment in Depression 11.3 Cognitive Impairment One of the models to explain cognitive impair- and Depression Severity, Age ment in depression states that depressed patients Group, and Remission cannot efficiently distribute and utilize cognitive resources (Anacker and Hen 2017). This hypoth- In a meta-analysis that assessed the correlation esis assumes that cognitive impairment in between the severity of depression and the level depressed patients is not a disorder of a specific of cognitive impairment, significant correlations area of cognitive function, but is due to lack of were observed between the severity of depression energy required to perform cognitive functions in and some aspects of cognitive impairment (i.e., general. Unlike AD patients that have impaired episodic memory, executive function, and pro- semantic recall, depressed patients have well- cessing speed), while there was no significant maintained semantic memory. Many studies have correlation between severity of depression and revealed that explicit memory for recent informa- semantic memory or visual-spatial memory tion is impaired in both AD and depressed patients (McDermott and Ebmeier 2009). Other studies and that implicit memory is only impaired in AD have reported worsened processing speed and patients, but not in depressed patients. These executive function with increased severity of results demonstrate how cognitive impairment is depression, more specifically, with increased often observed during the performance of effort- apathy (Boone et al. 1995; Feil et al. 2003). ful tasks in patients with depression. Many studies have reported that different pat- Another model hypothesized about the corre- terns of cognitive impairment are observed in dif- lation between specific cognitive functions and ferent age groups of depressed patients. Relatively specific neuroanatomical locations. This model is younger patients exhibit impairments in concen- 11 Cognitive Dimensions of Depression: Assessment, Neurobiology, and Treatment 153 tration, short-term memory, and working mem- and AD. However, considering that LOD is ory, while language- or learning-associated mostly premonitory or an early symptom of AD, functions remain normal (Mormont 1984; Savard it is difficult to validate depression as a true risk et al. 1980). In contrast, older depressed patients factor for AD. In contrast, early-onset depression report impaired memory as their chief complaint (EOD) often occurs in younger or middle-aged and can present similar to AD patients. patients and has a long disease duration until the Impairment in executive function in older onset of AD. Therefore, this allows us to validate depressed patients was associated with planning, whether depression is a true risk factor for AD. ordering, structuring, and abstract thinking. There are five published studies investigating Sometimes, these impairments were associated the relationship between EOD and AD, including with a recurrence or relapse of depression (Pisljar four prospective cohort studies and one case- et al. 2008). One study suggested that different control study. All of these studies found that EOD cognitive impairments were observed for differ- played a key role in the pathogenesis of AD, ent ages of onset of depression. Individuals with reporting a two- to fourfold increase in risk of early-onset depression often exhibit impairment AD onset (Barnes et al. 2012; Dal Forno et al. in episodic memory, while later-onset depression 2005; Dotson et al. 2010; Geerlings et al. 2000; is often associated with impaired executive func- Green et al. 2003). One of these studies reported tion and processing speed (Herrmann et al. 2007). that, although the risk of AD increased by four- Previously, researchers believed cognitive fold in EOD patients, there was no association impairment in patients with depression was asso- between LOD and the onset of AD (Geerlings ciated with the severity of depression and there- et al. 2000). Another study reported that depres- fore thought that cognitive impairment should sion increased AD risk twofold and that value disappear after the remission of depression (Basso increased to fivefold at 1 year prior to the onset of and Bornstein 1999). However, some recent stud- AD. In conclusion, EOD is considered an impor- ies report cases of persistent cognitive impair- tant risk factor for AD, but whether it is a direct ment, even after the remission of depression. cause or if there is a third factor mediating the Some studies found that even after a significant association between depression and AD remains improvement in depressive symptoms, there were unclear. Furthermore, the relationship between many cases of persistent cognitive impairment for LOD and AD is still very unclear. over 6 months and that impairment was more pronounced in effortful task performance than in automatic performance (Hammar et al. 2003). 11.5 Neurocognitive Function Thus, some claimed that cognitive impairment Tests for Patients should be regarded as a trait marker of depression with Depression (Marazziti et al. 2010). This is the key reason why cognitive impairment in depression should not be To date, there have been few specially designed considered as a mere symptom, but a possible tools for measuring cognitive function within prognostic marker of progression into neurocog- depression. For depression, typical neurocogni- nitive disorder (i.e., Alzheimer’s disease). tive function tests are used. The selection of a particular neurocognitive function test is based on various factors, and a differential diagnosis is 11.4 Association Between Early- the most important factor to be considered. For Onset Depression example, to assess whether impaired memory is and Cognitive Disorders due to AD, depression, or aging, general neurocognitive function, including various cognitive Most studies that established a relationship dimensions, should be assessed for potential between depression and neurocognitive disorders impairment. Furthermore, test levels of difficulty focused on the relationship between late-onset should vary from easy to difficult to reveal the depression (LOD) in patients over 60 years old deterioration of cognitive function regardless of 154 S.W. Jeon and Y.-K. Kim the severity of depression. The following are (Mayberg et al. 1999). In a fMRI study, depressed basic dimensions of neurocognitive function tests patients exhibited increased amygdala reactivity to assess overall cognitive function (Table 11.2). while performing emotion-processing tasks and decreased dorsolateral prefrontal cortex (DLPFC) activation while performing cognitive tasks 11.6 Cognitive Biological Model (Mayberg et al. 1999; Seminowicz et al. 2004; of Depression Siegle et al. 2007). Moreover, depressed patients showed decreased functional connectivity The amygdala in depressed patients has greatly between the amygdala and the DLPFC. The cor- enhanced resting metabolism, and exposure to ticolimbic dysregulation model is a neurobiologi- aversive stimulation results in a greater increase cal mechanism that utilizes these observations to in activation of the amygdala (Seminowicz et al. explain cognitive impairment in depression 2004; Siegle et al. 2007). In contrast, resting (Comte et al. 2016). metabolism of the prefrontal cortex (PFC) is First, cognitive impairment in depression greatly reduced in patients with depression occurs through bottom-up processing. The pro-

Table 11.2 Neurocognitive function tests, according to cognitive function dimension 1. Consciousness, attention, orientation 4. Visuospatial skills (a) Consciousness (a) Copy drawings (interlocking pentagon, a • Glasgow Coma Scale clock face, a house, or a person) (b) Concentration (b) Rey-Osterrieth complex figure test • Digit span 5. Executive function and higher cortical functions • Reverse digit span (a) Calculation • Reverse sequence (b) Similarity proverb • Serial 7s (c) Judgment • Continuous performance (d) Multiple loop (c) Orientation: time, person, place (e) MN sequence 2. Memory (f) Go-no-go test (a) Verbal (g) Fist-edge-palm test • 4 unrelated word test (h) Trail making test • Paired associated learning test (i) Stroop test • Story recall test (j) Praxis • Rey auditory verbal leaning test • Ideomotor praxis • California verbal learning test • Ideational praxis • Hopkins verbal learning test 6. Others (b) Visual (a) Agnosia • Visual reproduction • Visual agnosia, prosopagnosia, • Visual paired associates environmental agnosia, stereognosis • Rey-Osterrieth complex figure test (b) Right-left disorientation (c) Wechsler Memory Scale (WMS) (c) Neglect 3. Language • Line bisection test (a) Spontaneous speech • Star cancelation test • Fluency, articulation, prosody, grammar, paraphasia (b) Verbal fluency test • animal naming test (c) Naming and word finding • Boston naming test (d) Comprehension • Follow simple commands • Follow commands, using objects • Answer yes-no questions • Reading comprehension (e) Repetition (f) Reading (g) Writing 11 Cognitive Dimensions of Depression: Assessment, Neurobiology, and Treatment 155 cess begins with hyperactivity of the limbic sys- tion, not only cognitive function but also emo- tem, represented by the amygdala, followed by tional controlling function is impaired. Therefore, hyper-activation of the PFC, frontal cortex, ACC, recent studies on cognitive function in depression hippocampus, and subgenual cingulate cortex. highlight the use of amyloid positron emission These hyperactivities cause problems with redis- tomography (PET) scans. tribution of cerebral blood flow. The brain con- One of the most important tasks when diag- trols oxygen distribution through redistribution nosing neurocognitive disorders, especially AD, of cerebral blood flow (Disner et al. 2011), and is to identify the histopathology of the brain. The problems in oxygen distribution can affect cogni- characteristic pathological finding of AD is a tive function in various regions of the brain. neurofibrillary tangle (NFT), composed of tau Second, weakened top-down processing proteins, within the cell and amyloid plaques out- causes cognitive impairment in depression. side the cell. Amyloid plaques are composed of Weakened top-down processing results in diffi- peptides called amyloid-β (Aβ), and amyloid cas- culties with controlling emotions. Structures cade theory hypothesizes that the accumulation associated with top-down processing include the of Aβ induces pathology through neurotoxins and DLPFC, medial prefrontal cortex (MPFC), ven- NFT, eventually resulting in impaired cognitive trolateral prefrontal cortex (VLPFC), and, from function (Hardy and Higgins 1992). Recently, the subcortical region, anterior cingulate gyrus advances in nuclear medicine allowed for radio- (ACC) and thalamus. The DLPFC is associated logical assessment of amyloid accumulation. with rumination and processing of bias, the Amyloid positron emission tomography (PET) MPFC is associated with self-referential sche- can identify Aβ accumulation levels in the brain mas, and the VLPFC is associated with attention by injecting a tracer to detect Aβ (Herholz and to bias. When top-down regulation is weakened, Ebmeier 2011; Villemagne et al. 2011). Based on the cognitive controlling ability of the PFC is this, amyloid PET is expected to become a useful weakened, while the emotional reactivity of the diagnostic tool for the differential diagnosis of amygdala is enhanced. Unstable connections depression and AD. In fact, there are studies cur- between the PFC and subcortical areas result in rently being performed to predict the progression an inability to react and judge properly against from depression to AD in depressed patients with stimulation and eventually result in a decline in concurrently impaired cognitive function utiliz- cognitive function (Roiser et al. 2012). ing amyloid PET (Chung et al. 2016; Harrington In summary, the brain of depressed patients is et al. 2015; Tateno et al. 2015). Moreover, there is characterized by increased bottom-up emotional a high chance of amyloid PET being used to bio- reactivity (by activation of the amygdala) and logically assess the level of cognitive dysfunction decreased top-down emotional regulation (by in patients with depression. deactivation of the DLPFC). In other words, depressed patients have weakened top-down cognitive control and enhanced bottom-up emotional 11.8 Utilization of Amyloid PET activation and therefore have abnormal cognitive in Depression function. In conclusion, impaired cognitive function in patients with depression causes problems In a study published in 2008 (Butters et al. 2008), in the neurofunctional network. the authors performed amyloid PET on eight depressed patients (composed of six individuals with mild cognitive impairment [MCI] and two 11.7 Amyloid Positron Emission cognitive normal [CN] individuals) and eight Tomography (PET) Scans control subjects. The results showed similar levels of amyloid accumulation for the CN depressed Some studies suggest that depression occurs as a patients and the control group. Among the six way to express neurodegeneration (Baldwin et al. patients with MCI and depression, three showed 2005). They suggest that, due to neurodegenera- similar levels of amyloid accumulation as the AD 156 S.W. Jeon and Y.-K. Kim patient group, and the remaining three showed axis due to hypercortisolemia. One of the studies varying levels. They suggested, based on these (Green et al. 2006) found increased amyloid pro- results, that amyloid accumulation has the poten- duction when dexamethasone was injected in tial to diagnose cognitive impairment in patients mice, which was due to increased expression of with depression. Furthermore, they reported that amyloid precursor protein (APP) and β-APP the frontal lobe and precuneus were the signifi- secretase. In a mouse model of depression cant regions of amyloid accumulation associated induced by sudden restraint or chronic isolation, with depression. amyloid levels increased in the hippocampus In a study published in 2009 (Lavretsky et al. (Kang et al. 2007). This was activated by an 2009), the authors performed amyloid PET and injection of corticotropin-releasing hormone tests to assess depressive and anxiety symptoms (CRH) into the hippocampus and was suppressed in 23 MCI and 20 CN subjects. The results by pretreatment with a CRH antagonist. showed that for the MCI group, depression scores A study published in 2015 (Tateno et al. 2015) and anxiety scores were associated with amyloid reported that later onset of depression was corre- accumulation in the lateral temporal lobe and lated with significantly increased accumulation posterior cingulate cortex, respectively. For the of Aβ. Moreover, among elderly depressed CN group, depression scores and anxiety scores patients, the amyloid-positive group was signifi- were associated with amyloid accumulation in cantly older, and the period between the onset of the medial temporal and frontal lobes, respec- depression and the time when patients received tively. The authors suggested that the presence of the amyloid PET scan was significantly shorter. MCI made a significant difference in the patho- The authors concluded that amyloid pathology physiological mechanism of emotional condi- had a greater impact on the onset of depression in tions and anxiety. the case of late-onset depression. In a study published in 2012 (Madsen et al. Another study published in 2016 (Chung et al. 2012), the authors compared amyloid accumula- 2016) performed amyloid PET scans on 39 MCI tion between 28 elderly subjects (mean patients with a history of depression and 39 MCI age = 61 years old) who once had depression and patients with no history of depression. When they remitted and 18 healthy control subjects. They compared the results, the depression group had reported no significant relationship between significantly higher levels of βA accumulation in depression and increased amyloid accumulation bilateral frontal lobes, and the authors suggested and suggested that depression should not be con- that this region could be a biomarker for depres- sidered a risk factor for AD. However, results sion in MCI patients. Another study (Brendel from more recent studies showed a significant et al. 2015) divided 371 MCI patients into 2 association between depression and AD. In a groups (with and without depression). From the study published in 2014 (Wu et al. 2014), the entire cohort, 206 were amyloid positive and 165 authors compared amyloid PET scan results were amyloid negative, and Aβ accumulation was between 25 subjects with depression and 11 CN increased in the frontotemporal lobes and insula subjects (>60 years old). The results showed that, in depressed patients in the amyloid-positive relative to CN patients, depressed patients had group. significantly increased amyloid accumulation in There are continuous studies using amyloid the parietal lobe and precuneus. This result sup- PET to identify the correlation between depres- ports the findings of the 2008 study, which found sion and cognitive function, as well as to identify a significant accumulation of βA in the same whether depression is a risk factor for region. AD. Meaningful results are being published, and Some previous animal studies identified an the accumulation of results from more prospec- association between depression and amyloid tive studies with larger sample sizes will allow us pathology. Depression is associated with failure to better understand the pathophysiology behind to control the hypothalamic-pituitary-adrenal depression-induced cognitive impairment. 11 Cognitive Dimensions of Depression: Assessment, Neurobiology, and Treatment 157

11.9 Vascular Pathology 2004), however, showed that although there was in Depression with Cognitive no change in cognitive function in the sertraline Impairment treatment group, post hoc analyses showed improvement in cognitive function for female Cerebrovascular risk factors have great effects on subjects, while no cognitive changes or worsen- depression and cognition. Subjects with more ing cognition were observed for male subjects. In than two cerebrovascular risk factors had more a double-blind study comparing moclobemide severe symptoms of depression compared with and a placebo, treatment provided improvement those without cerebrovascular risk factors, and for not only depression but also for cognitive the outcomes of cognitive function tests were function (Roth et al. 1996). Tricyclic antidepres- poorer (Barch et al. 2012). In other words, more sants (TCAs) were found to worsen cognitive cerebrovascular risk factors cause a higher chance function in some patients (Petracca et al. 1996; of structural changes in the brain, and individuals Reifler et al. 1989). with more cerebrovascular risk factors have a The biggest issue for medication treatment of higher chance of developing depression with depression with cognitive impairment is that no cognitive impairment. Frequent observation of large-scale prospective study has been performed. deep white matter hyperintensities on MRI was When analyzing 11 different randomized associated with poorer outcomes on neurocogni- placebo-controlled studies, 5 studies showed sig- tive tests. More specifically, there was a close nificant effects over placebo (sertraline (Lyketsos relationship with executive function and memory et al. 2003), clomipramine (Petracca et al. 1996), tests. Looking at MRI studies published to date, maprotiline (Fuchs et al. 1993), moclobemide subcortical ischemic change appears to play a (Roth et al. 1996), citalopram (Nyth and Gottfries key role in the onset of depression (Geerlings 1990)), while 6 studies showed no significant et al. 2012; Saavedra Perez et al. 2013). effect over placebo (sertraline (Banerjee et al. Furthermore, these vascular factors have a rela- 2011; Rosenberg et al. 2010), mirtazapine tively strong relationship with cognitive function. (Banerjee et al. 2011), venlafaxine (de Therefore, vascular physiology could be a com- Vasconcelos Cunha et al. 2007), imipramine mon cause for both depression and reduced cog- (Reifler et al. 1989), fluoxetine (Reifler et al. nitive function. 1989)). A recent double-blind placebo-controlled study showed significant improvement for all three groups (sertraline-, mirtazapine-, and 11.10 Drug Treatment placebo-treated groups) after 13 weeks (Banerjee of Depression with Cognitive et al. 2011). In contrast, medication treatment Impairment groups showed more side effects compared to control groups. In other words, this study found The pathophysiology of cognitive impairment in that representative antidepressants, such as ser- depression is not yet known, and this could also traline or mirtazapine, did not have a significant be a multifactorial disorder. Therefore, there is no effect on improving cognitive function. A recent clear theoretical guideline for treatment of meta-analysis showed similar results. Both depression with cognitive impairment, and treat- response rates and remission rates were not sig- ment is not simple. In addition, there is a dearth nificantly better than those of the placebo group of large-scale prospective studies on this issue. (Nelson and Devanand 2011). The effects of antidepressants on cognitive Once it is decided to use antidepressants to function vary between different studies. In sertra- treat depression with cognitive impairment, it is line (Lyketsos et al. 2000, 2003) and fluoxetine recommended to use selective serotonin reuptake studies (Tariot et al. 1998), there was no signifi- inhibitors (SSRIs) rather than TCAs. Treatment cant correlation between antidepressant use and should continue regardless of initial improve- cognitive function. Another study (Munro et al. ment. Cognitive deficits can be persistent even 158 S.W. Jeon and Y.-K. Kim after depression is remitted, and in such cases, activation result in cognitive impairment. To the condition can progress into neurocognitive assess cognitive function in depression, typi- disorders such as AD. If the patient does not cal neurocognitive function tests to assess respond to antidepressants, additional medica- overall cognitive function are preferred over tions can be given. However, augmented treat- specific examination tools. Recently, amyloid ment for depression with cognitive impairment PET is being highlighted for its usefulness in patients is not established, and treatment plans patients with depression and cognitive impair- should be decided after regular monitoring of ment, and many studies are being done on this patient conditions. topic. Since the effects of antidepressants on The effects of cholinesterase inhibitors against cognitive function are not completely estab- depression are not clear. In a galantamine study lished, regular monitoring of patients is monitored for 21 weeks, overall Neuropsychiatric required to provide best treatment. 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Jan Jaracz

12.1 Introduction 12.2.1 Cytokines

Epidemiological studies convincingly point to Pro-inflammatory cytokines represent a class of the frequent comorbidity of depression and proteins which play a central role in the immune chronic pain. Bair et al. (2003) who reviewed 14 system and in the inflammatory response. studies published between 1957 and 2003 dem- Interleukin-1β (IL-1β), interleukin2 (IL-2), inter- onstrated that 65% (range 15–100%) of depressed leukin-6 (IL-6), interleukin-8 (IL-8), and tumor patients reported pain. The same authors identi- necrosis factor-α (TNF-α) are involved in activa- fied 42 papers investigating the occurrence of tion of lymphocyte, macrophage, and neutrophil depression in people suffering from chronic pain as well as the regulation of immunoglobulin by of different etiology. Symptoms of depression production B cells. were detected in 52% (range 1.5–100%) of Cytokines exert a modulatory effect on several patients in pain clinics. This observation may aspects of brain functioning. IL-1 and, to a lesser inspire to formulate a hypothesis that both condi- extent, Il-6 and TNF-α activate the hypothalamo- tions may share common pathophysiological pituitary-adrenocortical (HPA) axis leading to mechanisms. glucocorticoid receptor resistance and hypercortisolemia. Hyperactivity of HPA axis is a well-documented biological marker of major 12.2 Pathophysiology depression (Zunszain et al. 2011). Cytokines produce a modulatory impact on The first assumption refers to neurotransmitters, neurotransmitter systems. First of all they reduce i.e., serotonin, noradrenaline dopamine, and glu- availability of tryptophan, which is a precursor tamate as well as pro-inflammatory cytokines, of 5-HT. This in turn leads to deregulation of substance P, and brain-derived neurotrophic fac- both monoamine synthesis and reuptake, caus- tor (BDNF). The second conjecture relates to ing reduced monoamine availability, and, brain structures involved in the pathogenesis of according to monoamine hypothesis, induces both depression and the processing of pain. symptoms of depression (Miller et al. 2009; Müller 2014). Moreover, inflammation increases the activity of kynurenine pathway of tryptophan metabolism by induction of indoleamine J. Jaracz 2,3-dioxygenase (IDO). This metabolic switch Department of Adult Psychiatry, Poznan University increases the production of quinolinic acid, of Medical Sciences, Poznań, Poland e-mail: [email protected] which agonizes NMDA receptors (NMDA-R)

© Springer Nature Singapore Pte Ltd. 2018 163 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_12 164 J. Jaracz and finally leads to reduced neuroplasticity (Jeon elevated (Dowlati et al. 2010; Liu et al. 2012; and Kim 2016). Cytokines also have a signifi- Young et al. 2014). cant negative impact on dopamine synthesis, The causes of increased levels of pro- packaging, and release which may cause symp- inflammatory cytokines in depression have not toms of depression (Felger 2017). Pro- been precisely elucidated so far. Recently, Slavich inflammatory cytokines have an impact on and Irwin (2014) have proposed a “social signal neuroplasticity by affecting important aspects of transduction theory of depression.” The basic neuronal functioning particularly apoptosis, oxi- assumption of this theory is that stress upregu- dative stress, and metabolic derangement, as lates immune mechanisms involved in the inflam- well as by impairing axonal and dendritic matory response. A secondary effect is branching (Hayley et al. 2005). It has been dysregulation of neuroendocrine and neurotrans- shown that IL-1β refrains long-term potentia- mitter systems which disturb brain functioning. tion, a form of neuronal plasticity which is a The final result of these dysfunctions is the neural substrate of learning and memory (Hayley appearance of symptoms of depression. et al. 2005; Pickering and O’Connor 2007). Data Bai et al. (2014) investigated the relationship suggest that these cognitive functions are com- between pro-inflammatory cytokine levels and monly affected in major depression (MD). pain symptoms in patients with major depressive It has been postulated that cytokines and che- disorder (MDD) and minor depressive disorder. mokines excessively produced in different dis- The level of soluble P-selectin, but not of other eases can sensitize neurons of the first pain pro-inflammatory cytokines, appeared to be a synapse and, in this way, cause central sensitiza- significant predictor for the presence of both tion which eventually results in the activation of somatic and pain symptoms in depression. An neurons by innoxious signals (Schaible 2014; association between increased pain sensitivity Clark et al. 2013). These changes promote long- and increased TNF-α concentration was found in term maladaptive plasticity, resulting in persis- depressed female patients (Euteneuer et al. 2011). tent neuropathic pain (Ellis and Bennett 2013; However, the association of normalization of Maes et al. 2012). cytokines levels with an improvement in painful Four lines of evidence indicate a relationship symptoms in depressed patients has not been between elevated levels of pro-inflammatory studied so far. cytokines, chronic pain, and depression. First, several studies have shown elevation of pro- inflammatory cytokines in neuropathic pain and 12.2.2 Brain-Derived Neurotrophic other pain conditions, such as arthritis. The neu- Factor (BDNF) tralization of cytokines seems to have an analgesic effect (Schaible 2014; Shubayev et al. 2010). BDNF plays a role in the formation of neural pro- Second, depression is commonly reported in liferation, growth, and survival. Opposite abnor- somatic disorders related to activation of inflam- malities of BDNF secretion have been found in matory mechanisms including asthma (Goodwin depression and chronic pain. A decreased level of et al. 2004), rheumatoid arthritis (Murphy et al. BDNF in major depression was reported in sev- 2012), inflammatory bowel disease (Walker et al. eral studies and confirmed in meta-analysis con- 2008), and coronary heart disease (Celano and ducted by Molendijk et al. (2014). However, Huffman 2011). Third, depression is a common higher than normal serum levels of BDNF were side effect in patients treated with cytokine thera- detected in chronic pain conditions like fibromy- pies due to cancer and hepatitis (Capuron et al. algia (Haas et al. 2010) and in irritable bowel 2000; Musselman et al. 2001). Fourth, results of syndrome (Yu et al. 2012). Interestingly, in meta-analyses have provided strong data that patients with fibromyalgia, BDNF levels corre- serum levels of the pro-inflammatory cytokines lated with severity of symptoms of depression IL-1, IL-6, and TNF-α in major depression are (Nugraha et al. 2013). 12 Overlapping Chronic Pain and Depression: Pathophysiology and Management 165

Data reviewed recently by Nijs et al. (2015) ment with sertraline plus placebo (Amidfar et al. confirmed that the BDNF’s upregulation leads to 2016). Ketamine noncompetitively antagonizes sensitization of peripheral nociceptors, dorsal the NMDA receptors. Meta-analysis of nine clin- root ganglia, spinal dorsal horn neurons, and ical studies confirmed a significant reduction of brain descending inhibitory and facilitatory path- symptoms of depression after a single-dose infu- ways. It has been also found that the BDNF val- sion of ketamine (Kishimoto et al. 2016). 66met polymorphism marks vulnerability for Preclinical studies indicate that metabotropic chronic multisite musculoskeletal pain compared glutamate receptor 5 (mGlu5) negative allosteric to val66val carriers (Generaal et al. 2016). BDNF modulator (NAM)—basimglurant—causes dis- in turn modulates fast excitatory (glutamatergic) inhibition of discrete glutamate neuronal net- and inhibitory (GABAergic/glycinergic) signals. works in brain circuits involved in mood and emotion regulation. Therefore it has been postulated that this agent is a promising antidepressant 12.2.3 Glutamate (Fuxe and Borroto-Escuela 2015). Some data suggest that pharmacologically induced inhibi- Glutamate is considered as a primary excitatory tion of mGlu5 receptors and amplification of neurotransmitter in the human central nervous mGlu2/3 and mGlu4/7/8 receptors may cause system. Receptors which transduce glutamate reduction of symptoms intensity in both depres- signaling fall into two categories: ionotropic sion and chronic pain (Golubeva et al. 2016). (NMDA, AMPA, and kainite receptors) and metabotropic receptors (mGLU). Three groups (I–III) of mGLU receptors have been identified 12.2.4 Substance P on the basis of their location, impact on K+ and Ca++ channels, and the role in excitatory and Neuropeptide substance P acts by binding to the inhibitory processes. neurokinin-1 receptor (NK-1R). Both substance mGLU receptors, particularly from group I, P and NK-1R are widely distributed in the central are localized in brain structures involved in pain nervous system, particularly in the amygdala, processing. Increased expression of mGLU 1/5 hypothalamus, periaqueductal gray matter, locus receptors was identified in animal models of coeruleus, and parabrachial nucleus, and are pain. There is growing evidence suggesting the colocalized with serotoninergic and noradrener- potential role of mGLU receptor agonists in treat- gic neurons. Originally, it has been hypothesized ment of acute and chronic pain (see Golubeva that substance P plays a role as nociceptive trans- et al. 2016 for review). mitter in afferent sensory fibers. The presence of In depression, numerous studies have demon- substance P and NK-1R receptors in limbic strated higher serum and cerebrospinal fluid regions implied their role in the regulation of (CSF) levels of glutamate, suggesting enhanced emotion processing and in responses to stress glutamatergic neurotransmission. Also postmor- (Bittencourt et al. 1991). tem studies showed alterations in glutamate In major depression, an elevated level of sub- receptors in MDD (Hashimoto 2009). stance P in serum (Bondy et al. 2003) and in cere- Indirect evidence pointing to the role of the brospinal fluid (Geracioti et al. 2006) has been glutamate system in major depression arise from demonstrated. In patients who responded to treat- studies demonstrating the antidepressant effect of ment with antidepressants, a level of substance P drugs which modulate glutamatergic neurotrans- gradually decreased (Bondy et al. 2003). Some mission. Memantine blocks current flow through experimental studies indicate that the effect on the channels of N-methyl-d-aspartate (NMDA) serotonin and noradrenaline systems caused by receptors. Results of the recent study imply that NK-1R antagonists is similar to that caused by in patients with MDD treatment with memantine, antidepressants (Blier et al. 2004). However, results add-on to sertraline was more effective than treat- of clinical studies led to ambiguous conclusions. 166 J. Jaracz

Amelioration of symptoms of major depression tioning of this system may cause such symptoms of was reported in two studies using orvepitant (Ratti depression as anhedonia and lack of motivation. et al. 2013) and aprepitant (Kramer et al. 1998) The dopaminergic system also exerts a modulatory agents which block central NK-1R. Contrary to effect on the perception of nociceptive signals. This these results, the study by Keller et al. (2006) did effect is illustrated by frequent comorbidity of not demonstrate the efficacy of aprepitant in MDD. Parkinson’s disease and chronic pain (Jarcho et al. 2012; Mitsi and Zachariou 2016). These data imply that in the pathogenesis of 12.2.5 Neurotransmitters: Serotonin both depression and chronic pain, an interaction (5-HT) and Noradrenaline of immune, endocrine, and neurotransmitter sys- (NA) and Dopamine (DA) tems play a central role. These abnormalities probably cause dysregulation of brain structures The monoamine hypothesis of depression was involved in the regulation of emotion and pro- formulated 50 years ago. It posits that depletion cessing of pain. of concentrations of 5-HT, NA, and DA has a causative role in pathogenesis of depression (Delgado 2000). A reduction of signaling in 12.2.6 Brain Networks of Depression ascending serotonin neurons, projecting from and Pain midbrain raphe and noradrenaline neurons—projecting from locus coeruleus pathways to limbic Functional neuroimaging enables identification system and frontal cortex—is responsible for of cortical and subcortical structures involved in “psychological” symptoms of depression. the perception of different aspects of pain, also It has been postulated that the malfunction of referred to as “pain matrix.” Primary and second- descending 5-HT and NA neurons may modify ary somatosensory cortices and the IC are respon- perception of pain and cause painful physical sible for encoding the sensory aspects of pain, its symptoms in depression (Stahl 2002). These neu- location, and duration. The emotional and moti- rons have an inhibitory role in pain perception. vational aspects of pain perception are processed Two reciprocally connected anatomic structures in the ACC, IC, amygdala, and NAc. The prefron- play a key role in the inhibition of pain. The first, tal cortex plays a role in the regulation of pain the periaqueductal gray (PAG), receives fibers perception (Apkarian et al. 2005; Bushnell et al. from the amygdala, hypothalamus, and frontal 2013). cortex. The second, the rostral ventromedial Structures involved in processing the affective medulla (RVM), receives inputs from the thala- component of pain are also relevant to under- mus, parabrachial regions, and noradrenergic standing a neural basis of depression. In short, neurons from the locus coeruleus. Descending emotion and reward processing are regulated by projections from the RVM increase the release of the amygdala and ventral striatum. The medial 5-HT in the dorsal horn leading to the antinoci- prefrontal cortex and ACC regulate the process- ceptive effect. The RVM contains “on cells” ing of emotion and the autonomic regulation of which facilitate pain transmission as well as “off emotion. Both the dorsolateral (DLPFC) and the cells” which inhibit pain perception. Moreover, ventrolateral (VPFC) prefrontal cortex, by their stimulation of the PAG and RVM can release NA connections to the limbic region, are involved in into the spinal dorsal horn. The final antinocicep- the cognitive control of emotions. Disturbances tive effect is mediated by its NA binding to of these structures and connecting pathways alpha-2 receptors (Ossipov et al. 2014). account for affective, motor, and cognitive symp- Ascending dopaminergic transmission from the toms of depression (Kupfer et al. 2012) and also ventral tegmental area to the NAc and prefrontal chronic pain (Lee and Tracey 2010). cortex plays a key role in the regulation of mood, Neuroimaging studies have demonstrated modest salience, motivation, and reward. Aberrant func- structural and functional abnormalities in the 12 Overlapping Chronic Pain and Depression: Pathophysiology and Management 167 frontal-limbic regions of depressed patients investigate whether brain responses to painful (Apkarian et al. 2004; Arnone et al. 2012; Busatto stimuli in depressed patients normalize after 1 2013) and in chronic pain conditions like fibro- and 8 weeks of treatment with duloxetine. The myalgia and chronic back pain (Kuchinad et al. results imply that the clinical improvement in the 2007; Burgmer et al. 2009; Robinson et al. 2011; course of treatment with duloxetine was related Ivo et al. 2013; McCrae et al. 2015). to a significant reduction of activation in, i.e., the The prefrontal cortex is implicated in continu- pregenual ACC, right prefrontal cortex, and pons, ous monitoring of the external world and the regions overactivated at baseline. maintenance of information in short-term mem- Results of several studies indicate dysfunction ory and in governing efficient performance con- of IC in the regulation of pain perception in trol in the presence of interfering stimuli, as well depression. IC possesses an extensive connection as in the regulation of perception and the behav- with frontal-limbic structures (Graff-Guerrero ioral expression of pain. In the context of pain et al. 2008; Strigo et al. 2010). Neuroimaging perception, Lorenz et al. (2003) argue that the studies provided evidence for the functional reor- DLPFC plays a role in “keeping pain out of mind.” ganization of the IC in major depression. In Results of functional brain imaging studies in depressed patients, emotional processing was patients with depression and chronic pain also shifted to the dorsal anterior insula—regions nor- indicate to abnormal function of common brain mally activated in response to physical pain. This structures. Early PET studies of depressed patients phenomenon seems to explain why depressed provided evidence that brain glucose metabolism individuals perceive pain in response to nonin the prefrontal cortex is decreased (Mayberg painful stimuli (Mutschler et al. 2012). et al. 1999; Kimbrell et al. 2002) These observa- A wealth of experimental and clinical data tions were confirmed by more recent reports (Li shows that mesolimbic dopaminergic neurons et al. 2015). The second neuroimaging marker of have the modulatory role in the perception of major depression, confirmed in a meta-analysis of pain. Dysfunction of the NAc and the ventral teg- functional imaging studies, is increased activity in mental area were documented to induce excessive the medial and inferior prefrontal cortex, the basal pain in animal models (Saadé et al. 1997). Then ganglia, and in the amygdala—neural systems PET studies showed abnormalities in the striatal supporting the regulation of both pain and emotion dopaminergic system in patients with atypical (Fitzgerald et al. 2008). Interestingly, dysfunction facial pain (Hagelberg et al. 2003a, b) and burning of the prefrontal cortex was also demonstrated in mouth syndrome (Hagelberg et al. 2003a). patients with rheumatoid arthritis (PET study) Deficits of dopamine are also linked with the (Jones and Derbyshire 1997) and in fibromyalgia common comorbidity of pain and depression in (fMRI study) (Loggia et al. 2015). Parkinson’s disease. However, dysfunction of the Evidence suggests that in patients with MDD, reward dopamine reward system is postulated as modulatory mechanisms of pain perception are a cause of core symptoms of depression anhedo- ineffective. During painful stimulation in unme- nia, reduced motivation, and decreased energy diated depressed patients exposed to painful heat levels (Nestler and Carlezon 2006). stimulation, activation in periaqueductal gray, rostral anterior cingulate, and prefrontal cortices was decreased in comparison to non-painful 12.3 Management stimuli. These structures are responsible for pain and emotion modulation. Moreover, increased The first tricyclic antidepressant (TCA)—imipra- activation in the right amygdala, anterior IC, and mine—was introduced in the 1960s. Somewhat ACC may suggest a bias toward affective pro- later, the effectiveness of this class of drugs in the cessing of pain which was also observed during management of chronic pain was discovered. In anticipation of pain (Strigo et al. 2008). The aim the last decade of the twentieth century, several of the study by López-Solà et al. (2010) was to new classes of antidepressants, namely, selective 168 J. Jaracz serotonin reuptake inhibitors (SSRIs) and SNRIs, comparison to a placebo group (Vahedi et al. were accepted for treatment of depression and 2005). Good efficacy of citalopram (Tack et al. other psychiatric disorders. Subsequently, these 2006), but not paroxetine (Masand et al. 2009), drugs turned out to be useful in the treatment of was also reported. Furthermore, in an open- chronic pain syndromes. As a consequence, in labeled study, the treatment with duloxetine the WHO three-step ladder of management of caused an improvement in gastrointestinal symp- chronic pain, antidepressants are recommended toms (Brennan et al. 2009). Ford et al. (2009) in as adjuvant treatment to nonopioid and opioid their systematic review and meta-analysis found analgesics (Kapur et al. 2014). Clinical evidence evidence for the efficacy of TCAs or SSRIs in the suggests that antidepressants are effective in the treatment of distension, pain, and stool consis- management of chronic pain conditions (i.e., tency in patients with IBS. In a more recent meta- neuropathies, back pain) and functional somatic analysis, Xie et al. (2015) concluded that TCAs syndromes (i.e., fibromyalgia and irritable bowel may also ameliorate symptoms of IBS, whereas syndrome) and in the treatment of PPS in the the authors did not find strong evidence support- course of major depression. ing the efficacy of SSRIs for the treatment of IBS. In recommendations regarding pharmacologi- These data suggest that in the aforementioned cal treatment of neuropathic pain, Dworkin et al. painful conditions, dual-action antidepressants (2010) argue that TCA, SNRIs, gabapentin, and possibly have a superior effect on pain in com- pregabalin, as well as topical lidocaine, are meth- parison to SSRIs. PPS in depression are likely to ods of first-line management. These recommen- have a different neurobiological basis than neuro- dations were supported by two subsequently pathic pain, painful functional syndromes. published meta-analyses, confirming the efficacy Hence, one may presume that extrapolation of of TCA and SNRIs in the treatment of neuro- results from studies of patients with primary pain pathic pain (Griebeler et al. 2014; Finnerup et al. conditions to recommendations for patients with 2015). These two groups of antidepressants depression and PPS is not justified. appeared also to be useful in the management of The efficacy of antidepressants with different non-neuropathic chronic pain in the course of mechanisms of action for reducing severity of rheumatoid conditions, lower back pain, and pain in psychiatric disorders was the aim of sev- headaches, whereas studies with SSRIs provided eral studies. Two randomized, double-blind stud- inconsistent results (Dharmshaktu et al. 2012). ies demonstrated that fluoxetine (Luo et al. 2009) Functional somatic syndromes—fibromyalgia and citalopram, but not reboxetine (Aragona (FM) and irritable bowel syndrome (IBS)—mani- et al. 2005), alleviated symptoms of somatoform fest among other symptoms by unexplained pain pain disorder. The efficacy of SNRIs in treatment and commonly co-occur with depression. Results of PPS in depression was widely investigated. of clinical studies and their meta-analyses consis- The advantageous impact of venlafaxine on both tently confirm the efficacy of amitriptyline and symptoms of depression and chronic pain was SNRIs (duloxetine, milnacipran, and venlafaxine) found in an observational study of 505 patients in reducing pain and other symptoms of FM treated in primary care (Begré et al. 2008) and in (Arnold et al. 2013; Chappell et al. 2008; Häuser an 8-week study of patients with first-episode et al. 2012; VanderWeide et al. 2015), whereas depression with painful symptoms (Huang et al. Walitt et al. (2015) did not find convincing evi- 2013), whereas a 6-week investigation of patients dence for SSRIs’ efficacy in treating pain, fatigue, with depression and co-occurring chronic lower and sleep problems in patients with FM. Studies back pain showed a modest therapeutic effect on examining the usefulness of antidepressants in the pain of 150 mg of venlafaxine. At the final point treatment of IBS have provided inconsistent con- of the study, only 26.4% of participants responded clusions. Results of a 12-week double-blind study in both conditions (Rej et al. 2014). in constipation-predominant IBS showed a better Duloxetine is another potent, dual-reuptake response in patients treated with fluoxetine in inhibitor of 5-HT and NA. This medication has 12 Overlapping Chronic Pain and Depression: Pathophysiology and Management 169 been studied in several placebo-controlled, ran- mechanism of action is recommended. The ratio- domized trials which showed that duloxetine is nale for this strategy was investigated in patients effective in reducing pain in depressed patients with MDD with considerable pain, who did not (Brannan et al. 2005; Fava et al. 2004; Raskin et al. respond or partially responded during 6 weeks of 2007). The results of a meta-analysis of 11 ran- treatment with SSRIs (Perahia et al. 2009). After domized, placebo-controlled studies conducted by switching to duloxetine, significant diminution of Ball et al. (2011) confirmed these findings. pain severity, time in pain, and interference with The issue of whether serotonergic drugs are as functioning due to pain was noted. The authors of effective as noradrenergic agents in the treatment another study found that in patients with moder- of PPS in depression was the aim of our study. ate to severe pain in the course of MDD initially We found that during 8-week treatment, both treated with escitalopram and who did not serotonergic (escitalopram) and noradrenergic improve after 4 weeks, a switch to duloxetine at (nortriptyline) antidepressants were equally effi- this point of the study led to earlier alleviation of cacious in the alleviation of PPS in depression pain intensity and better response in terms of (Jaracz et al. 2015). functional remission than in a group of patients In clinical practice, SSRIs are recommended as were change to duloxetine took place after a first-line treatment of depression. So a relevant 8 weeks (Romera et al. 2012). question arises as to whether SSRIs are as effec- The relationship between improvement of tive as SNRIs in patients with depression and painful symptoms and basic symptoms of PPS. A multicenter, randomized, non-blinded, depression seems to be an interesting theoretical parallel group 12-week trial conducted by and practical problem. In this regard, two Martinez et al. (2012) showed that, in terms of hypotheses should be considered. The first of depression remission rate, the efficacy of dulox- these is that the reduction of pain is secondary to etine was similar to that of generic SSRIs (citalo- an improvement of core depressive symptoms, pram, fluoxetine, paroxetine, or sertraline), and the second is that antidepressive drugs have whereas the impact of duloxetine on PPS was sub- a direct impact on PPS. The view prevails that stantially better. These findings are contradictory there is a bidirectional relationship between to the results, published earlier, of a pooled analy- reduction of severity of depression and intensity sis of eight studies comparing the efficacy of of pain (Kroenke et al. 2011). Moreover, a sig- duloxetine (40–120 mg/day) and paroxetine nificant pain reduction between weeks 2 and 4 (20 mg/day) in depressed patients. Both drugs appeared to be a good predictor of a positive appeared to be comparably effective in the reduc- response to treatment with duloxetine (Schneider tion of painful symptoms assessed by visual ana- et al. 2011). The relationship between PPS and log scale (VAS) (Krebs et al. 2008). Taken these efficacy of treatment was also investigated by findings into account, the authors conclude that Robinson et al. (2013) in a post hoc analysis of there is no clear evidence to suggest the superiority two 8-week studies comparing duloxetine of SNRIs over SSRIs in the treatment of MDD 60 mg/day and a placebo. Applying a path analy- with accompanying pain. This assumption cor- sis, the authors found that the probability of roborates the results of a recent meta-analysis con- obtaining remission in patients treated with ducted by Gebhardt et al. (2016). The authors duloxetine is dependent on improvement in pain included 19 studies investigating the efficacy of and functional impairment. Moreover, the alle- different classes of antidepressants in the treat- viation of pain and mood severity was related to ment of primary depressive disorder with pain functional improvement in patients with PPS symptoms and found no relevant differences associated with MD. among SNRIs and SSRIs in the alleviation of PPS. A path analysis carried out in two studies of In patients with depression with inadequate MD patients showed that, at least 50% of the response to treatment with SSRIs switching to duloxetine impact on pain was independent of the another antidepressant, preferably different improvement in the psychological symptoms of 170 J. Jaracz depression (Fava et al. 2004; Mallinckrodt et al. study. This intervention was more effective in 2003). These results indicate that in patients with terms of improvement of disability, depression, MD, antidepressants convey both direct and indi- pain intensity, and pain interference in compari- rect analgesic effects. son to a group of patients treated “as usual.” It has been well documented that cognitive and emotional factors play a modulatory role in pain perception (Bushnell et al. 2013). 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Kiwon Kim and Hong Jin Jeon

13.1 Introduction on depression, would be effective dealing both with physical health and with mental health Interaction between depression and medical ill- (Smith et al. 2016). nesses is well known by the impact of depression to medical illness with negative risk behaviors and psychobiological changes and by impact of 13.2 Biological Mechanism medical illness to depression with biological Between Depression changes and complications (Egede 2007; Katon and Medical Illness et al. 2007; Katon 2011). More burdens of medi- and Chronic Stress cal symptoms, functional disability, larger costs followed by significant increases in utilization, 13.2.1 Biological Mechanism Related and poorer self-care coupled to increased mor- to the Hypothalamic- bidity and mortality would be related to comor- Pituitary-Adrenal (HPA) Axis bid depression (Narasimhan et al. 2008). Through pro-inflammatory interactions, hypo- The bidirectional interaction between depression- thalamic pituitary axis dysfunctions, altered related inflammation and inflammation induced function in autonomic nervous system, and from physical illness is a well-known theory changed metabolic factors, accompanied with suggesting novel antidepressant development negative lifestyles, depression can worsen the and leading to the development of specialty of progress of medical illnesses. Therefore, careful psychoneuroimmunology (Leonard 2017). His acknowledgment of depression in medically ill torically, stress-induced hypercortisolemia has condition, following collaborative management been understood as a part of adaptive response which belonged to “fight-or-flight” response. But it can be applied to protective function only limited to acute situations, which in the prolonged K. Kim stress response dissociated from the initiating Department of Neuropsychiatry, Seoul National University Bundang Hospital, stimulus; this component of adaptive mechanism Seongnam, South Korea can be harmful to the brain and peripheral organs e-mail: [email protected] (Segerstrom and Miller 2004). H.J. Jeon (*) The alteration coupled to chronic stress and Department of Psychiatry, Depression Center, cellular immunity brings alteration in the charac- Samsung Medical Center, Sungkyunkwan University teristics of glucocorticoid receptors consisted of School of Medicine, Seoul, South Korea e-mail: [email protected] their expression and sensitivity (Quan et al. 2003).

The so-called glucocorticoid receptor desensitiza- of immune system. Triggered by the pathogen, tion, which is a combination of increased inactive the innate immune system initiates the release of alpha-glucocorticoid receptor isoform and the histamine, prostaglandins, bradykinin, sero- decreased active beta-form of the receptors tonin, and leukotrienes, producing a localized induced by pro-inflammatory cytokines, repre- inflammatory response including vasodilation sents the declined response to the peripheral glu- and pain, gathering macrophages. cocorticoids (Pace and Miller 2009). Usually, in The adaptive immune response includes the the acute stress reaction, glucocorticoids down- functions of T cells and B cells, which are known regulate the expression of inflammation, but in the to be lacking in the bran system. But T cells rooted chronic stress reaction following chronic medical from the periphery system also circulate to the illness, glucocorticoid receptor desensitization brain and spinal cord through the meninges, cho- leads to increased inflammatory state. roid plexus, and cerebrospinal fluid. Blood-brain Chronic activation of the hypothalamic- barrier, which has been known as physical barrier, pituitary-adrenal (HPA) axis accelerates this phe- conversely can work for the route of large mole- nomenon bringing exaggerated release of cules and cells depending on the region of the glucocorticoids coupled with hindrance in the brain or of the choroid plexus regions and the deg- plasma binding capacity of corticosteroid bind- radation stage of the astrocyte-pericyte sheath ing globulin. These changes include both cellular (Leonard 2017). reduction in the translocation of glucocorticoids The pro- and anti-inflammatory cytokines receptors and reduction in the reactivity of recep- including IL-1β, IL-6, TNF-α, IFN-γ, tor protein in immune cells, either in peripheral IL-antagonist, and TGF-β boost the HPA axis, tissues or in the hippocampus, which was classi- followed by upregulation of cortisol synthesis, fied as essential region of negative feedback reg- and activate the tryptophan-kynurenine pathway ulation of the HPA axis (De Kloet et al. 1998). (Galic et al. 2012). These phenomena, which can lead to the neurotoxic N-methyl-d-aspartate (NMDA) glutamate agonist quinolinic acid pre- 13.2.2 Biological Mechanism Related cipitating oxidative stress and neurodegeneration to the Immune System are highly observed features in late life depression (Myint and Kim 2003). Neuroinflammation includes implication of immune-related process occurring inside of the brain and spinal cord, which is a consequence of 13.3 General Issues as Clinical harm brought by infection, psychological stress, Characteristics in Depression and physical stress. Followed by neuroinflamma- with and Without Physical tion, the innate immune cells including the Illness microglia, astrocytes, and oligodendroglia, reacted by the stimulus, are encouraged to release In this section, clinical manifestations related to cytokines, chemokines, and accessory inflamma- depression comorbid to medical illnesses will be tory mediators, known as the prostaglandins. described in crude way, which will be discussed in Such harmful and maladaptive inflammatory detail, lately. In endocrine disease classification, response in the brain system is clearly manifested depression is quite common clinical characteris- in the major neurological disorders, embracing tics in Cushing’s syndrome manifested as major cerebrovascular events, multiple sclerosis, and depression, often with melancholic subtype, com- neurodegenerative diseases like Alzheimer’s dis- monly accompanied with irritability and emo- ease or Huntington’s disease (Lee et al. 2010). tional lability, vegetative symptoms, anhedonia, Previously dividing the immune response into psychomotor retardation or agitation, decreased the innate and adaptive components, the brain has concentration, and suicidal thoughts (Kelly 1996; been considered to be a special region in regard Sonino et al. 1993). People with hypothyroidism 13 Clinical, Biological, and Therapeutic Characteristics 177 show depression or anergia (Sternbach et al. 1983), comes (Bair et al. 2003). Patients with both pain while people with primary hyperparathyroidism and depression showed larger number of general accompany depression, tiredness, forgetfulness, practice visits, more frequent tests, higher rate of decreased concentration, uneasiness, sleepless, antidepressant change, and more frequent refer- and irritability (Tsukahara et al. 2008). ral to secondary care (Watson et al. 2009). More Neurological disorders, which can be associated severe work dysfunction has been observed in with dysfunctional regulation of chronic inflam- patients with comorbid pain and depression mation, including multiple sclerosis, meningioma, mediated by both sickness absence and loss of and Parkinson’s disease contain major depressive productivity (Demyttenaere et al. 2010). disorder features and concomitant anxiety (Gonera While assessing patient with pain, careful his- et al. 1997; Kantorova et al. 2017). tory taking related to current or past maltreatment In malignant disorders, loss of ambition, loss or shock would be necessary. The clinician should of motivation, or lack of energy to proceed accom- show empathy on their medical illness and pain panied with vegetative symptoms seems to be with structured interview. Acknowledging patient’s common in pancreatic cancer (Grassi et al. 2014). behavior related to pain and illness would be an In lung cancer (Montazeri et al. 1998) and gastric essential part of interview. Delicate approach on cancer (Andersen et al. 2014), all depressive fea- invasive test and on using medication which can tures can be manifested as related to its shared bring addiction is necessary. Every time, careful mechanisms or precipitated by paraneoplastic consideration on psychiatric evaluation and related syndromes or concomitant medications and interview should be prepared. There are several poorly controlled pain. Heart disease especially in fundamental rules for administrating opioid anal- myocardial infection, major depressive clinical gesics. First, make strong therapeutic relationship features, demoralization, somatic and generalized between clinician and the patient. Second, careful anxiety, panic, and agoraphobia all can be under- checkup for the psychiatric status such as comorbid stood as early manifestations of comorbid medi- depression or anxiety should be accompanied with cal illnesses (Ottolini et al. 2005). AIDS patients therapeutic approach related to pain. Third, enough also report somatic and nonsomatic symptoms of dose of pain killer with appropriate duration with depression ranging from sadness to low mood and regular phase should be administrated to the anhedonia usually 1.5 years before their diagnos- patient, not to make the patient crave for additional tic sentence and continue to report these symp- pain killer. Fourth, it would be better to use “around toms thereafter (Lyketsos et al. 1996). the clock” rather than with prn medication. Long- acting sustained-release dosage form of pain killer would be preferred to short-acting dosage form of 13.4 Depression with and injection type. Regular and quite frequent thorough Without Pain evaluation for the pain itself would guide necessary approaches to the clinician. Pain and depression commonly exist simultaneously, bringing 2.5–10 times increase in anxiety or depression in patients with pain (Cocksedge 13.5 Depression with and et al. 2014; Means-Christensen et al. 2008). Without Autoimmune Comorbid pain can blur the fine description of Disorders mood change and interfere with treating depression, which depressed patients frequently com- Frequent comorbidity with depression and autoim- plain about pain than their low mood (Bair et al. mune disorders was discussed in previous section. 2003). Though clinician has detected depression However, few longitudinal studies have gone comorbid with pain, clinicians are frequently apt through to prove immune responses affecting the to be focused on pain management than their psy- brain and leading increased risk of mood disorders. chological treatments, which can bring poor out- From a nationwide longitudinal follow-up study, 178 K. Kim and H.J. Jeon autoimmune disease and infections seemed to be Interestingly, not all therapies need to be immu- risk factors for subsequent mood disorder diagno- nosuppressive as evidenced by the success of fish sis. Their associations seem to be in line with an oil for antioxidant properties in fatigue (Arriens immunologic hypothesis for incidence of mood dis- et al. 2015). Otherwise, anticytokine therapies, orders in these patients (Benros et al. 2013). Inside targeting IFN-α and its receptors, may bring ben- of autoimmune disease patient, systemic inflamma- efit independently unaffecting peripheral organs. tion can induce a “sickness behavior,” with symp- Inflammatory bowel disease (IBD), one of the toms of fatigue, loss of appetite, apathy, decreased well-known autoimmune disorders, also frequently social interaction, concentration difficulty, and seems to be accompanied with depression. Recent sleep problems. These symptoms are similar to reconceptualization of depression as clinical phe- symptoms of depression, and studies have sug- nomenon representing activated immune-inflam- gested that in vulnerable patients, prolonged sick- matory, oxidative, and nitrosative stress pathways ness behavior can progress to depression. consisted of tryptophan catabolite, autoimmune, Unrestrained acute and chronic inflammation and gut-brain pathways. Oxidative and nitrosative has unintentional detrimental effects on cogni- pathways are combination of the pathogenesis in tion, mood, and fatigue. The chronic inflamma- IBD. Usually lower quality of life and increased tory state in systemic lupus erythematosus (SLE) morbidity in IBD are associated with increased with recurrent episodes of acute escalation brings depression prevalence, suggesting the depression the necessary cascade for altered CNS processes role with modulation on IBD. Increased oxidative that govern cognition and mood. Clinically, cen- and nitrosative stress processes in depression coin- tral neuropsychiatric SLE (NPSLE) syndromes cide with the biological underlying mechanisms of including cognitive impairment, mood distur- IBD, suggesting increased comorbidity of both dis- bances, and fatigue are both transient and chronic, orders (Martin-Subero et al. 2016). and neuronal damage alone from direct antibody In some patients, depressive symptoms remit or MMP-mediated toxicity or ischemia, embolic with aggressive medical treatment of underlying events, or atherosclerotic disease would not lead IBD progression, while others need additional to transient phenomena. However, altered cyto- behavioral interventions or symptom-targeted kine- and chemokine-mediated signaling through medication because of their functional impairment peripheral or central pathway may impact synap- or persistence of depression. Not all patients with tic plasticity and LTP in a short time, bringing a IBD show depression, especially when observed result of transient cognitive impairment. during the IBD remission phase (Greenley et al. Both anti-NMDAR and anti-P antibodies have 2010; Reed-Knight et al. 2014). More thorough been shown to be associated with synaptic plasticity longitudinal studies discriminate depressive phe- in region of hippocampus, in addition to their neu- notypes and different mechanisms related to con- rotoxic influences, suggesting additional results as comitant depression in Crohn’s disease (CD) and transient cognitive impairment or mood distur- ulcerative colitis (UC). Comprehensive evaluation bances. The same pro-inflammatory cytokines have of both neurobiological and psychosocial aspects been shown to promote oxidative stress resulting in related to depression will help clinician intervene DAMPS production and TLR engagement leading in patient’s health-related quality of life. to extreme fatigue. For it is important in SLE pathogenesis and dose-dependent associations of therapeutic effect of itself on neuropsychological 13.6 Depression with and symptoms of fatigue, depression, and seizures, Without Endocrine Disorders IFN-α is thought to be important clue on SLE. Depression is one of the most commonly Excessive or lack of thyroid hormones can cause reported symptoms in SLE with debilitating depression but also can be fixed by suitable thy- effects on quality of life, and the ultimate goal is roid treatment (Hage and Azar 2012). Thorough to develop appropriate therapeutic strategies. thyroid function test, detecting subclinical 13 Clinical, Biological, and Therapeutic Characteristics 179

hypothyroidism, also can be helpful in nonre- drome are observed to have difficulties in distin- sponse group of depression (Hage and Azar guishing emotional states and have impaired 2012), in which, in case of confirmation of sub- activation of brain structures responsible for per- clinical hypothyroidism, prescription of thyroid ception, processing, and regulation of emotions hormone in modest levels would be helpful. In similar to those found in major depression thyroid hormone augmentation regimen, triiodo- (Langenecker et al. 2012). Normalizing level of thyronine with dose between 25 and 50 micro- cortisol through appropriate treatment can bring gram per day is preferred to thyroxine for its treatment effect to the comorbid depression, biological activity in the brain (Orsi et al. 2014). decreasing accompanied percent of patients’ Contraindication of using triiodothyronine in cor- (Lau et al. 2015; Osswald et al. 2014). onary artery disease or chronic heart failure and Relationship between diabetes and depression precaution in diabetic patients should be noted. has been discussed for many years for their simi- Patients with polymorphism which means lower lar mechanisms and impacts. Fetal or maternal conversion activity of thyroid hormone were more stress, consistent low socioeconomic status, and likely to react to triiodothyronine augmentation poor health behaviors in individuals accompany- (Cooper-Kazaz et al. 2009). Even if assessment of ing genetic predisposition might promote dys- thyroid dysfunction is not the primary step for functional HPA axis, circadian rhythm shifts, and depressive patients, when patients are not respond- precipitation in the innate inflammatory response. ing to treatment either accompanying history of Altered regulation of these biological pathways thyroid disease or concomitant signs and symp- might bring insulin resistance and type 2 diabe- toms of thyroid dysfunction, thyroid evaluation tes, depression, dementia, and cardiovascular dis- should be considered for screening. ease. Excess pro-inflammatory cytokines in the The most common psychiatric representation brain resulting in increased neuroactive metabo- of Cushing’s syndrome is mood disorders. lites coming from decomposition of tryptophan Depression occurs in approximately 25% of the and reduced serotonin would lead to depression. patients in the prodromal phase of Cushing’s syn- Also close association between type 1 diabe- drome (Sonino et al. 1993). The incidence, type tes and depression is striking, during adjustment of mood disorders, and response to treatment are to diagnosis of type 1 diabetes and treatment not related to the etiology of Cushing’s syndrome course with increasing vulnerability to depres- (Sonino and Fava 2001). The potential risk fac- sion. It may be related to more sensitive brain tors related to depression are old age, being which leads to quick end effects of these biologi- female, high levels of cortisol in the urine before cal pathways or first environmental stress impact treatment, and more severe clinical condition bringing central dysregulation of metabolism (Sonino et al. 1998). Still clear conclusion (Moulton et al. 2015). whether depressive disorders result from direct Even though screening and treatment for effect of hypothalamic-pituitary-adrenal axis dis- depression in diabetes are still incomplete, detect- orders or indirect effect of disfigurement, pain, ing depression in diabetes with validated instru- and a lack of self-appearance is not existing. ments can be effective if there are subsequent Functional hypercortisolism in major depression treatment pathways. To prevent negative interac- (Carroll et al. 2012; Tirabassi et al. 2014) was tion between diabetes and depression, all three suggested in a ground of animal models, and the approaches should focus on remission of depres- hippocampus is particularly sensitive to hyper- sion, improvement of depressive symptoms, and cortisolism brought by exposure to exogenous fine glucose control. Through collaborative care glucocorticoids or heavy stress as hippocampal and stepped approaches, numerous psychological neurons have a high density of glucocorticoid and medical interventions could lead to depres- receptors, which in the case of chronic hypercor- sion treatment in diabetes. However, further evi- tisolism may lead to a selective shrinkage of the dence should be proposed for treatment evaluation hippocampus. Individuals with Cushing’s syn- for depression subtypes in diabetic individuals, 180 K. Kim and H.J. Jeon the cost-effectiveness of treatments, healthcare als is essential in situation such as risk of service use, accompanying cultural impacts, and self-injury or others’ injury, severe depression or new treatment approaches including preventive agitation, or the psychotic state or delirious state. interventions (Petrak et al. 2015). Such careful assessments should be applied with collaborative team approach, accompanying clear identification of signs and symptoms in 13.7 Depression with and Without depression, cancer symptoms, stressors, risk fac- Cancer tors, and vulnerability. Before starting antidepressant medication especially including Depression is common in individuals with cancer administration of interferon, medical cause or (Currier and Nemeroff 2014), supported by recent substance problem related to depression must be major meta-analysis (Mitchell et al. 2011) report- considered and managed. ing 16% prevalence of major depression in oncology and hematology inpatient and outpatient individuals. Elderly patients with metastases 13.8 Depression with and Without showed 2.2 times increased ration of depression, Major Organ Failures while individuals with cognitive impairment showed 3.6 times increased likelihood (Mystakidou 13.8.1 Depression with and Without et al. 2013). However, differential diagnosing Myocardial Disease between pathological and normal bereaving reac- and Congestive Heart Failure tions to cancer is major challenging step. Though hardship on this assessment, depression even in Both an increase in coronary heart disease (CHD) subthreshold condition should be alarmed for its in individuals with depression and increased negative influence on quality of life, treatment morbidity and mortality in CHD patients who compliance, suicidality and mortality rate. From become depressed are well-known interaction. these backgrounds, all individuals with cancer One large prospective study found that depres- should be screened for depressive symptoms from sive symptoms had more great likelihood of CHD the initial visit, with appropriate interval follow- events in late life, especially sudden cardiac ups correlated to clinical progress, including post- death, with a specific relationship between this treatment, at the time of recur, progressed phase, outcome and antidepressant use (Manea et al. and transition period considering palliative care. 2012). Fifteen to twenty percent of individuals Valid and reliable assessments with phased screen- with myocardial infarction or angina are reported ing and assessment should be applied, with full to have major depressive disorder (MDD) identification of the pertinent history of depression (Mavrides and Nemeroff 2013). And these indi- risk factors. About 25–30% of individuals usually viduals were reported to be associated with fully report depressive mood and anhedonia, increased mortality and decreased cardiovascular which should complete the full version of the outcome. Between close relationship with coro- Personal Health Questionnaire (PHQ-9) (Kroenke nary artery disease and depression, few mecha- et al. 2001). Even though the usual cutoff score for nisms including inactivity, decreased heart rate PHQ-9 is ten, for individuals with cancer, PHQ-9 variability (Whooley et al. 2008), platelet hyper- cutoff score is applied as eight (Manea et al. 2012). activation (Morel-Kopp et al. 2009), and And applying assessment with consideration of increased inflammatory markers or HPA activity culture, tailoring assessment, and treatment option are thought to be existed. Speaking of chronic for learning disabilities or cognitive impairments heart failure, 21.5% of individuals with heart fail- and careful approach with differentiating depres- ure were reported to have depression, higher in sion in elderly patients are necessary. more severe heart failure, which leads to higher Appropriate referral to a psychiatrist, psy- mortality rate and following cardiac events (Diez- chologist, physician, or other trained profession- Quevedo et al. 2013). 13 Clinical, Biological, and Therapeutic Characteristics 181

13.8.2 Depression with and Without Individuals with both CVD and active phase of Chronic Obstructive depression were reported to have higher 5-year Pulmonary Disease (COPD) mortality rate than those with stroke alone. Previously, the location of a stroke was suggested to Forty-one percent of patients with COPD were be an important mediating factor to poststroke observed to accompany with mild to moderate depression, which now has been found no evidence, depressive symptoms, and the most severe compromised with other consistent predictors, depressed individuals seemed to be more hospi- including sequelae of stroke such as physical dis- talized (Fan et al. 2007). The most severe depres- ability, cognitive impairment, and severity of stroke sive patients were reported to have significantly (Carson et al. 2000; Hackett and Anderson 2005). increased 3-year mortality rate as odds ratio of 2.7 increased tendency of dyspnea and decreased body weight (Janssen et al. 2010). 13.9.2 Depression with and Without Parkinson’s Disease

13.8.3 Depression with and Without Approximately 8–17% of Parkinson’s disease Chronic Renal Failure (CRF) patients are reported to have major depression, but differential diagnosis between comorbid Through subjective report-based depression major depression and Parkinson’s disease and screening in chronic kidney disease (CKD), 20% patients with sole Parkinson’s disease is difficult of individuals with CKD were estimated to have because of similar symptoms such as psychomo- depression, while 23% of individuals with dialy- tor retardation and restricted facial expression. sis were estimated to have depression (Palmer Although detecting comorbid depression is diffi- et al. 2013). Both social and biological risk fac- cult, prevalence of depression in Parkinson’s dis- tors and the consequence of renal failure and ease has been reported to be positively associated dialysis on loss of control in life and quality of with severity of Parkinson’s disease and accom- life make this comorbid depression in CKD panied dementia (Aarsland et al. 2011). higher (Bautovich et al. 2014). Multiple poor outcomes such as frequent and long hospitalizations, poor compliance to treatment, and high mortality 13.9.3 Depression with and Without rate can be associated with depression in Dementia CKD. Although these consequences, rated of diagnosis and followed appropriate management The prevalence of depression in dementia is esti- in depression co morbid to CKD remain unclear mated at approximately 25% (Enache et al. 2011; and low (Hedayati and Finkelstein 2009). Orgeta et al. 2014). Individuals with dementia are recommended to go through evaluation and follow-up evaluation for depression over time (Ihl 13.9 Depression with and et al. 2011; Sorbi et al. 2012). Ruling out for sec- Without Neurological ondary causes of depression also should be Disorder assessed. The application of a valid tool for screening depression in dementia includes the 13.9.1 Depression with and Without Geriatric Depression Scale (GDS), Cornell Scale Cerebrovascular Disease for Depression in Dementia (CSDD), or Dementia Mood Assessment Scale (DMAS) (Hort et al. The prevalence of comorbid depression in inpa- 2010; Sorbi et al. 2012). Among these instru- tients with cerebrovascular disease (CVD) is ments, the CSDD, clinician rating tool which can approximately 20%, and prevalence in outpatients cover caregivers’ depression with high sensitiv- with CVD is about 23% (Robinson 2003). ity, was more commonly recommended (Callahan 182 K. Kim and H.J. Jeon et al. 2006; Hort et al. 2010). Sophisticated 13.10 Therapeutic Approaches assessment is essential to find cognitive disorders in Depression with in geriatric population with depression through and Without Medical Illness fine neuropsychological investigations. The lack of generalization in feasible Alzheimer’s disease Clinicians must apply careful therapeutic inter- neuroimaging and neurochemical CSF biomark- ventions considering side effects and impair- ers and low rate application of this assessment in ments already existing due to the medical late-life depression make this correct diagnosis illnesses or other concomitant prescriptions. harder. Drug interactions and metabolism should be Even though psychological interventions have sophisticatedly managed especially with indi- been proved for their beneficial results, recent viduals with renal or hepatic dysfunction. Major antidepressant use in individuals with both issues related to drug interventions contain the dementia and depression has still been ques- effect of SSRIs on cytochrome P450 enzyme tioned. Further studies should focus on clinical (CYP450) activity and controversial bleeding and biological features to predict cognitive risk. Despite these sophisticated considerations impairment in both early- and late-life depres- needed for management, this medication found sion. Devotion to find neurobiology of depres- to have significant advantage over placebo in sion comorbid to cognitive impairment is also remission and/or response with similar efficacy necessary, involving networks or neurotransmit- between SSRIs and TCAs, in depression with ter systems for precise diagnosis in depression chronic medical illnesses: CVA, COPD, cancer, alone and concomitant neurodegenerative disor- Parkinson’s disease, diabetes, and cardiovascu- ders with depression. More large-scale, collab- lar disease (Taylor et al. 2011). However, matter orative researches on late-life depression are of this therapeutic intervention lies in poorer needed, covering clinical, neuroimaging, neuro- response to antidepressants and more adverse psychological, genetic, neurochemical, and envi- effects (Mitchell and Subramaniam 2005). Safe ronmental perspective. Careful approaches to application of antidepressants in medically ill prevent cognitive decline in patients with late-life individuals also should be focused considerably. depression are also essential. Big data with full Such concern is like using antidepressants as tri- description of demographic, psychopathological, cyclic antidepressants (TCAs) in individuals and genetic biomarker and imaging is necessary, with heart diseases. Individuals with arthritis, considering heterogeneous features observed in pain management, and osteoporosis should be depression group and pathological location of the managed with careful assessment in interaction brain in depression. These researches should be with concomitant medication and antidepres- analyzed with both cross-sectional and longitudi- sants (Caughey et al. 2010). Antidepressants, nal methods. Transfertilized form of researches psychosocial interventions, and other medica- such as the precision medicine paradigm (Collins tions to treat depression should be accompanied and Varmus 2015) adopted from oncology can be with managing dysfunctional conditions includ- a key to solve this ambiguity. Accepting that indi- ing endocrine alterations, chronic pain, and viduals with depression and neurodegenerative altered inflammation. Integrated care for depres- disorders could have complex genetic, epigene- sion in full concept of comorbidity also can tic, and genomic patterns is necessary, bringing bring better prognosis related to depression but molecular and cellular pathways which can be needs sophisticated forms targeting special tracked and also worked as targets for treatment. comorbid medical illnesses. Recently, collabora- These conditions can precede far before clinical tive care or stepped care approaches have symptoms emerge in depression and degenera- appeared to be promising in these situations tive disorders, bringing possibility of comprehen- (Miller et al. 2013; Woltmann et al. 2012). The sive exploratory biomarkers, supporting precision collaborative care consisted of a medically medicine. supervised nurse, the general practitioner work- 13 Clinical, Biological, and Therapeutic Characteristics 183 ing as guidelines, and collaborative care man- Considering significant prevalence of depres- agement, to control risk factors associated with sion in medical illnesses and its impact on the multiple illnesses. They work as stratified struc- prognosis of medical illnesses expressed as tures, comprised of structured evaluation, multi- morbidity or mortality, careful assessment of disciplinary treatment, and follow-up monitoring. depressive symptom screening and severity With these interventions, clinicians can also should be prepared with validated assessment. focus on outcomes including mortality, morbid- Grounded from previous researches, screen- ity, and risk factors for both physical illness and ing for depression must be followed by appro- depression. 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Tsukahara K, Sugitani I, Fujimoto Y, Kawabata Whooley MA, et al. Depressive symptoms, health behav- K. Surgery did not improve the subjective neuropsy- iors, and risk of cardiovascular events in patients with chological symptoms of patients with incidentally coronary heart disease. JAMA. 2008;300:2379–88. detected mild primary hyperparathyroidism. Eur Arch Woltmann E, Grogan-Kaylor A, Perron B, Georges Otorhinolaryngol. 2008;265:565–9. H, Kilbourne AM, Bauer MS. Comparative effec- Watson L, Baird J, Hosel V, Peveler R. The effect of tiveness of collaborative chronic care models for concurrent pain on the management of patients with mental health conditions across primary, spe- depression: an analysis of NHS healthcare resource cialty, and behavioral health care settings: system- utilisation using the GPRD database. Int J Clin Pract. atic review and meta-analysis. Am J Psychiatry. 2009;63:698–706. 2012;169:790–804. Burnout Syndrome and Depression 14

Renzo Bianchi, Irvin Sam Schonfeld, and Eric Laurent

We cannot have a successful science if we let our become a hotspot of occupational health research data lie to us. To attain cumulative knowledge, we must detect and correct those lies. If we do this, we (Schaufeli et al. 2009b; Schonfeld and Chang can successfully apply Occam’s razor and uphold 2017; Weber and Jaekel-Reinhard 2000). The the important principle of scientific parsimony. We syndrome has been associated with a variety of can discover the simplicity at the deep structure negative occupational consequences—including level that underlies the apparent and confusing complexity at the surface structure level.—Schmidt impaired work performance, absenteeism, and (2010, p. 240). job turnover (e.g., Schaufeli et al. 2009a; Swider and Zimmerman 2010)—and adverse health outcomes (e.g., Ahola et al. 2010; Toker et al. 2012). Relatedly, burnout research has resulted, in recent 14.1 Introduction years, in various recommendations and calls for action regarding the management of job stress The burnout syndrome has elicited growing inter- (e.g., Epstein and Privitera 2016; Shanafelt et al. est among the psychology and the psychiatry 2017). community since it was first described in the In this chapter, we provide an overview of the mid-1970s (Freudenberger 1974, 1975; Maslach burnout syndrome. We start by depicting the pio- 1976; Maslach and Pines 1977). Generally neering phase of burnout research that led to the viewed as a job-induced affliction (Maslach et al. introduction of the burnout construct in the scien- 2001; Schaufeli and Taris 2005), burnout has tific literature. We then describe the shift from initial exploratory and mainly qualitative research on burnout to more systematic, quantitative research R. Bianchi (*) Institute of Work and Organizational Psychology, on the syndrome. Finally, we summarize the most University of Neuchâtel, Neuchâtel, NE, Switzerland recent findings pertaining to the characterization e-mail: [email protected] of the burnout syndrome. These findings compel- I.S. Schonfeld lingly suggest that the syndrome referred to as Department of Psychology, The City College of the burnout is a depressive condition and not a dis- City University of New York, New York, NY, USA tinct entity. The findings call for more conceptual e-mail: [email protected] parsimony and theoretical integration in psychol- E. Laurent ogy and psychiatry, in the interest of more effec- Laboratory of Psychology (EA 3188), Bourgogne Franche-Comté University, Besançon, France tive treatment and prevention strategies and e-mail: [email protected] enhanced transdisciplinary communication.

14.2 The Dawn of Burnout ment—irritability, depersonalization, neglect, Research withdrawal from work, and derogatory and cal- lous attitudes toward recipients—that under- The burnout syndrome was first described by mined their professional efficacy. “Burnout” was Freudenberger (1974) as he was working as an used as an umbrella label for these symptoms unpaid clinical psychologist in an alternative (see also Maslach and Pines 1977; Pines and healthcare agency based in New York City.1 Maslach 1978). Freudenberger (1974) observed that some of the The dawn of burnout research was thus volunteer staff, which included the author him- marked by an empiricist (i.e., atheoretical and self, developed a constellation of symptoms in data-driven) approach to (occupational) health, response to their daily struggle to look after their relying on methods such as exploratory inter- patients—mostly drug addicts. Based on his field views, on-site observations, case-studies, and observations, Freudenberger (1974, 1975) char- personal experiences (Leiter and Maslach 2016; acterized burnout as a slowly installing syndrome Maslach et al. 2001). Importantly, the initial pub- involving, among other signs and symptoms, lications dedicated to the burnout syndrome did fatigue, physical weakness and susceptibility to not include any review of already-described illness, sleep disturbance, weight alteration, irri- stress-related conditions (Bianchi et al. 2017d). tability and frustration, crying spells, cynical and Moreover, the burnout construct was elaborated suspicious attitudes, psycho-rigidity, and profes- independently of the research carried out in psy- sional inefficacy. Freudenberger (1974) indicated chiatry and, more globally, in medicine. that the burned-out individual “looks, acts and Controlled clinical investigations were not con- seems depressed” (p. 161). Freudenberger (1975) ducted. The symptom picture associated with further noted: “In their negativism the burn-out burnout was not compared with the symptom pic- seems to be expressing his own depressed state of tures of stress-related conditions identified in the mind” (p. 79). Etiologically speaking, the burn- past. out syndrome has been viewed, from the outset, In the next section of this chapter, we continue as the product of a long-term discrepancy our examination of the history of the burnout between the expectations and resources of the construct by focusing on the development, from individual on the one hand and the actual out- the 1980s, of methods designed to study the burn- comes and demands of his/her activity on the out syndrome more systematically. other (Freudenberger 1974, 1975). Freudenberger and Richelson (1980) thus considered the burnout syndrome to be “brought about by devotion to 14.3 Shifting from Exploratory a cause, way of life, or relationship that failed to to Systematic Research produce the expected reward” (p. 13). on Burnout The emergence of the burnout construct was also stimulated by social psychological research 14.3.1 The Definition conducted in California. Maslach (1976) came to and Assessment of Burnout use the term “burnout” as she was studying emo- Symptoms tions and coping strategies among human services workers. In so doing, she observed that The first standardized measure of burnout symp- some workers experiencing unresolvable job toms, the Maslach Burnout Inventory, was stress (i.e., work overload) developed symptoms designed in the early 1980s (Maslach and Jackson of exhaustion and counterproductive detach- 1981; Maslach et al. 2016). On the basis of the data collected during the exploratory phase of burnout research, Maslach and Jackson (1981) 1 Fifteen years earlier in France, Veil (1959) described states of job-related exhaustion within a psychiatric created a pool of 47 items. The items were admin- framework. istered to a sample of workers from various 14 Burnout Syndrome and Depression 189 health and service occupations (e.g., teachers, b; Kristensen et al. 2005; Shirom 2005; Shirom nurses, social workers) and then subjected to a and Melamed 2006). factor analysis. Ten factors emerged from this Five versions of the MBI are currently avail- initial analysis, of which four accounted for over able: the MBI-Human Services Survey (MBI- three-fourths of the variance. The application of HSS), the MBI-Educators Survey, the diverse item selection criteria (e.g., a factor load- MBI-General Survey (MBI-GS), the MBI for ing exceeding 0.40 on only one of the four fac- Medical Personnel, and the MBI-GS for Students tors, a “high” item-total correlation) and the (Maslach et al. 2016). The MBI-GS has been conducting of additional factor analyses eventu- designed to allow virtually any occupational ally resulted in a 22-item questionnaire involving group to be assessed for burnout (Maslach et al. three dimensions: emotional exhaustion (e.g., 1996). The MBI-GS contains 16 items phrased in “Working with people all day is really a strain for generic ways. In the MBI-GS, the three dimen- me”), depersonalization (e.g., “I feel I treat some sions of burnout have been relabeled exhaustion recipients as if they were impersonal ‘objects’”), (e.g., “Working all day is really a strain for me”), and a sense of (reduced) personal accomplish- cynicism (e.g., “I doubt the significance of my ment (e.g., “I deal very effectively with the prob- work”),2 and (loss of) professional efficacy (e.g., lems of my recipients”). Emotional exhaustion “I can effectively solve the problems that arise in refers to feelings of being emotionally drained my work”). The three dimensions of the MBI-GS and exhausted by one’s work. Depersonalization have been assumed to be equivalent to those of involves a cynical attitude toward one’s job and previous versions of the MBI. However, the an unfeeling and impersonal way of responding validity of this assumption remains open to to people one is working with (e.g., clients or col- question (Larsen et al. 2017; Shirom 2003). For leagues). Reduced personal accomplishment example, in a factor analytic study of the three defines a tendency to evaluate oneself negatively subscales of the MBI-GS and the depersonaliza- and to feel incompetent and dissatisfied with tion subscale of the MBI-HSS, Salanova et al. one’s achievement on the job. The MBI assesses (2005) found that a four-factor model of burnout burnout symptoms within a 1-year time window, with separate depersonalization and cynicism based on a 7-point scale (from 0 for “never” to 6 dimensions fit their data better than a three-factor for “everyday”). model with depersonalization and cynicism col- Importantly, while the developers of the MBI lapsed into one factor. conceptualized burnout as a three-component The MBI has been the most widely used mea- syndrome combining emotional exhaustion, sure of burnout to date (Schaufeli et al. 2009b). depersonalization, and a sense of reduced per- The hegemonic status of the MBI in burnout sonal accomplishment, they formally recom- research led some researchers to conclude that mended, in contravention of this conceptualization, “burnout is what the MBI measures” (Schaufeli that the three components of burnout be examined and Enzmann 1998, p. 188; Schaufeli 2003, p. 3). separately, “given our limited knowledge about However, alternative measures, associated with the relationships between the three aspects of slightly different conceptualizations of the burnout burnout” (Maslach et al. 1996, p. 5). This recommendation has been criticized because it implies that individuals who suffer only from emotional 2 While cynicism has generally been characterized in burn- exhaustion, only from depersonalization, or only out research as a negative, to-be-treated symptom (cynicism without caring, indifference), it is worth underlining from reduced personal accomplishment will be that cynicism is multifaceted and can also be considered a considered as suffering from the same condition, “strategic virtue” (healthy cynicism) reflecting the enact- “burnout,” although they present with symptom ment of a “realistic” and pragmatic, rather than “idealis- profiles that are, by definition, different and poten- tic” and romanticized, view of one’s work (e.g., in terms of personal expectations and aspirations). As noted by tially call for different management strategies Rose et al. (2017), “tempered cynicism can protect the (Bianchi et al. 2017b; Brisson and Bianchi 2017a, inner core of care and good practice” (p. 693). 190 R. Bianchi et al. construct, have been developed over time. For 14.3.2 The Unresolved Problem instance, the Burnout Measure (Pines and Aronson of Burnout Diagnosis 1988; Pines et al. 1981) is intended to assess burnout as a combination of physical, emotional, and Although standardized measures of burnout symp- mental exhaustion. The Shirom-Melamed Burnout toms are available, it is worth noting that no bind- Measure (SMBM) operationalizes burnout as a ing or consensual criteria for (differentially) syndrome combining physical fatigue, cognitive diagnosing burnout have been established in more weariness, and emotional exhaustion (Shirom than 40 years of research (Bianchi et al. 2017d; 2003; Shirom and Melamed 2006). The Oldenburg Doulougeri et al. 2016; Weber and Jaekel-Reinhard Burnout Inventory features only two subscales, 2000). As an illustration, burnout is not recognized exhaustion and disengagement (Demerouti et al. as a nosological category in the latest versions of 2001; Halbesl eben and Demerouti 2005). The the Diagnostic and Statistical Manual of Mental Copenhagen Burnout Inventory distinguishes Disorders [DSM-5; American Psychiatric between personal, work-related, and client-related Association (APA) 2013] and International burnout (Kristensen et al. 2005). Despite their dif- Classification of Diseases (ICD-10; World Health ferences, the main conceptualizations of burnout Organization 2016).4 The absence of a diagnosis share the assumption that exhaustion is the core of for burnout is fundamentally problematic in that it the syndrome (Cox et al. 2005; Schaufeli and undermines the ability of occupational health spe- Enzmann 1998; Seidler et al. 2014). As put by cialists to treat and prevent burnout. A key, yet Maslach et al. (2001), “exhaustion is the central overlooked, corollary of the impossibility of iden- quality of burnout and the most obvious manifes- tifying “cases” of burnout is that the prevalence of tation of this complex syndrome” (p. 402).3 the syndrome cannot be estimated (Bianchi et al. “Exhaustion-only” conceptualizations of burnout 2015a, 2016a, b, 2017c; Brisson and Bianchi (e.g., Kristensen et al. 2005; Shirom and Melamed 2017b). This state of affairs questions the validity 2006) reflect the view that depersonalization/cyni- of dozens of studies dedicated to estimating the cism and loss of personal accomplishment/profes- prevalence of burnout and drains the recurrent sional efficacy do not need to be included in the claims about the “burnout epidemic” of their sub- syndrome because such constructs respectively stance (Bianchi et al. 2017b, d; West et al. 2016). refer to possible strategies to cope with (emo- Among other authors (e.g., Bianchi et al. tional) exhaustion and possible long-term conse- 2015a, 2016a, b), Brisson and Bianchi (2017b) quences of (emotional) exhaustion (Kristensen lamented “the widespread tendency among burn- et al. 2005, p. 194; Shirom and Melamed 2006, out researchers to put the cart before the horse by pp. 179–180). trying to estimate the prevalence of a syndrome that cannot be formally diagnosed” and pointed 3 Maslach and Leiter (2016) recently seemed to change their mind regarding the centrality of exhaustion in the burnout syndrome, indicating that “the experience of cyn- 4 In the ICD-10, burnout is only briefly mentioned among icism may be more of a core part of burnout than exhaus- the factors influencing health status and contact with tion” (p. 109). This turnaround is intriguing given (a) the health services. Interestingly, in The Netherlands, burnout inconsistent findings on which it is based (Leiter and has sometimes been equated with (job-related) neurasthe- Maslach 2016, p. 97), (b) the fact that “exhaustion is… nia (e.g., Schaufeli et al. 2001). Neurasthenia is indexed more predictive of stress-related health outcomes than the as a disorder in the ICD-10. Long considered to be part of other two components [of burnout]” (Maslach and Leiter melancholia (see Gamma et al. 2007), neurasthenia was 2010, p. 726), and (c) the conclusions of meta-analytic first viewed as a distinct entity in the nineteenth century reviews suggesting that exhaustion is the dimension of (Beard 1869; van Deusen 1869). Within the “neurasthenic burnout that is “the most responsive to the nature and approach” to burnout, burnout thus overlaps with a disor- intensity of work-related stress” (Shirom 2003, p. 249). der isolated about 150 years ago. Other Dutch researchers Moreover, in a meta-analytic review of 16 studies (Taris (e.g., Kleijweg et al. 2013) have equated burnout with 2006), only emotional exhaustion (not depersonalization undifferentiated somatoform disorder, a derivative of or reduced personal accomplishment) was found to be neurasthenia that has been removed from the DSM-5 associated with decreased job performance. because of its lack of distinctiveness (APA 2013, p. 812). 14 Burnout Syndrome and Depression 191 out the worrying use of clinically and theoreti- burnout with depression is also detectable in the cally arbitrary identification criteria in burnout very dimensions of the MBI (emotional exhaus- research (e.g., cutoff scores reflecting mere tion, depersonalization, and reduced personal tercile-based splits).5 It should be noted that the accomplishment; Maslach et al. 1996, 2016), as criteria used for identifying “cases” of burnout highlighted by Schonfeld (1991) and Bianchi et al. have not only been arbitrary. They have also (2017a). To take but one example, emotional shown considerable heterogeneity from one exhaustion has been shown to overlap with fatigue study to another (Bianchi 2015; Doulougeri et al. and loss of energy on the one hand and depressed 2016), thereby jeopardizing between-study com- mood on the other hand (Bianchi et al. 2017a), two parability. All in all, it must be acknowledged diagnostic criteria for major depression (APA that the research dedicated to estimating the prev- 2013). After having examined each dimension of alence of burnout has been conspicuous by its the MBI in relation to depression, Bianchi et al. vacuity. As a consequence, the findings derived (2017a) concluded that emotional exhaustion, from that research have been confusing for occu- depersonalization, and reduced personal accom- pational health researchers and practitioners and plishment refer to depressive signs and symptoms have not offered public health decision-makers under nonpsychiatric terms. valid grounds on which to base their policies. More recent descriptions of burnout have been similarly suggestive of depression. For example, Maslach and Leiter (1997) wrote that burnout is 14.4 The Realization that Burnout not only about the “presence of negative emo- Is a Depressive Condition tions” but also about the “absence of positive ones” (p. 28), a picture that is reminiscent of 14.4.1 Early Clues depressed mood and anhedonia—the two core symptoms of depression (APA 2013). Maslach From the outset, burnout has been described in et al. (2001) asserted that there is “a predomi- ways that were strongly evocative of depression. nance of dysphoric symptoms” in burnout The overlap of burnout with depression is explicit (p. 404). Schaufeli and Buunk (2004) indicated in the initial descriptions of burnout proposed by that “first and foremost, burnt-out individuals Freudenberger (1974, 1975). Indeed, symptoms feel helpless, hopeless and powerless” (p. 399), such as fatigue, sleep disturbance, weight altera- three feelings that are hallmarks of depression tion, or dysphoric mood constitute diagnostic cri- (Abramson et al. 1989; APA 2013; Laborit 1986; teria for major depression (APA 2013). Symptoms Peterson et al. 1993; Pryce et al. 2011). such as irritability and frustration, although not Another source of concern regarding the dis- diagnostic criteria for major depression, are fre- tinctiveness of burnout has lain in the (presumed) quently observed in depressed individuals, espe- etiology of the syndrome. In effect, unresolvable cially in male and/or young patients (APA 2013; stress, which is thought to play a causative role in Judd et al. 2013). Judd et al. (2013) found that irri- the development of burnout (Maslach et al. 2001; tability/anger during major depressive episodes Shirom 2003), has been shown to be at the center was a clinical marker of a more severe, chronic, of the etiology of depression (Laborit 1993; and complex depressive illness. The overlap of McEwen 2004; Pizzagalli 2014; Willner et al. 2013).6 There is robust evidence, from research conducted in psychiatry, behavioral psychology, 5 Diagnostic criteria for burnout would have required a clear specification of (a) the symptoms to be considered in clinical assessments, (b) the minimal duration and fre- 6 As emphasized by Sapolsky (2004), “it is impossible to quency of the exhibited symptoms, (c) the expected understand either the biology or psychology of major impact of the exhibited symptoms on the patient’s (work) depressions without recognizing the critical role played in life, and (d) differential diagnosis procedures. The identi- the disease by stress” (p. 271) and “genes that predispose fication of distinctive biological correlates would have to depression only do so in a stressful environment” also been helpful. (p. 345). 192 R. Bianchi et al. and neurobiology, that depressive symptoms con- been viewed as a pathology of loss of gratification stitute basic responses to unresolvable stress in (i.e., loss of pleasure, happiness, or satisfaction in Homo sapiens, as in many other species (see life). As reported by Beck and Alford (2009), loss Bianchi et al. 2017d). It is worth noting that the of gratification is the most frequent complaint depressive feelings of helplessness and power- among depressed patients (p. 19). Importantly, lessness can be viewed as direct consequences of under stress, a gratifying action is an action that the experience of unresolvable stress. From this allows the individual to neutralize the stressor. perspective, the individual feels helpless and pow- Unresolvable stress is thus synonymous with a erless precisely because he/she cannot neutralize long-term impossibility of acting in a manner that the encountered stressors through effective action. is gratifying—neurobiologically, of activating Put differently, the individual does not feel in con- one’s reward system and shutting down one’s pun- trol vis-à-vis the encountered stressors. ishment system. All in all, depression can be con- Hopelessness can be viewed as the expectation ceived of as the product of a deficit of positive, that this absence of control will last, that is, that rewarding experiences (i.e., experiences that acti- helplessness and powerlessness will be experi- vate the brain reward system), and an excess of enced again and again in the presence of the negative, punitive experiences (i.e., experiences stressors. The individual anticipates that he/she that activate the brain punishment system), with will not be able to manage in the future what he/ depressed mood and anhedonia two key symptoms she could not manage thus far. Because, in the of this disequilibrium (e.g., Bogdan and Pizzagalli individual’s eye, action has proven to be ineffec- 2006; Dombrovski et al. 2013; Pryce et al. 2011; tive in neutralizing stressors, passivity (i.e., inac- Rolls, 2016; Wu et al. 2017).8 In view of the above, tion) and resignation become the predominant the putative etiology of burnout could thus be con- responses in the face of adversity. From an evolu- sidered to mirror the etiology of depression. tionary standpoint, passivity can be considered preferable when stressors cannot be neutralized because passivity at least prevents the waste of 14.4.2 Attempts to Distinguish energy associated with the production of ineffec- Burnout from Depression tive action (Klinger 1975; Laborit 1986, 1993; Nesse 2000). In spite of the aforementioned similarities Freudenberger and Richelson’s (1980) early between burnout and depression, many burnout claim that burnout results from an investment researchers have hypothesized that their entity of (cost) that is devoid of the expected return on investment (benefit) is also relevant to burnout- 8 depression overlap.7 Indeed, depression has long The well-established link between depression and suicide (Chesney et al. 2014) suggests that survival is not an objective under any condition in human beings. Everything happens as if human beings struggled for survival only as long 7 The view that burnout is etiologically related to an imbal- as they consider their life worth living (i.e., sufficiently ance between investments and outcomes has been recur- gratifying). The specific relationship between anhedonia rently expressed in the literature. As an illustration, and suicide supports this view (Winer et al. 2014), as does Heifetz and Bersani (1983) wrote: “It is not the heavy the finding that (a) the brain reward system is hypoactive in emotional investment per se that drains the provider; depressed patient (Dombrovski et al. 2013) and (b) indi- rather it is an investment that has insufficient dividends” viduals with major depressive disorder report blunted lev- (p. 61). More recently, this mismatch has been described els of both anticipatory and consummatory pleasure and in terms of (lack of) reciprocity between what the job elevated levels of both anticipatory and consummatory gives and what it takes (see Schaufeli 2006). The same displeasure for daily activities (Wu et al. 2017). As sum- logics is at the heart of several current models of occupa- marized by Dombrovski et al. (2013), “suicide can be tional strain such as Siegrist’s (1996) effort-reward imbal- viewed as an escape from unendurable punishment at the ance model. Freudenberger and Richelson’s (1980) early cost of any future rewards” (p. 1020). Following a similar view that burnout results from an imbalance between line of reasoning, it can be suggested that suicide occurs investments and outcomes thus remains very lively among when the perspective of dying has become definitely more burnout researchers. rewarding than the perspective of going on living. 14 Burnout Syndrome and Depression 193 interest was a distinct entity (Iacovides et al. the last decades, a large body of research has in 2003; Maslach et al. 2001). Three arguments fact been dedicated to the social determinants of have been frequently advanced in support of the depression (e.g., socioeconomic status and social view that burnout is not merely “old wine in new network; Gilman et al. 2002; Lorant et al. 2007; bottles” (Schaufeli and Enzmann 1998). Ritsher et al. 2001; Rosenquist et al. 2011; Proponents of the burnout/depression distinc- Sapolsky 2005).10 Moreover, the stress-depression tion claimed that, in contrast to depression, burn- relationship evidently implicates the social envi- out was a job-related and work-specific syndrome ronment, given that the social environment is a (e.g., Maslach et al. 2001, p. 404). This claim, key contributor to stress (Gilbert 2006; Pizzagalli however, has been shown to be problematic 2014). In a recent study that included 3021 medi- because (a) depression can also be job-related,9 cal interns, Fried et al. (2015) found that all nine (b) the job-related character of a syndrome is not symptoms of major depression (APA 2013) nosologically discriminant per se—a job-related increased—on average by 173%—in response to depression remains a depression—and (c) the the stress of medical internship over a 1-year postulate that the burnout phenomenon is period. Second, and more fundamentally, the restricted to work is logically specious (Bianchi “social focus argument” advanced by some burn- et al. 2015d; Kahn 2008; Niedhammer et al. out researchers is epistemologically spurious. 2015; Wang 2005). Taking the problem the other Indeed, a difference in the perspectives adopted way round, the extent to which burnout can be on given syndromes (e.g., individual versus considered a job-induced syndrome has remained social) should not be confused with a difference unclear (Bianchi et al. 2017b; Weber and Jaekel- between the syndromes themselves. Burnout and Reinhard 2000). While burnout has been found to depression can both be examined from an indi- be predicted by occupational factors (Schaufeli vidual or a social perspective. Incidentally, we et al. 2009a), research on the variance in burnout note that moving back and forth from an individ- explained by non-occupational factors has been ual to a social level of observation is likely to be scarce (Hakanen and Bakker 2017). Interestingly, fruitful in the study of any (psycho)pathology.11 in a recent study involving 468 Swiss health pro- Finally, it has been asserted that burnout dif- fessionals, only 44% of the participants reporting fers from depression because the symptoms of burnout symptoms considered their job to be the burnout are, in the early stages of the burnout main cause of these symptoms (Bianchi and process, rather circumscribed to work—they do Brisson 2017). not contaminate the whole life of the individ- Another argument employed to distinguish ual—whereas the symptoms of clinical depres- burnout from depression has consisted in con- sion are pervasive (see Pines and Aronson 1988, trasting the so-called social focus of burnout p. 53; Schaufeli and Enzmann 1998, p. 39). Such research with a supposedly “individual focus” of a comparison, unfortunately, is inconsistent depression research (e.g., Pines and Aronson (Bianchi et al. 2015b). In effect, when comparing 1988, p. 53). This argument has been found to be the early stages of the burnout process with clini- invalid, for at least two reasons. First, the argu- cal depression, burnout researchers contrast the ment is grounded in a false presupposition, early stages of the burnout process with the late namely, that depression would not have been stages of the depressive process, while remaining studied from a social perspective. An explicitly social perspective was taken, for instance, by 10 In a meta-analysis, Lorant et al. (2003) found compel- Brown and Harris (1978) in their classic study of ling evidence for socioeconomic inequality in depression “the social origins of depression” in women. Over (see also Adler and Stewart 2010). 11 Even psychosis (including schizophrenia), the variance of which is thought to be strongly explained by the genetic 9 Methods allowing the specific link between job stress makeup of the individual, has been fruitfully studied from and depression to be investigated are available, both in a social-environmental standpoint (Shah et al. 2011; research and medical settings (Bianchi et al. 2017). Wicks et al. 2010). 194 R. Bianchi et al. silent regarding what is supposed to distinguish All in all, the arguments invoked in support of “clinical burnout”12 from clinical depression. The the burnout-depression distinction have not stood comparison thus appears to be underlain by a up to scrutiny. We now review recent empirical defective articulation of dimensional (i.e., findings pertaining to the characterization of the continua-based, process-focused) and categorical burnout syndrome in relation to depression. (i.e., taxa-based, state-focused) approaches to burnout and depression (Bianchi et al. 2017d). The difficulty coordinating dimensional and cat- 14.4.3 Recent Research on Burnout- egorical approaches to psychopathology has long Depression Overlap been encountered in burnout research, as illustrated by the view that burnout could be a phase 14.4.3.1 Associations Between in the development of a depressive disorder (e.g., Burnout and Depressive Ahola et al. 2005). This problem is well- Symptoms summarized in the following excerpt: Burnout and depressive symptoms have long …there is the question of whether burnout is a con- been found to be positively correlated (e.g., tinuous condition or a dichotomized state. Are Meier 1984), with moderate to high correlations there degrees of burnout that can be experienced or generally reported. It has often been suggested, is one either burned out or not?—Cox et al. (2005, however, that burnout and depressive symptoms p. 190). should be distinguished because, although sub- Because dimensions and categories constitute stantial, their correlation was not perfect. A new two ways of describing the properties of psycho- light has been shed on this assumption over the logical phenomena (Pickles and Angold 2003), last years. the question is not to determine whether burnout The assumption that burnout and depression is a continuous condition or a dichotomized state. cannot be viewed as a single entity because the The description of burnout within a dimensional two constructs share significant, but limited, vari- or a categorical approach depends on the per- ance (e.g., Schaufeli and Enzmann 1998) has spective that the investigator chooses to adopt on been tested as such in a recent study. Bianchi et al. burnout, as a function of his/her objectives. (2016c) examined the extent to which the correla- Burnout, just as depression, can be studied as a tion between burnout and depressive symptoms process or an end-state (Bianchi et al. 2017d). (respectively assessed with the SMBM and the There can be degrees of severity in burnout as in PHQ-9) differed in strength from the correlation depression; qualitative leaps can be considered in between the affective-cognitive and somatic burnout as in depression. Assuming that burnout symptoms of depression. The results of the study is per se a process and depression is per se an indicated that the correlation between burnout and end-state would be confusing, once again, the depressive symptoms (r = 0.73) was similar in phenomena of interest with the approaches strength to the correlation between the affective- adopted to study those phenomena. Such episte- cognitive and somatic symptoms of depression mological confusion leads the investigator to (r = 0.68). Because the affective-cognitive and make superfluous, and misleading, distinctions. somatic symptoms of depression are considered Such distinctions result in a counterproductive to form a unified entity with a correlation of 0.68, fragmentation of knowledge that threatens con- the authors concluded that there was no apparent ceptual parsimony and impedes theory building obstacle to viewing burnout and depression as one (Cole et al. 2012; Le et al. 2010; Schmidt 2010). entity with a correlation of 0.73. Furthermore, emotional exhaustion—the core of burnout—has been found to be more strongly 12 We use inverted commas here because there are no bind- associated with “classical” depressive symptoms ing or consensual diagnostic criteria for “clinical burnout”; “clinical burnout” has remained uncharacterized. than with the other two dimensions of burnout— We follow the same rule in the rest of the chapter. depersonalization and reduced personal accom- 14 Burnout Syndrome and Depression 195 plishment—in many studies (see Bianchi et al. specifically focusing on workers scoring at the 2015b). In view of these findings, the claim that upper end of the burnout continuum. Bianchi depersonalization and reduced personal accom- et al. (2013) found evidence that individuals with plishment constitute more cardinal features of relatively high frequencies of burnout symptoms burnout than “classical” depressive symptoms (based on the MBI) reported as many depressive appeared to proceed from an incoherent reason- symptoms (based on the Beck Depression ing (Bianchi et al. 2015d). By definition, a syn- Inventory-II) as patients diagnosed in psychiatry drome refers to a group of concomitant signs and for a major depressive episode. In a study of 5575 symptoms (Shirom 2005). If emotional exhaus- French schoolteachers (Bianchi et al. 2014), in tion more often co-occurs with “classical” which burnout was assessed with the MBI, about depressive symptoms than with depersonaliza- 90% of the individuals experiencing burnout tion and reduced personal accomplishment, symptoms at least a few times a week met criteria excluding “classical” depressive symptoms from for a provisional diagnosis of depression, as the burnout syndrome while including deperson- established by the PHQ-9 (Kroenke and Spitzer alization and reduced personal accomplishment 2002). Similar results were obtained in the USA in the burnout syndrome is unwarranted. (Schonfeld and Bianchi 2016) and New Zealand Recent research has additionally suggested (Bianchi et al. 2016c) based on teacher samples that the magnitude of the association between and in Switzerland (Bianchi and Brisson 2017) burnout and depressive symptoms had been dis- based on health professional samples, in studies torted downward in the past due to measurement that used the SMBM to assess burnout. A strength artifacts. Indeed, burnout is most frequently of the abovementioned studies is that they relied assessed within a 1-year (with the MBI) or a on conservative cutoff scores for categorizing 1-month (with the SMBM) time window, whereas burnout. Because such cutoff scores correspond depression is most frequently assessed over a 1- to relatively high frequencies of burnout symp- or a 2-week period (e.g., with the Center for toms, they show close adherence to the theoreti- Epidemiologic Studies Depression Scale [CES- cal characterization of so-called clinical burnout. D] and the PHQ-9). Such differences in response Schaufeli and Buunk (2004) signalled that frames can reduce the magnitude of the obtained full-blown burnout reflects “a final stage in a correlations in the absence of actual differences breakdown in adaptation that results from the between the examined phenomena. In a study long-term imbalance of demands and resources” that standardized the time window of the assess- (p. 389). According to Leiter and Maslach (2005), ment of burnout and depressive symptoms, a “burned out” worker feels “constantly over- Bianchi et al. (2016d) found a correlation of 0.83 whelmed, stressed and exhausted” (p. 2). These between the two variables. When corrected for descriptions imply that the use of liberal cutoff attenuation, the correlation reached 0.91, a mag- scores, associated with relatively low symptom nitude that is suggestive of empirical redundancy frequencies, is unwarranted when burnout is between the constructs under scrutiny—as examined as an end-state (see also Schaufeli and recalled by Le et al. (2010), “two supposedly dis- Enzmann 1998, p. 58).13 Although suboptimal in tinct constructs should not correlate 1.00 or near a context where burnout remains nosologically 1.00” (p. 113). In support of this hypothesis, undefined, the strategy that consisted in relying associations of such magnitudes (rs around 0.80 on conservative cutoff scores to categorize burn- or 0.90) have been found when correlating two out at least had the advantage of being sustained measures of depression (Kung et al. 2013; Luteijn by a clear rationale. Available descriptions have and Bouman 1988) or two measures of burnout (Shirom and Melamed 2006) with one another 13 (see also Wojciechowski et al. 2000). The use of liberal cutoff scores in some earlier studies (e.g., Ahola et al. 2005) is likely to account for the weaker The overlap of burnout with depression has evidence of burnout-depression overlap observed in those also been examined categorically, with the aim of studies. 196 R. Bianchi et al. suggested that an individual with full-blown have been found to be similarly associated with a burnout experiences burnout symptoms on a number of variables such as depressive cognitive daily basis, consistent with the fact that burnout style (including ruminative responses and pessi- symptoms, once they have fully developed, are mistic attributions), self-rated health, physical stable over time—for instance, exhaustion is typ- activity, neuroticism, extraversion, job satisfac- ically unrelieved by ordinary rest or sleep, and tion, job adversity, workplace social support, cynicism involves a deeply ingrained negative stressful life events, and antecedents of anxiety or attitude toward one’s work. depressive disorders (Bianchi and Schonfeld Other categorical investigations of burnout 2016; Bianchi et al. 2016d; Faragher et al. 2005; and depression have been conducted. In a three- Rössler et al. 2015; Schonfeld and Bianchi 2016; wave, 7-year study, Ahola et al. (2014) examined Toker and Biron 2012). both within- and between-individual variations in In sum, recent empirical research has consis- burnout and depressive symptoms (assessed with tently shown that burnout and depressive symp- the MBI and the short form of the Beck toms are inextricably linked (Bianchi et al. Depression Inventory, respectively) based on a 2017d). This conclusion has been supported by sample of 3255 Finnish dentists. The study both dimensional and categorical analyses of showed that burnout and depressive symptoms burnout and depression, conducted in the frame- clustered together and increased or decreased work of both cross-sectional and longitudinal commensurately over time, with low, intermedi- studies. The conclusion appeared to be viable not ate, and high levels of burnout symptoms being only when the MBI was used but also when alter- respectively accompanied by low, intermediate, native measures of burnout, such as the SMBM, and high levels of depressive symptoms. Similar were employed. results were found in another cluster-analytic study, involving a sample of French teachers and 14.4.3.2 Factor Analyses of Burnout two waves of data collection (Bianchi et al. and Depression Measures 2015c). The view that burnout is distinct from depression Consistent with these findings, in a study of has strongly relied on the finding that burnout and 5897 Austrian physicians, Wurm et al. (2016) depression loaded on different factors when self- observed that the likelihood of meeting the crite- reported measures of burnout and depression were ria for a provisional diagnosis of depression (as submitted to factor analyses (Maslach et al. 2001). established by the Major Depression Inventory) Thus, in one of the most influential studies linked gradually increased with the severity of burnout to this research area, Leiter and Durup (1994) con- symptoms (assessed with the Hamburg Burnout cluded that burnout and depression were best Inventory). Compared to participants with no modeled as two second-order factors—while noticeable symptoms of burnout, participants acknowledging the strong correlation (0.72) with the most elevated levels of burnout symp- between these factors. The study, however, had a toms had a 93-fold higher risk of being identified number of limitations, such as (a) the poor fit of as clinically depressed. the constructed models, (b) the exclusion of nearly Finally, we note that the research dedicated to half the depression items from the confirmatory the nomological network of burnout and depres- factor analysis for reasons of skewness, and (c) the sion has not resulted in fully consistent findings non-consideration of the different time windows (Bianchi et al. 2015b). Most probably, this state attached to the measures of burnout and depressive of affairs is due to (a) the heterogeneity of the symptoms. conceptualizations and operationalizations of More recent studies offered investigators a burnout used in past research and (b) the previ- different view of the relationships between the ously mentioned methodological problems that factors underlying the measures of burnout and affected research on burnout-depression overlap. depressive symptoms. Bianchi et al. (2016d) used This being underlined, burnout and depression the SMBM and the PHQ-9 to assess burnout and 14 Burnout Syndrome and Depression 197 depression, respectively. As a reminder, the (expressed by heightened concentrations of high- SMBM includes three subscales, physical fatigue, sensitivity C-reactive protein [hs-CRP] and cognitive weariness, and emotional exhaustion. fibrinogen) whereas in men, depression, but not The factor analyses carried out by the authors burnout, was positively associated with hs-CRP revealed that the depression latent variable cor- and fibrinogen concentrations. By contrast, related more strongly with the physical fatigue, examining the question of whether burnout could cognitive weariness, and emotional exhaustion be distinguished from depression based on heart latent variables than the latter three latent vari- rate variability, brain-derived neurotrophic factor, ables correlated with each other. Such results and hippocampal volume, Orosz et al. (2017) did confirmed that depressive symptoms lie at the not find conclusive evidence for burnout’s dis- heart of the burnout syndrome. tinctiveness. Beyond the specific limitations In a study that aimed at overcoming the limita- attached to one study or another, biological tions of past factor analytic studies by using more research on burnout and depression has been ren- sophisticated modeling techniques, Schonfeld dered fundamentally inconclusive by the non- et al. (2017) assessed burnout with the MBI and consideration of depression subtypes in the depression with both the 10-item version of the conducted studies (Bianchi et al. 2015b). CES-D (CES-D-10) and the PHQ-9. The study Considering depression subtypes is central in sample comprised 734 US teachers. The results of biological research on burnout and depression an exploratory factor analysis indicated that the because different depression subtypes have been items of (a) the emotional exhaustion and deper- associated with opposite neurovegetative, sonalization subscales of the MBI, (b) the CES-D- immune, and endocrine profiles. For instance, 10, and (c) the PHQ-9 substantially loaded on one depression with melancholic features has been single factor. The items of the (reduced) personal associated with insomnia, aphagia, sympathetic accomplishment subscale of the MBI were found hyperactivity, decreased immune function, and to load only partly on that factor. A confirmatory hypercortisolism, whereas depression with atypi- factor analysis that controlled for potential item cal features14 has been associated with hypersom- overlap in the measures of depressive symptoms nia, hyperphagia, sympathetic hypoactivity, and emotional exhaustion established that there increased immune function, and hypocortisolism was a high correlation (0.85) between depressive (Gold and Chrousos 2002; Lamers et al. 2013). symptoms and emotional exhaustion, suggestive These differences directly bear on the status of of a unique underlying construct. variables such as microinflammation, heart rate The results of the latest factor analytic studies variability, brain-derived neurotrophic factor, or of burnout and depression measures have con- hippocampal volume. Thus, the neglect of depres- solidated the view that burnout and depressive sion subtypes can result in misleading conclu- symptoms form a unified structure. Put differ- sions regarding burnout-depression overlap. ently, these results have suggested that it would Emblematically, the argument that burnout is dis- be misguided to isolate burnout from the spec- tinct from depression because burnout involves trum of depression. hypocortisolism whereas depression involves hypercortisolism caves in as soon as atypical 14.4.3.3 Biological Research depression is taken into consideration (Bianchi on Burnout and Depression et al. 2015b). Over the last years, the overlap of burnout with Because subtypes of depression have been depression has been increasingly investigated ignored in biological research on burnout and from a biological standpoint. Heterogeneous findings have emerged from this line of research. 14 For instance, Toker et al. (2005) found that in The term atypical “does not connote an uncommon or unusual clinical presentation” (APA 2013, p. 186). women, burnout, but not depression, was posi- Depression with atypical features is a frequently encoun- tively associated with microinflammationtered form of depression. 198 R. Bianchi et al. depression, the studies conducted in this area Instead of multiplying “depression-like” could not inform us about burnout-depression constructs, we recommend that investigators overlap. Researchers should be more aware of, concentrate their present and future efforts and careful about, the heterogeneity of depres- on (a) more harmoniously coordinating sion in the future. dimensional and categorical approaches to depression (Cuthbert and Insel 2013; Kotov Conclusion et al. 2017), (b) further developing a flexible, In this chapter, we proposed an overview of multiscale (e.g., sub-individual, individual, burnout, from the introduction of the construct interpersonal, social) framework for the in the mid-1970s to the growing realization study of depressive conditions, and (c) better that the syndrome was better conceived of as a understanding how the forms taken by depressive condition. Long questioned, the depression can vary as a function of the dura- distinction between burnout and depression tion and intensity of the unresolvable stress has eventually been shown to be problematic, experienced by the individual and the devel- both logically and empirically. Recent studies opmental stage(s) at which the individual helped clarify the issue of burnout-depression experiences unresolvable stress (Bale and overlap at theoretical and epistemological lev- Epperson 2015; Koenig et al. 2011). Such an els and provided us with compelling evidence agenda is in our estimation promising in that the pathogenesis of burnout is depressive terms of knowledge production and integra- in nature. tion. The relationship between stress and The history of burnout research suggests depression, through the impossibility of that transdisciplinary communication and effective/gratifying action, offers a privi- methodological standards should be strength- leged access to the general principles of ened to avoid the proliferation of constructs human adaptation. that, in fact, refer to the same phenomena. 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Young Sup Woo and Won-Myong Bahk

15.1 Introduction studies have investigated the association between obesity and psychopathology, including depres- Both obesity and depression are common prob- sion, but these studies reported a negative asso- lems, with major public health implications. The ciation. These studies on the personality and lifetime prevalence of major depression is 6.5– psychopathology of obesity have compared 21.0%, and the World Health Organization groups of obese and nonobese individuals and (WHO) has ranked depression the fourth leading reported no link between obesity and psychologi- cause of disability and has anticipated it to be the cal correlates. For example, Moore et al. (1962) second leading cause by 2020 (Kessler and examined the relationship between obesity and Bromet 2013). The prevalence of obesity is high mental health using data obtained from 1660 per- as well and has rapidly increased over the past sons selected as representative of 110,000 inhab- three and a half decades, with 11% of men and itants of a residential area of New York City. In 15% of women obese in 2014 (Arroyo-Johnson mental health indices, obese individuals made and Mincey 2016). more pathological scores on “immaturity,” “rigid- The potential association between depression ity,” and “suspiciousness” than nonobese indi- and obesity has been proposed because of the viduals, but there were no significant differences high prevalence of both conditions and the fact in anxiety and depression levels. Rather, some that symptoms of depression include changes in researchers reported less psychopathology in appetite/weight, sleep, and psychomotor activity obese individuals than normal-weight individu- (Stunkard et al. 2003) and that psychological als. Crisp and McGuiness (1976) reported that aspects such as negative body image and self- obese men have lower levels of depression than esteem, maladaptive schemas, and body image normal-weight men (“jolly fat” hypothesis). It is dissatisfaction in obese people could lead to not surprising that negative or heterogeneous depression (Gavin et al. 2010). A number of early results were obtained from early studies because those studies had methodological limitations such as using a single measure and various and arbitrary definitions of obesity (Friedman and Y.S. Woo • W.-M. Bahk (*) Brownell 1995). Department of Psychiatry, Yeouido St. Mary’s However, results supportive of the “jolly fat” Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea hypothesis have primarily been observed for e-mail: [email protected] older, male cohorts and were conducted two or

© Springer Nature Singapore Pte Ltd. 2018 203 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_15 204 Y.S. Woo and W.-M. Bahk more decades ago. Recent epidemiological stud- 15.2.1 Obesity Predicting ies demonstrated that obesity is associated with an Depression: Prospective increased risk of developing depression (Simon Studies et al. 2006; Dong et al. 2004; Dearborn et al. 2016) although the precise mechanisms underly- In the Alameda County Study (Roberts et al. ing the interaction between obesity and depres- 2003), obese (BMI ≥ 30) adults over age 50 had sion have not been elucidated. In this chapter, to elevated odds ratios of depression (2.09) 5 years better explicate the pathophysiological mecha- later, and this was significant even after control- nisms underlying interaction between obesity and ling for potential covariates. The increased future depression, we demonstrate the association risk for developing depression/depressive symp- between depression and obesity in recent litera- toms in obese populations at baseline has been ture. From a clinical point of view, this could reported repeatedly in several subsequent longi- imply the importance of monitoring obesity in tudinal studies, with female subjects having an depressed patients and, vice versa, paying atten- odds ratio of 5.25 (Kasen et al. 2008), elderly tion to depressed mood in patients with obesity. subjects having an odds ratio of 1.60 (Godin et al. 2012), and a large prospective cohort study of men and women subjects in which the odds ratio 15.2 The Association Between for depression per standard deviation increase in Depression and Obesity: body mass index (BMI) was 1.11 (Bjerkeset et al. Recent Epidemiological 2008). Recently, in a meta-analysis conducted by Studies Luppino et al. (2010), an obese person was more likely to develop depression (unadjusted Based on the strong probability that depression OR = 1.55). and obesity will occur together, a considerable Some studies suggest that the future risk of number of studies in recent decades have studied depression may be disproportionately affected by the association between depression and obesity. potential confounding factors. In a large longitu- Several cross-sectional studies with general pop- dinal study, baseline obesity did not affect the ulation found a positive association between risk of future depressive symptoms in overall depression and obesity. Atlantis et al. reviewed subjects, but obesity was associated with 20 cross-sectional studies and reported that obe- increased risk of symptoms of depression in sub- sity and depression are positively associated in jects of higher socioeconomic status (SES), with women, but not in men, in studies from the a relative risk of 1.97 (Fowler-Brown et al. 2012). United States. However, the association was not In addition, the increased risk of depression in found in studies from populations other than the obese people could be attributed in part to physi- United States (Atlantis and Baker 2008). A meta- cal inactivity. A study examining the prospective analysis of 17 cross-sectional studies (de Wit association of BMI and physical activity with et al. 2010) found that there was an overall posi- depressive symptoms in young women (Ball tive association between depression and obesity, et al. 2009) showed that physical activity seems with an odds ratio (OR) of 1.18, and the associa- to be protective against the onset of depressive tion was significant for females but not signifi- symptoms, but the increased risk of depressive cant for males in subgroup analysis. Overall, symptoms associated with weight gain is not alle- although cross-sectional studies support this viated. Moreover, recent studies suggest that association, evidence from cross-sectional stud- metabolically unhealthy obesity and metaboli- ies does not provide a clear picture of the rela- cally healthy obesity may have different effects tionship between depression and obesity. Hence, on the risk of future depression. Hamer et al. longitudinal studies are necessary to examine the (2012) reported that metabolically unhealthy contextual relationship between depression and obesity increased the risk of depressive symp- obesity. toms at follow-up, with an OR of 1.5, compared 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 205 to the nonobese healthy control, whereas meta- depressed populations were significantly higher bolically healthy obesity did not. Besides, in the in risk of developing obesity compared to non- aforementioned meta-analysis (Luppino et al. depressed, with an OR of 1.19. The risk of later 2010), significant predictive effects of baseline obesity was particularly higher for adolescent obesity for future depression were observed in females (OR = 2.57). In another meta-analysis studies conducted in the United States (Luppino et al. 2010), baseline depression/ (OR = 2.12), although this effect was not signifi- depressive symptoms significantly increased the cant in studies conducted in Europe (OR = 1.33, risk of later obesity (OR = 1.58). In this meta- nonsignificant). analysis, there were no specific moderators of this association. Taken together, depression may increase the risk of future obesity, but some other 15.2.2 Depression Predicting factors, including gender, may moderate this Obesity: Prospective Studies association.

The results from studies on the effects of depression on future obesity are a little more controver- 15.3 Moderators sial compared to studies on the effect of obesity on of the Relationship Between later depression. In the late 1990s, Pine et al. Depression and Obesity (1997), Bardone et al. (1998), and Barefoot et al. (1998) reported results from longitudinal studies Initial researches examining the bidirectional that investigated the effects of depression/depres- relationship between depression and obesity sive symptoms in adolescence on the risk of obe- failed to consider the complexity and heterogene- sity in adulthood. In one study, depression in ity of the relationship. As noted by Friedman and adolescence predicted obesity in early adulthood Brownell, various moderators including biologi- (Pine et al. 1997; Beydoun and Wang 2010). In cal, behavioral, cognitive, and social factors another study (Barefoot et al. 1998), depressive might be involved in the relationship between symptoms in adolescence exaggerated pre-exist- obesity and depression. ing weight change tendencies; initially lean sub- Among sociodemographic factors, being jects with depressive symptoms gained less weight female and on a low income conferred risk of than the non-depressed control, and initially heavy comorbid obesity and depression. The associa- subjects with depressive symptoms gained more. tions of age, ethnicity, marital status, and In the other study (Bardone et al. 1998), adoles- educational attainment with the relationship cent depression did not affect BMI at follow-up. between depression and obesity were not consis- Whether depression/depressive symptoms tent (Preiss et al. 2013). Psychological and social may contribute to future obesity has been incon- variables also moderate the relationship between clusive in subsequent studies: some indicated that depression and obesity. Anger, sadness, and baseline depression can predict future obesity excitement were associated with the relationship (Goodman and Whitaker 2002) or abdominal in female depression and obesity and low inter- obesity (Vogelzangs et al. 2008), but others pos- personal effectiveness, loneliness, and ineffective ited that depression did not increase the risk of conflict resolution in male (Musante et al. 1998). future obesity (Roberts et al. 2003). Moreover, Negative body image, experience of weight- gender may be a mediating factor for the relation- related stigma, and low social/interpersonal ship between depression and future risk of obe- activity were associated with the relationship sity. The increased risk of developing obesity in between depression and obesity across both gen- depressed subjects has been observed only in ders as well (Gavin et al. 2010; Preiss et al. 2013). females in some studies (Richardson et al. 2003; As for behavioral factors, physical activity has Hasler et al. 2005; Fowler-Brown et al. 2012). In an influence on the relationship between obesity a meta-analysis of 16 studies (Blaine 2008), and depression. Additionally, the relationship 206 Y.S. Woo and W.-M. Bahk could be differently influenced by physical activ- Lin and Su 2007). As will be discussed below, ity by gender (Beydoun and Wang 2010; Siegel central adiposity may not only cause or exacer- et al. 2000; Jorm et al. 2003). In one study, bate metabolic abnormalities but also incur neu- depression led to lower levels of physical activity, ropsychiatric impairments, including depression. which led to a BMI increase in females, while it Moreover, saturated fatty acids can disturb the led to less physical activity, which led to lower leptin and insulin signaling pathway in the hypo- BMI in males. Dysfunctional eating and dieting thalamus, by reducing their catabolic actions behavior also influence the relationship between (Posey et al. 2009; Kleinridders et al. 2009). A obesity and depression. Stress and mood states high saturated fatty acid level in serum correlated such as depression and anxiety can have diver- with the severity of depression (Tsuboi et al. gent effects on feeding behavior. While stress and 2013). In conclusion, depression can induce an negative mood decrease appetite and weight in unhealthy diet, and a chronic unhealthy diet can some individuals, it can have an orexigenic and promote aggravation of depressive symptoms via weight-increasing effect in others. Increased inducing central adiposity and increasing serum preference for palatable, calorically dense food is saturated fat concentration. observed in stressed animals (Cottone et al. 2009) Another moderating variable is the severity of and depressed subjects (Macht 2008). Then, how obesity. In studies which compare the class of do stress and emotions affect eating? One way is obesity, subjects with class III obesity that sweet, fatty foods can improve mood (Gibson (BMI ≥ 40.0) had more than three times the risk 2006). Moreover, consumption of palatable food of depression than the control group, after con- can attenuate the stress response (Adam and Epel trolling for demographic and behavioral variables 2007). However, the relieving effect of palatable (Keddie 2011; Ma and Xiao 2010). One study food consumption on negative emotions and found that a 20-unit increment in BMI increased mood states does not persist. The association the risk for depression, with an odds ratio of 1.8 between stress/negative emotional state and pref- (Dong et al. 2004). Studies which compared erence for palatable food is thought to be medi- overweight with obesity reported that the obese ated by hypothalamic–pituitary–adrenal (HPA) group had more frequent depressive symptoms as activity and the opioidergic and dopaminergic well (Barry et al. 2008; Johnston et al. 2004). In reward system (Adam and Epel 2007; Gibson sum, although the severity of obesity was mea- 2006). Repeated stimulation of these pathways sured differently among studies, most studies induces adaptation and promotes the compulsive found a significant relationship between severity nature of overeating of energy-dense foods and of obesity and risk of depression. consequent obesity (reward-based stress eating In their review, Markowitz and colleagues model) (Gibson 2006; Adam and Epel 2007). (Markowitz et al. 2008) proposed two causal Stress also promotes secretion of glucocorticoids behavioral paths from obesity to depression, the and insulin, which increases food intake and obe- health concern pathway and appearance concern sity (Dallman 2010). Increased adiposity, in turn, pathway, and two pathways that link depression promotes vulnerability to depression (Novick to obesity, the direct physiological pathway and et al. 2005; Sharma and Fulton 2013). indirect psychosocial pathway, based on the Recent evidence suggested that the type of moderators. The health concern pathway involves food may have an impact on the risk of depres- functional impairment and poor perceived health, sion. The consumption of saturated/trans-fat-rich which lead to depression. In the appearance con- foods can increase the odds of depression via cern pathway, negative psychological/behavioral increase in overall and abdominal adiposity, aspects of obesity including stigma, body image while diets containing mostly unsaturated fats dissatisfaction, and repeated dieting make people reduce the odds of depression and decrease vulnerable to depression, especially in women depressive symptoms (Sanchez-Villegas and and those of high SES. Factors which make it Martinez-Gonzalez 2013; Edwards et al. 1998; more difficult for depression patients to care for 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 207 themselves effectively, e.g., poor adherence, binge eating, negative thoughts, and reduced social support, constitute the indirect pathway from depression to obesity. The direct physiolog- GCs signalling? ical pathway includes biological changes, which External Leptin resistance? will be discussed later. stressors Insulin resistance? In conclusion, evidence suggests that the bidi- Neuroinflammation? rectional association between depression and + obesity is mediated by several variables including severity of obesity, gender, experience of stigma, psychological characteristics, eating and HPA dysregulation dieting behavior, and SES. The moderating variables between obesity and depression should be ↑Cortisol better understood, so that integrated prevention ↑C-reactive and intervention strategies could be developed. protein

↑Insulin ↑Cytokines 15.4 Neurobiological Mechanisms ↑Leptin ↑Fatty ↓Adiponectin Underlying the Association acids ↑Resistin Between Depression and Obesity

Metabolic and endocrine disturbances linking Fig. 15.1 Disturbed metabolic signals which link obesity depression with obesity and visceral adiposity and depression. Changes in metabolic signals associated include HPA axis dysfunction, insulin and leptin with central obesity correlate with depression. resistance, inflammatory signals, and oxidative Consumption of energy-dense diets, especially those high stress (Fig. 15.1). in saturated fat, promote abdominal obesity which induces a variety of endocrine changes; function of the hypothalamic–pituitary–adrenal (HPA) axis is disturbed, and plasma levels of hormones involved in the regulation of 15.4.1 HPA Axis Dysfunction energy metabolism and mood, such as cortisol, insulin, leptin, adiponectin, and resistin, are altered. Obesity is posited to link metabolic disturbance and depression via Disturbance of the HPA axis and increased corti- inducing impairments in brain glucocorticoids and leptin sol levels are involved in the pathophysiology of and insulin receptor signaling. Central fat accumulation both depression and obesity. In abdominal obe- results in increased levels of circulating inflammatory sity, the negative feedback mechanism mediated mediators, leading to neuroinflammatory responses and depression. Abbreviations and symbols: ↑ increased, ↓ by cortisol is impaired and in turn leads to elevated decreased, GC glucocorticoid. Figure as originally pub- cortisol levels and increased cortisol secretion in lished in Hryhorczuk C, Sharma S and Fulton SE (2013). response to stress (Incollingo Rodriguez et al. Front Neurosci 7:177. doi: https://doi.org/10.3389/ 2015). In individuals with central obesity, a hyper- fnins.2013.00177 activated HPA axis results in a higher cortisol response to corticotrophin-releasing hormone (CRH) stimulation and increased response to have been causally linked to fat accumulation and stress (Pasquali 2012). In a recent systematic weight gain, as glucocorticoids induce adipocyte review, greater abdominal fat is associated with hyperplasia by promoting conversion of preadipo- greater responsivity of the HPA axis, reflected in cytes to mature adipocytes (Incollingo Rodriguez morning awakening and acute stress reactivity, et al. 2015). Especially, hypercortisolemia is asso- especially in adipocytes (Incollingo Rodriguez ciated with the accumulation of visceral fat et al. 2015). Increased cortisol concentrations (Brown et al. 2004; Kyrou and Tsigos 2009). 208 Y.S. Woo and W.-M. Bahk

Dysregulation of the HPA axis is also present It is known that HPA axis disturbance serves in depression. Glucocorticoids alter HPA activ- as a common pathophysiology of both obesity ity and the glucocorticoid receptor-associated and depression. However, as a high saturated fat emotional/behavioral effects of stress in mid- diet and visceral fat accumulation are important brain and limbic circuits, which regulate reward mediators of HPA disturbances and depression and emotion as well as exert effects on mainte- associated with obesity, there is more to be nance of energy homeostasis (Herman et al. explored regarding the contribution of HPA axis 2003). In animal studies, chronic exposure to disturbances to depression elicited by diet- cortisol and overexpression of glucocorticoid induced obesity. receptors in the brain induce depressive-like behavior (Gregus et al. 2005). In human subjects, serum cortisol concentrations are 15.4.2 Adipose-Derived Hormones increased in depression, especially in the melancholic subtype, while hypoactivity of the HPA 15.4.2.1 Leptin axis is reported in the atypical subtype. In spite Leptin is secreted by the adipocyte and its levels of these categorizations of depression subtypes, are correlated with percent body fat (Maffei et al. hypercortisolemic depression is suggested to be 1995). In obese people, high circulating levels of associated with increased visceral adiposity leptin are in proportion to their greater fat mass. (Hryhorczuk et al. 2013). Apart from its anorexigenic, anti-obesity effect, The relationship among excessive glucocorti- leptin is involved in mood regulation. In chronic coid, visceral obesity, and depression can be stress animal models of depression, leptin levels speculated by the central impairments in the adi- are suppressed with reduced sucrose preference, pocyte cortisol metabolism by 11β-hydroxysteroid which is regarded as an analog of anhedonia dehydrogenases (11βHSDs), which catalyze the (Willner 2005). In studies with transgenic mice, interconversion of active cortisol and inert corti- leptin-deficient ob/ob mice or leptin receptor- sone. While 11βHSD2 catalyzes rapid conversion deficit db/db mice showed increased behavioral of active cortisol to inactive cortisone, 11βHSD1 depression (Yamada et al. 2011). Another aspect catalyzes the intracellular regeneration of cortisol that should be considered is the antidepressant from inactive cortisone (Seckl 2004). efficacy of leptin. In animal studies, leptin Overexpression of 11βHSD1 is well-implicated administration induced antidepressive behavior in visceral fat accumulation and affiliated periph- in normal mice and reverse depressive behavior eral metabolic abnormalities such as insulin in chronic stress model and leptin-deficient ob/ob resistance (Tchernof and Despres 2013). Hence, mice (Yamada et al. 2011). These behavioral 11βHSD1 is widely localized in the brain, includ- effects of leptin were accompanied by increased ing the hippocampus and hypothalamus, which neuronal activation in the hippocampus, which is are associated with emotional regulation, and this considered to be an important region for regula- enzyme plays a key role in the glucocorticoid tion of the depressive state (Lu et al. 2006). theory of depression, numerous studies indirectly However, the relationship between leptin and suggesting that 11βHSD1 may be involved in depression is unclear in human subjects. Several depression (Wyrwoll et al. 2011). A single- clinical studies suggest a link between depression nucleotide polymorphism in the 11βHSD1 gene and lower levels, or increased levels, of leptin, is associated with altered expression of 11βHSD1 especially in women (Rubin et al. 2002; Zeman at the central feedback sites of the HPA axis and et al. 2009) and atypical depressive patients is also associated with higher risk of depression (Gecici et al. 2005). Moreover, antidepressant (Dekker et al. 2012). Recently, an animal study treatment either increased or did not change demonstrated that ablation of the 11βHSD1 gene leptin levels (Schilling et al. 2013). In a recent results in an antidepressant-like phenotype in meta-analysis, more conflicting results were mice (Slattery et al. 2016). reported (Carvalho et al. 2014): the peripheral 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 209 leptin level did not differ between depression mood. Leptin may affect mood via HPA axis patients and healthy controls, and between major functioning. The baseline concentrations of leptin depressive disorder individuals with severe are negatively correlated with mobilization of depression versus healthy controls. However, its glucocorticoid (Komorowski et al. 2000), and level was significantly higher for participants chronic stress-induced HPA activation decreases with mild/moderate major depressive disorder circulating leptin concentrations (Ge et al. 2013). compared to controls. Leptin serum levels did not Moreover, administration of leptin lowers high change after antidepressant treatment (Carvalho corticosterone levels and prevents the induction et al. 2014). The authors indicated that there was of CRH synthesis in the paraventricular nucleus significant heterogeneity between studiesand the activation of the CRH neurons in food- included for the leptin diagnostic meta-analysis. deprived ob/ob mice (Huang et al. 1998). Leptin Hence, they performed meta-regression analyses also plays a role in the pathogenesis of depres- to verify the possible influence of moderator vari- sion via the long form of its receptor (LepRb), ables and reported that a higher overall sample which mediates the biological actions of leptin BMI was associated with a significantly higher and leads to intracellular signal transduction in difference in leptin serum levels between major the midbrain and forebrain. Genetic deficiency of depressive disorder patients and healthy hippocampal LepRb results in leptin resistance controls. and a depression-like behavior in mice, and loss In the “leptin hypothesis of depression” (Lu of LepRb in glutamatergic neurons in the hippo- 2007), these conflicting results from human stud- campus and prefrontal cortex also induces a ies could be explained by the complexity of leptin depressive phenotype (Guo et al. 2013). One of response in obese subjects who have high levels the other ways that leptin signaling affects mood of leptin. In obese people, leptin resistance that is is by regulation of the dopaminergic and seroto- similar to the one that links type 2 diabetes and nergic systems. Leptin can modulate the meso- insulin resistance is caused, which blunts the cen- limbic dopaminergic system by restoring tyrosine tral action of leptin, despite increasing concentra- hydroxylase (the rate-limiting enzyme in dopa- tions (Munzberg and Myers 2005). It is well mine production) expression in the ventral teg- documented that leptin sensitivity is diminished mental area via regulating LepRb-expressing owing to impaired transport of leptin into the inhibitory neurons in the lateral hypothalamus, central nervous system (CNS) and reduced func- which innervates the ventral tegmental area tion of the leptin receptor and defective leptin (Leinninger et al. 2009). Leptin also activates receptor long isoform (LepRb) signaling (Myers signal transducer and activator of transcription 3 et al. 2012). In light of leptin’s ability to inhibit (STAT3), a key downstream mediator of leptin depressive behaviors in animal models, it is pos- receptor signaling, in dopaminergic neurons in sible that leptin resistance may contribute to the the ventral tegmental area (Fulton et al. 2006). higher rate for depression in obese people. This Leptin can regulate vesicular somatodendritic could also help to interpret some of the conflict- dopamine stores, dopamine transporter activity, ing results obtained in relation to circulating and dopamine release as well (Liu et al. 2011). leptin levels in depressed patients (Lu 2007). Although the role of serotonin–leptin interactions Moreover, in a population-based study, increased appears to be less clear, some studies report that risk for depression is associated with the interac- leptin can increase serotonin content and metabo- tion between leptin and abdominal obesity lism in the forebrain, but not in the frontal cortex (Milaneschi et al. 2014). Based on these observa- (Calapai et al. 1999; Harris et al. 1998). In line tions, it is supposed that low leptin signaling with these findings, hypothalamic 5-HT1A recep- rather than leptin level per se is related to depres- tor expression was increased, and serotonin turn- sion pathophysiology (Lu 2007). over in the hypothalamus and hippocampus was An interesting question that remains to be decreased in leptin-deficient ob/ob mice com- addressed is how impaired leptin signaling affects pared to lean control mice (Schellekens et al. 210 Y.S. Woo and W.-M. Bahk

2012). However, a recent study on rats has shown affected (Lehto et al. 2010). In summary, the link that leptin directly influences serotonin metabo- between peripheral adiponectin and resistin con- lism by increasing serum serotonin levels, while centrations and depression in human subjects is serotonin in brain tissue (hypothalamus and hip- still unclear. However, it deserves further expla- pocampus) seems to be decreased after leptin nation as to the potential role of adiponectin and administration (Haleem et al. 2015). In summary, resistin in the shared pathophysiology of depres- although there is not yet conclusive evidence sion and obesity. explaining the relationship between leptin and obesity mood, leptin is one of the major contributing factors in the pathogenesis of depression 15.4.3 Insulin comorbid with obesity in that leptin hypothesis explains the deficiency in depression and resis- The link between the development of insulin tance in obesity. resistance and obesity, especially visceral obesity (Hayashi et al. 2008), and between insulin resis- 15.4.2.2 Adiponectin and Resistin tance and depression (Kan et al. 2013) has been Adiponectin and resistin are other adipose- well documented. Prospective studies indicate derived hormones considered to take part in the that insulin resistance/metabolic syndrome with regulation of energy metabolism and insulin sen- obesity is associated with significantly increased sitivity. Adiponectin acts as an insulin-sensitizing risk of developing depression (Hamer et al. 2012). adipokine. The plasma levels of adiponectin are A small but significant association between thought to be changed secondary to metabolic depression and insulin resistance was observed in disturbance in obesity because they are nega- a recent meta-analysis, despite the effect size tively correlated with obesity, waist circumfer- attenuated in analyses adjusted for body weight ence, visceral fat, and insulin resistance in and other confounders (Kan et al. 2013). humans while not changed in metabolically Several studies were performed to determine healthy obesity (Hryhorczuk et al. 2013). There the role of insulin in mood. A growing body of are also evidences that the circulating level of evidence indicated that alteration in insulin sig- adiponectin is correlated with depressive symp- naling pathways including insulin availability toms, although the direction of changes is not and/or sensitivity or availability of insulin consistent; there are reports of both positive and receptor is important to the underlying patho- negative correlation between depressive symp- physiology of depression (Cha et al. 2017). toms and adiponectin concentration, or no change Insulin exerts its biological function mainly by in patients with depression (Hryhorczuk et al. binding its receptors distributed in the olfactory 2013). Plasma resistin levels in relation to obesity bulbs, cerebral cortex, hippocampus, cerebel- are more complicated; some early studies lum, and hypothalamus (Detka et al. 2015). The reported that resistin levels are increased with binding of the ligand to insulin receptors leads obesity in animal models and humans, but other to the phosphorylation of insulin receptor sub- studies found that resistin is downregulated in strate docking proteins (IRS), favoring the gen- obese animals and humans. In depressed patients, eration of intracellular signals. The two main the resistin level was increased in atypical depres- intracellular signaling pathways are the IRS- sion, but not in typical depression, and lowered in phosphatidylinositol 3-kinase (PI3K)-Akt path- a remitted state (Lehto et al. 2010; Weber- way and the Ras-mitogen-activated protein Hamann et al. 2007). In a recent meta-analysis kinase (MAPK) (MEK/ERK) pathway, which (Carvalho et al. 2014), peripheral adiponectin are known to be involved in depression patho- and resistin levels were significantly lower in physiology (Chaudhury et al. 2015). Moreover, depression patients compared to healthy controls. insulin may be acting to regulate mood by mod- With antidepressant treatment, adiponectin and ulating neurogenesis. As noted above, insulin resistin levels in depression patients are not receptor expression is high in the hippocampus 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 211 and olfactory bulb, which shows relatively high 15.4.4 Inflammatory Signals levels of adult neurogenesis (McNay and Recknagel 2011). Given that insulin serves as a Obesity is associated with systemic, low-grade growth factor and increases brain-derived neu- chronic inflammation. Pro-inflammatory cyto- rotrophic factor (BDNF) and vascular endothe- kines, including interleukin (IL)-1β, tumor lial growth factor (VEGF), which have trophic necrosis factor (TNF)-α, IL-6, and C-reactive effects on the amygdala, hippocampus, and pre- protein (CRP) levels and inflammatory signal- frontal cortex, and insulin-like growth factor 1 ing, have been reported to be increased in obe- (IGF-1) is a potential regulator of hippocampal sity (Gnacinska et al. 2009). Diverse mechanisms neurogenesis, then insulin resistance may lead contribute to the development of inflammation to decreased central insulin levels leading to associated with obesity. White adipose tissue, impaired neuroplasticity and function of key composed of adipocytes and stromavascular brain areas essential to regulation of mood fractions including macrophages and lympho- (Rosenblat et al. 2015). In addition to these cytes (Langlet et al. 2012), is one of the main roles of the brain insulin receptor, recent studies protagonists. Evidences suggest the positive demonstrated that altered insulin signaling path- association between visceral adiposity and cir- ways in the brain induce monoaminergic dys- culating levels of cytokines (Park et al. 2005; function. For instance, amphetamine-induced Visser et al. 1999). Adipocytes, together with dopamine release is significantly reduced by infiltrated macrophages and T cells that progres- insulin depletion, which suggests insulin signal- sively accumulate in the white adipose tissue, ing pathways may represent a mechanism for have the ability to potently secrete inflammatory regulating dopaminergic neurotransmission mediators (Capuron et al. 2017). In diet-induced (Williams et al. 2007). Along with this, circulat- obesity, the number and size of adipocytes ing levels of insulin can influence the function increase and immune changes occur. Adipose of the norepinephrine and serotonin transporter, tissue macrophages polarized into an M1 “clas- and in turn, extracellular levels of norepineph- sically activated” phenotype, which has rine and serotonin (Kemp et al. 2012). enhanced pro-inflammatory cytokine production In clinical studies, intravenous insulin and generated reactive oxygen species. increased hippocampal neuronal activity and Moreover, obesity induces a Th1 dominant state improved mood (Rotte et al. 2005), and intranasal which leads to a pro-inflammatory environment insulin improved mood and cognition in healthy, (Lee and Lee 2014). Obesity activates the innate obese, and Alzheimer’s disease patients (Shemesh immune system through Toll-like receptors et al. 2012). Recent clinical and preclinical trials (TLRs); binding of fatty acid to TLR4 activates examined the repurposing of antidiabetic medica- transcription factors such as NF-κB and activator tions, including an insulin-sensitizing agent, pio- protein 1 (AP-1). These proteins upregulate the glitazone (Colle et al. 2017), and glucagon-like expression of pro-inflammatory cytokines and peptide-1 (GLP-1) receptor agonists (Mansur chemokines (Konner and Bruning 2011). et al. 2017; Sharma et al. 2015), in depression. Obesity-induced inflammation also affects many The improvement of depressive symptoms by organs, including adipose tissue, liver, pancreas, pioglitazone was positively correlated with atten- and muscle. For example, the pro-inflammatory uation of insulin resistance (Kemp et al. 2012). shift also involves hepatocytes to be altered in Positive correlations between insulin resistance their metabolic function and Kupffer cells to be and severity of depressive symptoms have also skewed toward a pro-inflammatory phenotype. been reported in cross-sectional studies (Shomaker Together, diet and alterations to hepatic homeo- et al. 2010; Timonen et al. 2005). In sum, data stasis lead to the production of circulating pro- points toward insulin resistance as one of the cul- inflammatory mediators resulting in prits in obesity-induced depression, while enhanc- obesity-induced metabolic inflammation ing insulin signaling has an antidepressant effect. (Guillemot-Legris and Muccioli 2017). 212 Y.S. Woo and W.-M. Bahk

Recently, the gut microbiota alteration was The hypothalamus is a structure that is partic- considered as one of the possible mechanisms ularly affected by the increased inflammatory contributing to the development of obesity, par- process in the brain of obese individuals (Thaler ticularly with regard to modulation of inflamma- et al. 2012). The hypothalamic arcuate nucleus tion, energy metabolism, and body weight plays a critical role in controlling energy homeo- homeostasis (Finelli et al. 2014; Flint 2011; stasis and body weight by integrating peripheral Verdam et al. 2013). Altered gut microbiota com- metabolic cues such as leptin, insulin, or ghrelin. position induced by obesity—increase of the This role of hypothalamic arcuate nucleus and LPS-bearing species (Firmicutes and subsequent neuronal response is disrupted by Enterobacteriaceae) with a proportional reduc- neuroinflammation induced by obesity (Thaler tion in Bacteroidetes as well as bacterial rich- et al. 2012; Naznin et al. 2015). Exposure to a ness—alters epithelial cells of the intestinal high-fat diet increased reactive gliosis within a barrier while promoting the translocation of bac- week, and even one day of a high-fat diet feeding teria and their cell wall components, such as LPS, increased the number of microglia in the hypo- to activate macrophages that, in turn, will produce thalamus (Thaler et al. 2012; Waise et al. 2015). pro-inflammatory cytokines through induction of Obesity is also associated with increased hypo- TLR4. Increased concentrations of systemic LPS, thalamic expression of pro-inflammatory cyto- “metabolic endotoxemia,” and other bacterial kines such as IL-6 and TNF-α and activation of products or an increase in free fatty acid levels in IKKβ/NF-κB through elevated endoplasmic the liver, adipose, and muscular tissues resulting reticulum stress in the hypothalamus (Thaler in the recruitment of TNF-α- and IL-6-producing et al. 2012; Zhang et al. 2008). The neuroinflam- pro-inflammatory M1 macrophages and the role mation derived from obesity affects structures of inflammation in adipose tissue become more beyond the hypothalamus (Thaler et al. 2013; Lu evident (Bleau et al. 2015). et al. 2011; Guillemot-Legris et al. 2016). Similar A large body of evidence supports that the brain neuroinflammatory processes were observed in is a target of the systemic inflammatory process in the hippocampus or cerebral cortex in animal obese individuals. One of the potential mecha- models of obesity. Enhanced IKKβ/NF-κB- nisms through which inflammation affects the mediated inflammatory signaling, increased brain is altered bidirectional communication using expression of pro-inflammatory cytokines (e.g., inflammatory signals between periphery and brain IL-1β, IL-6, and TNF-α), and activation of astro- as a result of obesity. The protective function cytes and microglia were reported in the hippo- against peripheral inflammatory changes of blood– campus and cerebral cortex of obese animal brain barrier (BBB) could be disrupted by obesity models (Lu et al. 2011; Carlin et al. 2016). (Stranahan et al. 2016). In addition, the blood– The changes in inflammatory biomarkers in CSF barrier across the choroid plexus epithelium depression have been extensively studied. It is well could be compromised by systemic inflammation known that increased inflammatory cytokines can (Balusu et al. 2016). In response to changes in lev- induce depression-like behavioral changes in ani- els of peripheral mediators, including leptin, insu- mals and humans, as well as depressed patients lin, fatty acids, or cytokines, phenotypic changes showing an increased level of pro-inflammatory in brain cells occur. Microglia, resident immuno- cytokines such as IL-1, IL-6, and TNF-α, in addi- cytes in the CNS which produce inflammatory tion to increased concentrations of acute phase mediators, are activated by saturated fatty acids proteins including CRP, chemokines, and adhe- and monounsaturated fatty acids via the TLR4/ sion molecules (Pace and Miller 2009). The role of NF-κB pathway resulting in cytokine secretion cytokine in inducing depressive symptoms could and generation of reactive oxygen species in obe- be explained by dysregulated monoaminergic neu- sity conditions (Button et al. 2014). Astrocytes are rotransmission, impaired neuronal growth and sur- also activated by saturated fatty acids to produce vival, and altered HPA axis function, described IL-6 or TNF-α (Gupta et al. 2012). above (Kiecolt-Glaser et al. 2015). Cytokines 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 213 modulate production, transport, and metabolism and activation of c-JUN, which in turn constitutes of monoaminergic neurotransmitters, e.g., sero- the activator protein-1 (AP-1) complex, which tonin, dopamine, and glutamate, which affect has been shown to interfere with GR–GRE inter- mood (Capuron and Miller 2011) by stimulating actions (Pace and Miller 2009). Activation of the enzymes including indoleamine 2,3-dioxygenase TNF receptor triggers a signal transduction cas- (IDO) and GTP-cyclohydrolase 1 (GTP-CH1). cade that activates IκB kinase β (IKKβ), resulting Cytokines enhance tryptophan catabolism by in phosphorylation and dissociation of the IκB– stimulating indolamine 2,3-dioxygenase, by which NF-κB dimer. Released NF-κB translocates to depression could be promoted by slowing sero- the nucleus where it interferes with GR–GRE tonin production and enhancing potentially neuro- interaction (McKay and Cidlowski 1999). toxic, glutamatergic kynurenine metabolites Finally, IFN receptor activation results in phos- (Dantzer et al. 2011). By immune activation, phorylation of Janus kinase-1 (Jak1) which acti- GTP-CH1 which produces an essential cofactor vates STAT5, which, like NF-κB, inhibits for dopamine and serotonin biosynthesis, tetrahy- GR–GRE interactions through protein–protein drobiopterin (BH4) is activated to lead to produc- interactions in the nucleus (Hu et al. 2009). In tion of neopterin at the expense of BH4 formation these ways, cytokine signal transduction path- in activated brain immune cells (Capuron et al. ways through activation of inflammatory inter- 2017). Therefore, cytokine-induced GTP-CH1 mediaries, such as NF-κB, disrupt GR function activation reduces monoaminergic transmission and expression, leading to cytokine-dependent (Castanon et al. 2015). Consistent with these find- GR resistance that could further fuel depressive ings, increased brain kynurenine neurotoxic symptoms (Kiecolt-Glaser et al. 2015). metabolites, which are associated with impaired Inflammation may affect individuals differ- neurogenesis, are reported in depression (Campbell ently; it may contribute to depression in a subset et al. 2014; Steiner et al. 2011; Savitz et al. 2015; of individuals who have vulnerabilities in physi- Zunszain et al. 2012). Moreover, reduced BH4 lev- ologic systems, in whom even low levels of els are reported in depression (Hashimoto et al. inflammation is depressogenic. Raison and Miller 1994) and an increased neopterin level is posi- (2011) call this phenomenon “immune response tively associated with a number of depressive epi- element amplification.” This may include reduced sodes in depression patients (Celik et al. 2010). parasympathetic signaling, reduced production Neuroinflammation also hampers neuronal of BDNF, insensitivity to glucocorticoid inhibi- growth and survival. Increased pro-inflammatory tory feedback, increased activity to social threat cytokines cause excitotoxicity via modulation of in the anterior cingulate cortex or amygdala, and NMDA receptors, thereby reducing production reduced hippocampal volume. Indeed, these are of BDNF (Eyre and Baune 2012). Besides, oxi- all correlates of major depression that would dative stress caused by cytokines damages glial influence sensitivity to the depressogenic conse- cells in the prefrontal cortex and amygdala, key quences of inflammatory stimuli (Kiecolt-Glaser structures for mood regulation (Leonard and et al. 2015). Maes 2012). In addition to their effects on neural plasticity, cytokines dysregulate HPA axis functioning, a key characteristic of depression. In an 15.4.5 Oxidative/Nitrosative Stress inflammatory context, glucocorticoid resistance is acquired by inhibition of transcriptional activa- During energy production in the mitochondria, free tion of glucocorticoid response elements (GREs) radicals such as reactive oxygen species (ROS) and by glucocorticoid receptors, attributed to several reactive nitrogen species (RNS) are normally gen- mechanisms (Shelton and Miller 2010); activa- erated, and these perform numerous roles in regulation of IL-1 receptor activates mitogen-activated tion of cellular function. The ROS/RNS become protein kinases (MKKs), leading to phosphoryla- excessive by the imbalance between their production of MAPK and Jun N-terminal kinases (JNK) tion and clearance by antioxidant defenses. 214 Y.S. Woo and W.-M. Bahk

Excessive ROS/RNS can cause damage to cellular underpin both depression and obesity, and it seems components, induce harmful autoimmune that integrated impairments in redox and inflam- responses, and consequently facilitate failure of matory signaling pathways are the “common soil” normal cellular processes (Moylan et al. 2014). from which obesity and depression develop, even Several studies suggest that obesity can be though it is difficult to precisely trace which one associated with increased oxidative stress and a precedes the other. decreased defense system. Various factors associated with obesity such as a high-fat, high carbo- hydrate diet cause increased oxidative stress 15.5 Conclusion and Clinical through activation of intracellular pathways such Implications as NADH/NADPH oxidase and endoplasmic reticulum stress in adipocytes. Indeed, oxidative The bidirectional association between obesity stress can cause obesity through adipogenesis and depression is complex and affected by sev- regulated by ROS-mediated oxidative stress sig- eral common pathways. As discussed, evidence nals, and obesity may generate more ROS by shows that alterations in leptin, insulin, inflam- various mechanisms including chronic adipocyte matory signaling, and the HPA axis function, inflammation, fatty acid oxidation, overconsump- including glucocorticoid, may bridge obesity and tion of oxygen, accumulation of cellular damage, depression. In addition, it was suggested that the diet, and mitochondrial activity. Thus, obesity moderating effects of behavioral and social actors and oxidative stress appear to be connected to should be considered when examining the rela- each other through mutual sustenance mecha- tionship between obesity and depression. While nisms (Rani et al. 2016). Moreover, ROS modu- this chapter has been limited to the discussion of late the activity of signaling cascades mediated a few key biological pathways, it is acknowl- by the redox-sensitive transcription factors, such edged that several other factors are important in as NF-κB and AP-1, which can stimulate several the association between depression and obesity pro-inflammatory cytokines, which may further (Hryhorczuk et al. 2013). increase the overproduction of ROS (Rani et al. The shared biological mechanisms underly- 2016; Moylan et al. 2014; Bryan et al. 2013). ing depression and obesity and their moderators Increased oxidative stress is accompanied by bring to the forefront the necessity to identify the depression, as well (Berk et al. 2013). Depression “obese subtype” or “metabolic subtype” of is associated with decreased activity of enzymes depression as discussed by Mansur et al. (2015). involved in the respiratory chain, decreased ATP The validation of the concept of this subtype production, and other mitochondrial dysfunctions, may have important clinical implications. which can be a source for the accumulation of free Several studies have suggested that obesity radicals (Vavakova et al. 2015). Mitochondrial worsens treatment response (Woo et al. 2016), dysfunction affects various cell-signaling mole- and weight loss is often associated with improve- cules which may contribute in the pathophysiol- ments in depressive symptoms, and vice versa, ogy of depression via increased production of by inducing improvements in several physiologi- ROS/RNS and a misbalance in Ca2+ homeostasis. cal pathways that are disturbed in depression and In many studies, biomarkers of oxidative and obesity (Jantaratnotai et al. 2017). Thus, patients nitrosative stress, such as malondialdehyde with obesity should be evaluated for depression, (MDA), glutathione (GSH), NF-κB, and superox- and patients presenting depressive symptoms ide dismutase (SOD), are changed in depression. should be evaluated for obesity. The obese In addition to increased oxidative stress, depres- patient with depression should, in turn, be evalu- sion is associated with lower plasma concentration ated for eating behavior, distress, and impair- of antioxidants and lowered total antioxidant sta- ment owing to both conditions. It is also tus (Maurya et al. 2016). Taken together, it can be important to prevent further weight gain in these suggested that oxidative/nitrosative stress may patients. 15 The Link Between Obesity and Depression: Exploring Shared Mechanisms 215

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Boldizsár Czéh, Ove Wiborg, and Eberhard Fuchs

16.1 Introduction worldwide (Kessler and Bromet 2013). According to a recent WHO analysis, depression will be the Depressive disorders are characterized by a sub- leading cause of disease burden globally by 2030 stantial disturbance in persistent emotional state (WHO report EB130/9 2011). Effective thera- or mood. In the category of depressive disorders peutic interventions are available, but the cur- the following illnesses are included: disruptive rently existing antidepressant treatments are far mood dysregulation disorder, major depressive from being optimal and there is an urgent need disorder (including major depressive episode), for new, faster acting, more effective drugs and persistent depressive disorder (dysthymia), pre- also for preventive treatment strategies. menstrual dysphoric disorder, substance/ Despite extensive research efforts the patho- medication-induced depressive disorder, depres- physiology of mood disorders remains unre- sive disorder due to another medical condition, solved. The first effective antidepressant drugs other specified depressive disorder, and unspeci- were discovered only by serendipity. Hydrazine fied depressive disorder (for details see the derivatives (e.g., isoniazid, iproniazid) were orig- DSM-5 diagnostic manual). Because most of the inally developed for the treatment of tuberculosis currently available animal models aim to mimic and only by coincidence were found to have major depressive disorder thus, in this chapter we euphoric effects (Ramachandraih et al. 2011). will focus only on these. These compounds were the first non-selective, Major depressive disorder (MDD) is a severe irreversible monoamine oxidase inhibitors mental disorder affecting millions of people (MAOIs). The first tricyclic antidepressants, most prominently imipramine, were derived from anti- histaminic compounds. At the beginning, the B. Czéh (*) mood elevating characteristics of these drugs MTA – PTE, Neurobiology of Stress Research were viewed with great skepticism among doc- Group, Szentágothai Research Center, Pécs, Hungary tors, but then, in the 1950s, together with the dis- Faculty of Medicine, Institute of Laboratory covery of chlorpromazine, they revolutionized Medicine, University of Pécs, Pécs, Hungary the treatment possibilities of mental disorders e-mail: [email protected] (Healy 1999). The tricyclic antidepressants, O. Wiborg which are believed to act by inhibiting the plasma Department of Clinical Medicine, Aarhus University, membrane transporters of serotonin and/or nor- Aarhus, Denmark epinephrine provided a template for the develop- E. Fuchs ment of the modern day classes of antidepressants, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany such as the selective serotonin reuptake inhibitors

(SSRIs), noradrenaline reuptake inhibitors 2016a, b; Cryan and Mombereau 2004; Anisman (NRIs), and dual serotonin/noradrenaline reup- and Matheson 2005; Pryce and Fuchs 2016). take inhibitors (SNRIs). These discoveries led to Drug companies are interested in developing new the development of the monoamine theory which drugs, therefore, on one hand they are always was formulated in the 1960s as an explanation for open to new and expensive technologies, on the the pathophysiology of depressive disorders. other hand they need simple, high throughput, Since then, numerous limitations of the mono- and reliable behavioral models for compound amine theory have been revealed and the more screening (Berton and Nestler 2006; Cryan and recent concepts emphasize the involvement of Slattery 2007). Notably, the pharmaceutical various other neurotransmitter systems, as well industry has become severely disappointed dur- as changes of neuroplasticity in limbic brain ing the recent years because of their lack of suc- areas, epigenetic mechanisms, dysregulation of cess in the development of new drugs for the the hypothalamic-pituitary-adrenal axis, poten- treatment of mental disorders. They have con- tial inflammatory mechanisms, or even the dis- demned mental disorders as a challenge that is turbances of gut microbiota. “too difficult” to attract major investment (Hyman According to our present comprehension 2014). We have to face the fact that the traditional MDD develops as a result of interactions expectation on antidepressant development has between a genetic predisposition and environ- collapsed. In other words, it is now believed that mental factors. The depressive episodes are typ- it is unlikely that we can find new “druggable” ically triggered by psychosocial stressors targets in the brain (e.g., receptors or transport- (Klengel and Binder 2013; Mandelli and Serretti ers) and then, based on that finding we can 2013). Having this in mind, most of the cur- develop new pharmaceutical agents to rectify the rently available experimental models either neuronal (or glial) dysfunctions. Although excep- apply some kind of genetic manipulation or use tions do exist, see, for example, the recent dis- an environmental stressor to generate animals covery of agomelatine, the first melatonergic with a behavioral phenotype that resemble the antidepressant (de Bodinat et al. 2010). In sum, symptoms of MDD. But there are other models experts suggest that a radical paradigm switch is as well, such as the olfactory bulbectomy model, needed in the field of antidepressant drug the learned helplessness model, selective breed- research, if we really want to step forward (Insel ing models, or the drug-withdrawal-induced et al. 2013). anhedonia model (for more details, see, e.g., Czéh et al. 2016). Typically animal models for depressive disor- 16.2 Criteria for Valid Animal ders are used for the following two purposes: (1) Models of Depression to understand the pathophysiology of the illness and (2) to develop new treatment strategies Numerous attempts have been made to create (Willner 1984, 1997; Cryan et al. 2002, 2005a; animal models of depression and several crite- Willner and Mitchell 2002; Cryan and Holmes ria for their evaluation have been established. 2005; Berton and Nestler 2006; Nestler and The most widely cited criteria were developed Hyman 2010; Berton et al. 2012; Bouwknecht by McKinney and Bunney nearly 50 years ago 2015; Willner and Belzung 2015; Czéh et al. (McKinney and Bunney 1969). The authors 2016). Academic scientists usually aim to pro- proposed the following minimum requirements vide insight into the underlying neurobiology of for an animal model of depression: (1) it is the disorder and therefore they tend to apply “reasonably analogous” to the human disorder in more complex and time-consuming models, e.g. its manifestations or symptomatology; (2) there they generate a new transgenic animal, or use a is a behavioral change that can be monitored chronic stress model to mimic some aspects of objectively; (3) the behavioral changes observed the etiological factors (Willner 1984, 1997, 2005, should be reversed by the same treatment 16 Experimental Animal Models for Depressive Disorders: Relevance to Drug Discovery 225 modalities that are effective in humans; and (4) 16.3.1 Genetic and Optogenetic it should be reproducible between investigators. Models Later Willner (1984) formulated that a valid animal model for depression should have three The production of genetically engineered mouse major criteria: face validity, predictive validity, lines gives us the possibility to investigate the and construct validity. Face validity describes consequences of silencing or overexpressing the similarity between the behavioral pheno- specific genes that are thought to contribute to type and the clinical-symptom profile. For pre- the pathophysiology of the disease. There are dictive validity the amelioration or attenuation two possibilities: forward or reverse genetics. of the symptoms by clinical effective antide- Forward genetics is an unbiased approach in pressant treatments and, conversely, absence of which a large number of random mutations are changes by clinically ineffective treatment of generated in an organism (e.g., mice) using sim- the human disorder is required. For the crite- ple mutagenic techniques, followed by breeding rion construct validity similar neurobiological and screening for individuals with the desired underpinnings are required. The fourth crite- depressive-like behavioral phenotype. Afterwards rion, etiological validity, was originally intro- the responsible gene can be identified. Typically, duced by Abramson and Seligman (1977) and the reverse genetic approach is used which means states the triggering events that are known to be targeted genetic manipulations that result in important for eliciting the human disorder either loss- or gain-of-function mutants. should be the same used in animals. “Knockout mice” are the most well-known Unfortunately, none of the currently available examples, in which a specific target gene is dis- animal models fulfills these four criteria com- rupted, resulting in a loss-of-function mutant. pletely. There are complex models that repli- Conversely, gain-of-function mutant mice carry cate some symptoms of MDD, and a few simple additional copies of a specific gene in their behavioral “screens” (such as the forced swim- genome or have been generated by knock-in ming test) that have been useful for testing the techniques. There is a continuous and rapid efficacy of a specific group of antidepressant development of technologies in this field, for compounds (namely the SSRIs). example the discovery of conditional strategies (Branda and Dymecki 2004) or the development of new genome editing tools, for example ones 16.3 Animal Models that are based on CRISPR-Cas systems for Understanding (Heidenreich and Zhang 2016). the Pathophysiology In the beginning, most genetic models focused of Major Depressive Disorder on the key players of the monoaminergic neurotransmission and generated, for example the Numerous different models are used in preclini- 5-HT1A receptor knockout mouse model (Heisler cal research (for details, see, e.g., Willner 1984, et al. 1998; Parks et al. 1998; Ramboz et al. 1998) 1997; Cryan et al. 2002; Willner and Mitchell or the noradrenaline transporter knockout mouse 2002; Cryan and Holmes 2005; Cryan et al. model (Xu et al. 2000). Later models targeted the 2005a, b; Berton and Nestler 2006; Nestler and regulators of the HPA-axis and produced Hyman 2010; Berton et al. 2012; Bouwknecht corticotropin-releasing hormone receptor-1 2015; Willner and Belzung 2015; Czéh et al. (CRH-R1) knockout mice (Timpl et al. 1998; 2016). Due to the space limitations, we can only Müller et al. 2003; Refojo et al. 2011) or the type briefly summarize here the most commonly used II glucocorticoid receptor knockout mouse model models and the most interesting recent develop- (Pepin et al. 1992; Montkowski et al. 1995). ments. We recommend that the reader should More recently, the epigenetic events have been in look up the cited excellent reviews for more the focus of investigations on the genetic back- detailed descriptions on these models. ground of depressive disorders. Numerous data 226 B. Czéh et al. imply that transcriptional dysregulations may served as building block for the stress hypothesis contribute to the behavioral manifestations of of mood and anxiety disorders (e.g., Gold 2015). many psychiatric disorders, including major In consequence, this hypothesis has stimulated depression (Tsankova et al. 2007; Sun et al. 2013; the development of a number of experimental Nestler 2014) and the very recent knockout manipulations of the environment in animals, mouse models were generated to prove that. For with the aim of causing changes in behavior and example, the demonstration that mutation in the brain that have relevance to stress-related psy- gene of a chromatin modifier (Kdm5c gene) chopathologies in humans (for recent reviews, results in impaired social behavior, memory defi- see, e.g., Nestler and Hyman 2010; Slattery and cits, and aggression, and that Kdm5c-knockout Cryan 2014). Consequently, we will focus here mouse brains exhibit abnormal dendritic arbori- on the stressors rather than the stress response. zation and spine anomalies (Iwase et al. 2016). It is believed that psychosocial stress para- Others emphasize the role of environmental digms are more relevant to the human situation stressors in epigenetic plasticity (Nasca et al. than non-social stress paradigms, because the 2015). vast majority of stressors reported by patients Technical progress in molecular biology has suffering from psychiatric disorders are social in led to the development of a wide array of meth- nature (Keller et al. 2007). Therefore, there is a ods that enable the blockade or stimulation of growing consensus that social stress paradigms neuronal activity with high anatomical, genetic, are better placed to reveal the behavioral, neuro- and temporal precision. For a brief overview of endocrine, or immunological mechanisms under- these techniques, see, e.g., www.openoptogenet- lying chronic stress-induced pathology. However, ics.org or recent reviews (e.g., Kim et al. 2017; in order to maximize our understanding of the Jazayeri and Afraz 2017). Optogenetic tools have mechanisms underlying stress-related disorders, been applied to investigate the neurobiology of various different models are necessary, including various mental disorders (for review, see, e.g., models employing neurogenic pain (e.g., painful Steinberg et al. 2015; Marton and Sohal 2016) stimuli such as foot shock) or pharmacological including depressive disorders (Chaudhury et al. (e.g., corticosterone) stressors (Reber and 2013; Tye et al. 2013; Proulx et al. 2014). There Slattery 2016). These stressors are not in the are high expectations in the optogenetic toolkit focus of this chapter, instead this chapter com- since this approach may—in the long term—lead prises contributions that focus on psychogenic to the development of truly novel treatment strat- stressors. egies for depressive disorders (Covington et al. 2010; Friedman et al. 2014). 16.3.2.1 Models Based on Social Stress A considerable source of stressors is the social 16.3.2 Animal Models Based environment. According to Barnett, there are two on Stress actions which are the most significant psychosocial stressors: losses or losing control (over one’s Stress—the physiological response to an envi- life events) and fighting for the control (Barnett ronmental challenge—is a fundamental scien- 1958, 1964). Loss of social rank or social status is tific, clinical, and societal concept, which was a prime example of the more general kind of loss initially described by Hans Selye some 80 years incidents. These events are increasingly recog- ago (Selye 1936; Fink 2016). Today we know nized as important risk factors for the development that repeated or chronic stress is an important risk of major depressive disorder (Brown 1993; Keller factor for numerous affective and somatic disor- et al. 2007). To mimic the mechanisms involved in ders. The substantial evidence showing that the human situation a number of behavioral models chronic stress can increase the likelihood of have been validated to model depression by using major depressive disorder and anxiety disorders social disturbances as stressors. These models are 16 Experimental Animal Models for Depressive Disorders: Relevance to Drug Discovery 227 of particular value because they explore the envi- About 20 years ago Koolhaas et al. (1997) ronmental threats that an animal may be exposed in pointed out that social defeat is a special kind of its daily life. In social contexts, this might mean stressor. Social defeat is different from other loss of control by social defeat. stressors with respect to the quality and the mag- The most popular model of social defeat and nitude of the stress response. Moreover, it is stress is the resident-intruder paradigm. important to mention that social defeat induces Classically, it is applied in male rodents employ- alterations in a number of physiological and bio- ing social conflict between members of the same chemical read-outs, each of which may have dif- species to generate psychosocial stress. In the ferent temporal dynamics (Koolhaas et al. 2016). standard protocol the male intruder is relocated In this context, it should be mentioned that the into the home cage of another male, the resident. time of day of the exposure is also critical. This setting is regarded as an acute stress expo- Rodents like mice and rats are crepuscular- sure if the animals are allowed to fight on a single nocturnal animals. Generally they are active dur- occasion. If the intruder is exposed to the resident ing the dark phase and quiescent during the light repeatedly at several time points, ranging from phase of the light-dark cycle. Mice subjected to days to even weeks, it is regarded as a model of chronic social defeat stress during the dark phase chronic stress. In some experimental protocols, developed more pathophysiological signs com- the intruder is transferred to the cage of a singly pared with those subjected to the stressor during housed resident. In other cases, the intruder the light period (Bartlang et al. 2012). These find- replaces a cohabitating female in the resident’s ings demonstrate that stressor exposures at dis- cage. Usually within one to three minutes, the tinct times of the light-dark cycle may generate intruder is attacked and defeated by the resident. different stress responses. Immediately after that, the two animals are separated. For the next 30–60 minutes, the intruder is 16.3.2.2 The Chronic Mild Stress kept in a small wire-mesh compartment within Model the resident’s cage. Thus, the intruder is protected The chronic mild stress (CMS) model is recog- from direct physical contact, but remains exposed nized as an extensively validated depression to the stressful psychogenic olfactory, visual and model with high translational potential (Willner auditory stimuli emitted by the resident. After 1997, 2005, 2016a). There are several different this procedure, the intruder is returned to his names (mild, unpredictable, variable stress) for home cage. For comprehensive and detailed dis- the model, but they refer essentially to similar cussions of the different social defeat/stress pro- protocols. Typically, rats or mice are exposed to a tocols in mice and rats, see Hollis and Kabbaj number of mild stressors in an unpredictable (2014), Koolhaas et al. (2016), and Pryce and order for several weeks and over time they reduce Fuchs (2016). voluntary intake of rewards (Wiborg 2013). This For many years, it was thought that this is interpreted as a decreased motivation, or approach does not work in female rodents reduced sensitivity, for rewards and believed to because they do not fight with each other in a be the biological underpinning for anhedonia, the resident-intruder paradigm (Palanza 2001). cardinal depression symptom in humans. In addi- Recent studies, however, could demonstrate tion to realistic inducing conditions important social defeat in female rats when using older, lac- disease characteristics of MDD, like the chronic tating individuals as residents (Holly et al. 2012). and episodic nature of the disease, make the CMS Jacobson-Pick and coworkers reported an inter- model one of the most realistic animal models of esting finding in female mice. They demonstrated depression, once stressors are discontinued ani- that the stress-induced behavioral effects were mals recover spontaneously. more pronounced 2 weeks after exposure to the Sucrose intake is mainly applied as a readout stressor than they were 2 h afterwards (Jacobson- on anhedonic-like behavior and when using an Pick et al. 2013). outbred rat strain animals show an individual and 228 B. Czéh et al. graduated stress response, some become Lanius et al. 2010; Heim and Binder 2012; anhedonic-like while others cope with the applied Mandelli et al. 2015). stressors in order to maintain homeostasis Over the years, many experimental procedures (Bergström et al. 2008). This is an additional aimed at inducing early life stress at critical devel- advantageous feature of the model allowing for opmental periods in nonhuman primates and studies on stress-resilience mechanisms. If stress rodents have been described. Many of these manip- exposure is combined with chronic antidepres- ulations produce physiological and behavioral sant administration a subgroup of the anhedonic- changes with potentially lifelong and even trans- like rats recovers over time, however, a substantial generational consequences and represent a risk fac- fraction of the rats do not respond to treatment, tor for psychopathology (see, e.g., Newport et al. corresponding to clinical treatment refraction 2002; Pryce et al. 2005; Ambeskovic et al. 2017). (Christensen et al. 2012). The treatment responses Within this framework, maternal separation is represent additional interesting features of the a widely used experimental procedure. Studies model allowing for addressing antidepressant performed in rats have demonstrated that a single drug efficacy as well as time point for onset of or repeated separation of the pups from the dam action, which are both key issues in the develop- leads to acute or long-term effects on behavior ment of novel antidepressant medication. In addi- and physiology. Although broadly accepted as tion to anhedonic-like behavior the chronic stress model to disturb the mother–offspring relation- paradigm also induces long-lasting changes in ship, the reports of the effects of maternal separa- behavioral, neurochemical, neuroimmune, and tion show inconsistent findings for nearly all neuroendocrinological parameters resembling parameters investigated (for review, see, e.g., dysfunctions observed in depressed patients Daly 1973; Lehmann and Feldon 2000). A (Willner 1997, 2005; Wiborg 2013). possible explanation for this discordancy may be that maternal separation has become a collective 16.3.2.3 Models Based on Early-Life term for a variety of extremely divergent experi- Stress mental protocols (Lehmann and Feldon 2000). Early life stress models are based on initial stud- For example, as a model for parental neglect, the ies performed in rodents (Weininger 1953; Levine maternal deprivation stressor induces long-lasting 1957, 1967) and in nonhuman primates (Harlow structural and functional consequences (e.g., and Zimmermann 1959). Adverse experiences Oomen et al. 2010, 2011). In contrast, the extent during this critical developmental period of early of maternal care is promoted and increased by life such as prenatal (fetal) and/or postnatal repeated maternal separation models. Obviously, (infant/child) stress exposure, environmental tox- repeated separation is less stressful for the pups ins or undernutrition may cause a vulnerability for and thus often results in opposite effects com- developing various types of diseases in later life pared to the deprivation models (Enthoven et al. with potentially transgenerational consequences 2008; Schmidt et al. 2011). In line with these find- (for review, see Ambeskovic et al. 2017). ings Schmidt and colleagues question the validity Since the initial studies more than six decades of maternal separation—at least in rodents—as a ago a significant number of epidemiological robust model of depression. Summarizing the studies have indicated that prenatal and postnatal data from the literature, the authors conclude that environmental factors are associated substan- forthcoming experiments should aim to investi- tially with the etiology of neuropsychiatric disor- gate the magnitude to which the interaction ders. Negative experiences during this critical between genetic predisposition and pleasant or period of brain development such as emotional unpleasant stimuli in adulthood determines the and physical neglect, abuse or parental loss sig- impact of early life stress experiences in later life nificantly increase the risk of developing an challenges (Schmidt et al. 2011). affective disorder in adulthood (for review, see, Recently, Rice and colleagues described a e.g., Heim and Nemeroff 1999; Heim et al. 2010; novel mouse model for early life stress which has 16 Experimental Animal Models for Depressive Disorders: Relevance to Drug Discovery 229 both acute and long-lasting effects on the HPA mals that has been exposed to stress and/or genetic system as well as on cognitive functions in adult- modifications (Barkus 2013). This is an erroneous hood (Rice et al. 2008). In this model of chronic practice because experts of this field repeatedly early life stress the dam-pup interplay is signifi- point out that the behavioral response to a forced cantly disturbed by limiting the nesting and bed- swim stressor does not reflect depressive behavior ding material of the cages which results in (e.g., de Kloet and Molendijk 2016). abnormal, fragmented dam–pup interactions. Rearing pups in this stress provoking environment has durable consequences such as impaired hippo- 16.4 Animal Models in Drug campus-dependent learning and memory func- Discovery: Needs and Pitfalls tions as well as diminished survival of adult-born neurons (Naninck et al. 2015). During the recent decades, we experienced a severe disappointment in the usefulness of ani- 16.3.2.4 Simple Screening Tests mal models for the development of novel antide- or “Acute Behavioral Despair pressant drugs. On several occasions, Models” pharmacological targets which were strongly The development of animal models for depression supported by data from rodent models failed to has been strongly influenced by the needs and show convincing results when tested in clinical goals of the pharmaceutical industry. Their princi- trials. A careful analysis of the literature revealed pal objective is the discovery of drugs that are that in some cases, clinical efficacy has been faster acting or more effective and/or safer than predicted on the basis of inappropriate animal the already existing ones. These aims impose models, or some clinical trials have not targeted pragmatic constraints on the experimental the appropriate dose or clinical population designs. Drug development requires simple and (Belzung 2014). To avoid such disappointments reliable behavioral tests that can screen for the experts of this field repeatedly point out that we activity of a large number of compounds rapidly. should preferably use more complex animal Exactly for this purpose tests have been devel- models (Peters et al. 2015) that involve species oped, which are typically called “behavioral that have better homological validity and we despair models.” These are actually simple mod- should try to model subtypes of depression. els in which animals are subjected to an acute Compounds under development should be tested stressful situation, for example they are immersed in various models and not only their behavioral into water (forced swim test) or suspended by effects should be investigated, but one should their tails (tail suspension test) (Porsolt et al. measure other biomarkers as well, for example 1977a, b; Lucki 1997; Cryan et al. 2005a, b). In neuroendocrine changes or functional and mor- these tests, the animals either struggle or they phological changes in relevant brain areas become immobile and then these behaviors are (Rupniak 2003). Another problem that should be interpreted as “active coping” or “behavioral solved in the future is that many research groups despair.” These tests have been repeatedly criti- make modifications on the original protocol of cized that immobility simply demonstrates a posi- the complex models which then leads to a con- tive behavioral adaption in order to save energy fusing variability in the experimental outcomes and swimming is a reflex when animals are between research groups using the same models immersed in water. These tests proved to be valu- (Yin et al. 2016). able tools when researchers developed the selec- In summary, we should emphasize the follow- tive serotonin reuptake inhibitors (SSRIs) and the ing points: (1) in vivo models will keep their serotonin-norepinephrine reuptake inhibitors important role in drug discovery, simply because (SNRIs) (Lucki 1997; Cryan et al. 2005a, b). The these models are still more realistic than the in problem is that these tests are increasingly used to silico and in vitro models; (2) the studies should demonstrate a “depressive-like” behavior of ani- be properly designed with sufficient sample sizes, 230 B. Czéh et al. analyzed by appropriate statistical tests and the A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve conclusions should be data-driven; (3) there is no RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH. 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Deepali Gupta and Radhakrishnan Mahesh

17.1 Introduction both in patients and animal models of depression (Behr et al. 2012; Gupta et al. 2016; Hanson et al. Depression is among the most severe mental dis- 2011; Lanfumey et al. 2008; Leonard 2014; Tobe orders with a lifetime prevalence of 14.4% 2013). Thus, therapeutic approaches targeting (Kessler et al. 2012). According to a survey by overlapping set of multifaceted systems are criti- World Health Organization, depression was cally needed for the effective pharmacological ranked as the third leading cause of the global intervention. In this chapter, we will provide a burden of disease in 2004 and will move into first brief history on the evolution of clinically avail- place by 2030 (World Health Organization 2012). able antidepressant drugs followed by an update Despite a dramatic rise in treatment options on the relative efficacy and plausible mechanism (both pharmacological and nonpharmacologi- of antidepressant activity of most current cal), the pharmacotherapy of depression remains therapeutic approaches, targeting different sys- inadequate (Hindmarch 2002; Ruhé et al. 2006; tems implicated in the pathophysiology of Xue et al. 2013). This could be attributed, at least depression. in part, to the unclear pathophysiology of depression. During last several years, efforts have been made to understand the different aspects of mul- 17.1.1 Antidepressant Drugs: tifaceted pathophysiology of depression. Previous The Evolution studies have examined potential biological markers or predictors of depression and related disor- The observations made in the 1950s of the effects ders. Although work in this area has been of reserpine and isoniazid, in altering monoamine inconclusive, impairment of brain neurotrans- neurotransmitter (serotonin, noradrenaline, and mission, hypothalamic-pituitary-adrenal axis dopamine) levels and affecting depressive symp- hyperactivity, alteration in neurogenesis signal- toms, have led to the adoption of the monoamine ing pathways, enhanced brain oxidative stress hypothesis of depression (Delgado 2000; and inflammatory activity have been reported to Hirschfeld 2000; Schildkraut 1965). First put for- be strongly associated with depressive behavior, ward over 50 years ago, it states that depression is caused by the underactivity of monoamines in brain and that targeting this D. Gupta (*) • R. Mahesh neuronal deficit would tend to restore normal Department of Pharmacy, Birla Institute function in depressed patients. Accordingly, at of Technology and Science, (BITS)-Pilani, present, therapy for depression relies mainly Pilani, Rajasthan, India e-mail: [email protected] on several approaches intended to improve the

© Springer Nature Singapore Pte Ltd. 2018 235 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_17 236 D. Gupta and R. Mahesh monoaminergic transmission: reuptake inhibi- memory impairments, and drowsiness, due to tors, which increase synaptic concentration of antagonism of adrenergic, muscarinic, and hista- monoamines by inhibiting their synaptic reuptake; minergic receptors, respectively (Gray et al. 2015; monoamine oxidase inhibitors (MAOIs), which act Hillhouse and Porter 2015). Later on, selective to reduce metabolic degradation of monoamines; serotonin reuptake inhibitors (SSRIs) came into and monoamine receptor modulators, which facili- existence, which were reported to have better safety tate monoamine neurotransmission (Fig. 17.1). profile than TCAs, both in acute and long-term However, these therapies have reported limited treatment of depression (Hillhouse and Porter efficacy, limited tolerability and significant mecha- 2015). Subsequently, SSRIs have become first line nism-based side effects. In example, despite the antidepressants in all depressive conditions. vast therapeutic potential of MAOIs, the cheese However, this class of medications is not without reaction (characterized by increased heart rate, untoward effects, most notably that approximately hypertension, and sweating), due to concomitant one half of patients do not respond (Kaplan 2002) use of food containing high amounts of tyramine, and, during longer-term therapy, a significant has reduced the popular usage of MAOIs (Alkhouli minority, if not a majority, of individuals report et al. 2014). Problems associated particular to the sexual dysfunction as a side effect (Cassano and tricyclic antidepressants (TCAs) are dizziness, Fava 2004). Delayed onset of therapeutic effects is

5-HT, NE GPCR TrkR

Reduced cell Bcl-2 AC death

PI K BDNF release Glutamate ATP cAMP 3 Antidepressant- 5’AMP EPAC like effect PDE AKKT Neurogenesis and synaptic plasticity NMDAR MEK Ca++ AMPAR PKA GSK-3β

ERK CAMK CREB

BDNF Translation mRNA CREB P Transcription

Fig. 17.1 Signaling pathways regulating neurogenesis CREB activation triggers expression of brain-derived neu- and synaptic plasticity. Stimulation of postsynaptic G pro- rotrophic factor (BDNF) and other neurotrophic factors. tein-coupled receptors (GPCR) by neurotransmitters like BDNF downstream signaling via tropomyosin-related serotonin (5-HT) and norepinephrine (NE) leads to activa- kinase receptor (TrkR) stimulate phosphatidyl inositol-3 tion of a variety of second messenger systems, including kinase (PI3K)-AKT (A serine threonine kinase) pathway the cAMP (cyclic adenosine monophosphate)–protein lead to neuroprotection, neuroplasticity and neurogenesis. kinase A (PKA)–cAMP response element-binding (CREB) Activated glycogen synthase kinase-3β (GSK-3β) inhibits pathway and cAMP-EPAC (exchange proteins activated by CREB-BDNF signaling by CREB phosphorylation and cAMP)–MEK (mitogen-activated protein/ERK kinase)– gets inhibited by AKT mediated phosphorylation. ERK (extracellular signal-regulated kinase) pathway Phosphodiesterase enzymes (PDE) metabolize cAMP to (Duman and Voleti 2012; Quiroz and Manji 2002). 5′AMP (5′ adenosine monophosphate) and hence reduce Glutamate produces fast excitation of neurons via stimula- the level of cAMP (Duman et al. 2000; Krishnan and tion of ionotropic receptors, including AMPA and NMDA Nestler 2008; Quiroz and Manji 2002). Abbreviations: receptors, resulting in rapid depolarization and induction of Ca++ calcium ions, ATP adenosine triphosphate, CREB-P Ca++-calmodulin-dependent protein kinase (CAMK). phosphorylated CREB, AC adenyl cyclase 17 Antidepressant Therapy for Depression: An Update 237 another major concern with few SSRIs (Edwards been developed with improved efficacy and and Anderson 1999). reduced side effects. Since major side effects of Several new atypical antidepressants have the current antidepressants are largely based on been developed since then, which produce anti- their activity on catecholamines, focus has been depressant activity by inhibiting reuptake of given on targeting serotonergic system. other monoamines as well, such as serotonin- norepinephrine reuptake inhibitors (SNRIs) and 17.2.1.1 5-HT 3 Receptor Antagonists the norepinephrine-dopamine reuptake inhibitor In recent years, 5-HT3 receptors (5-HT3Rs) have (NDRI), bupropion. Although, some clinical tri- been recognized as a potential target for antide- als suggests that SNRIs may be more effective pressants. The only ligand-gated ion channel for the treatment of depression as compared to receptors of 5-HT receptor family, 5-HT3Rs, SSRIs, these differences are relatively modest have been determined to a play key role in several (Papakostas et al. 2007; Stahl et al. 2005). brain signaling processes affecting learning, Bupropion, on the other hand, is reported to be memory, cognition, depression, and anxiety. The equally effective drug with lowest risk of sexual functional role of 5-HT3Rs in depression was ini- dysfunction, compared to TCAs, MAOIs, SSRIs, tially identified in late 1990s, when drugs in clin- and SNRIs (Papakostas et al. 2007; Thase et al. ical use (such as ondansetron and zacopride), 2005). However, these classes of drugs tend to known to be potent 5-HT3R antagonists, reversed cause a broader array of side effects than the depressive-like state in rat learned helplessness SSRIs, including signs of noradrenergic activity test (Martin et al. 1992; Thiebot and Martin such as dry mouth, constipation, increased pulse, 1991). Since then, several investigators, includ- and blood pressure (Thase and Sloan 2006). ing us, have demonstrated the antidepressant-like Till date there is no ideal intervention for the effects of different 5-HT3R antagonists in acute management of depression that is effective and and chronic preclinical models of depression free from untoward effects. This could be due to (Table 17.1). In support of the preclinical find- the fact that the current therapeutic approaches ings, few clinical trials have evidenced the effec- were largely developed in the absence of defined tiveness of 5-HT3R antagonists. Separate studies molecular targets or even a solid understanding of have shown that 5-HT3R antagonists ameliorated disease pathogenesis. Within the past few years, depressive behavior predisposed in hepatitis- the understanding of biochemical pathways asso- infected patients (Piche et al. 2005), alcohol- ciated with the development of depression has dependent patients (Johnson et al. 2003), bulimic expanded. There is an unprecedented range of patients (Faris et al. 2000), and in patients with molecular drug targets within these pathways. fibromyalgia (Haus et al. 2000). Although no They have been identified on the basis of predicted information is available on the antidepressant roles in modulating one or more key aspects of the effect of 5-HT3R antagonists in patients with pathogenesis of depression. Several mechanistic depression alone, the reduction in depression categories for new therapeutic approaches can be scores associated with 5-HT3R antagonist treat- considered, which are discussed in later sections. ment in patients with chronic illness clearly suggests the efficacy of these candidates and warrants further evaluation. Moreover, based on the out- 17.2 New Targets and Treatments come of the preclinical and clinical studies, it for Depression may be suggested that 5-HT3R antagonists possess faster onset of action, better efficacy, rela- 17.2.1 Neurotransmitter Modulators tively good safety profile, and good therapeutic activity in drug-resistant cases (for review see Monoamine hypothesis is still being a dominated Rajkumar and Mahesh 2010). theory of depression. Several new antidepres- The plausible mechanism of their antide- sants acting on the monoaminergic system have pressant action is still not clearly elucidated; 238 D. Gupta and R. Mahesh

Table 17.1 The effect of 5-HT3R antagonists in acute and chronic models of depression 5-HT3R antagonists Behavioral model Observation Activity References Effect of 5-HT3R antagonists in acute models of depression Ondansetron (GR 38032F) Mouse forced swim Reduced duration of AD Ramamoorthy et al. test immobility (2008) Mouse tail Reduced duration of AD suspension test immobility Rat forced swim test Potentiated reduction AD Bétry et al. (2015) of immobility time by paroxetine Tropisetron (ICS205-930) Rat forced swim test Reduced immobility AD Bravo and Maswood time (2006) Bemesetron (MDL72222) Mouse tail Produced anti- AD Kos et al. (2006) suspension test immobility effects QCF-3 Mouse forced swim Reduced duration of AD Devadoss et al. ((4-benzylpiperazin-1-yl) test immobility (2010) (quinoxalin-2-yl) Mouse tail Reduced duration of AD methanone) suspension test immobility 4i (N-(3-Chloro- Mouse forced swim Reduced duration of AD Gupta et al. (2014a) 2-methylphenyl) test immobility quinoxalin-2-carboxamide) Mouse tail Reduced duration of AD suspension test immobility Vortioxetine Mouse forced swim Increased mobility, AD Guilloux et al. (Lu AA21004) test swimming and (2013) climbing durations Vortioxetine Rat forced swim test Reduced immobility Partial AD Mork et al. (2012) (Lu AA21004) time Produced no effect on swimming and climbing time A6CDQ, 4 (2-Amino- Mouse tail Reduced immobility AD Dukat et al. (2013) 6-chloro-3,4- suspension test time dihydroquinazoline hydrochloride) 6z (N-(Benzo[d]thiazol- Mouse tail Reduced immobility AD Gupta et al. (2014b) 2-yl)-3-methoxy suspension test duration quinoxalin-2-carboxamide) 7a (2-(4-phenylpiperazin- Mouse forced swim Reduced duration of AD Gautam et al. (2013) 1-yl)-1, 8-naphthyridine- test immobility 3-carboxylic acid) Mouse tail Reduced duration of AD suspension test immobility Ondansetron (GR 38032F) Mouse forced swim Reduced duration of AD Kordjazy et al. test immobility (2016) Mouse tail Reduced duration of AD suspension test immobility Tropisetron (ICS205-930) Mouse forced swim Reduced duration of AD Kordjazy et al. test immobility (2016) Mouse tail Reduced duration of AD suspension test immobility Effect of 5-HT3R antagonists in chronic models of depression 6o (N-n-butyl- Mouse chronic Reversed stress AD Bhatt et al. (2014) 3-methoxy quinoxaline- unpredictable mild induced increase in 2-carboxamide) stress duration of immobility and decrease in sucrose consumption 17 Antidepressant Therapy for Depression: An Update 239

Table 17.1 (continued) QCM-4 (3-methoxy-N- Mouse chronic Reversed stress AD Kurhe et al. (2014) p-tolylquinoxalin- unpredictable mild induced increase in 2-carboxamide) stress duration of immobility and decrease in sucrose consumption Vortioxetine Mouse forced swim Increased mobility, AD Guilloux et al. (Lu AA21004) test swimming and (2013) climbing durations 6z (N-(Benzo[d]thiazol-2-yl)- Mouse chronic Reversed stress AD Gupta et al. (2014b) 3-methoxyquinoxalin- unpredictable stress induced increase in 2-carboxamide) duration of immobility and decrease in sucrose consumption Ondansetron (GR 38032F) Mouse chronic Reversed despair AD Gupta et al. (2014c) unpredictable stress effects in FST and reward-related deficits in sucrose preference test 4i (N-(3-Chloro- Olfactory Reversed reward- AD Gupta et al. (2014a) 2-methylphenyl) bulbectomized rat related deficits in quinoxalin-2-carboxamide) sucrose preference test 4i (N-(3-Chloro- Corticosterone- Reversed despair AD Gupta et al. (2015) 2-methylphenyl) induced depression effects in FST and quinoxalin-2-carboxamide) in mice reward-related deficits in sucrose preference test

however, studies have reported that they do so by 17.2.1.2 5-HT 4 Receptor Agonists facilitation of 5-HT neurotransmission. Blockade Recent research supports a role for 5-HT4 recep- of 5-HT3Rs has been shown to facilitate 5-HT tors (5-HT4Rs) in the pathogenesis of depression neurotransmission, indirectly, by inhibiting as well as in the mechanism of action of antide- GABA-mediated negative feedback mechanism pressant drugs. Indeed, it has been found that of 5-HT release (Artigas 2013). 5-HT3Rs are 5-HT4R agonists induce similar molecular and highly distributed in cortical GABAergic inter- behavioral changes, as common antidepressants, neurons, where their activation triggers the in rodents. A 2-week treatment of RS67333, a release of GABA (Puig et al. 2004), which in turn 5-HT4R agonist, completely abolished depression- mediate tonic inhibition of 5-HT in dorsal raphe like behavior in the olfactory bulbectomy or nucleus (Puig and Gulledge 2011; Zhang et al. chronic mild stress rat models (Lucas et al. 2007). 2011). The other plausible modes of action have In line, short-term treatment of RS67333 reversed also been investigated. These include modulation novelty-suppressed feeding (NSF), anhedonic- of other brain neurotransmitter (NE and DA) sys- like state (sucrose consumption), and despair tems, normalization of HPA-axis hyperactivity, behavior in defeated mice (Gómez-Lázaro et al. enhanced brain oxidative stress, and altered syn- 2012; Pascual-Brazo et al. 2012). It has been sug- aptic plasticity (for review see, Gupta et al. 2016). gested that these effects could be associated with All these findings suggest the prominent partici- increased 5-HT levels in hippocampus. If fact, pation of 5-HT3Rs in an overlapping set of molec- after only 3 days of administration, RS67333 ular and cellular signaling pathways involved in the increased basal hippocampal 5-HT levels (Licht pathogenesis of depression and that 5-HT3Rs et al. 2010), suggesting a more rapid response antagonists may offer an effective approach for the in comparison with classical antidepressants. management of multicausal depression. Although evidence lacks clinical significance, changes 240 D. Gupta and R. Mahesh

in 5-HT4Rs binding sites in discrete brain regions of 17.2.1.4 5-HT 7 Receptor Antagonists the depressed suicide victims (Rosel et al. 2004) The 5-HT7 receptor (5-HT7R) is the most recently strongly suggest further research in 5-HT4R ago- identified member of the 5-HT receptor family nists as innovative and rapid onset therapeutic (Hedlund and Sutcliffe 2004). Soon after the dis- approach to treat depression. covery, the role of 5-HT7Rs have been identified in diverse processes of the central nervous system,

17.2.1.3 5-HT 6 Receptor Modulators modulated by 5-HT (Thomas et al. 2003; Faure Preclinical studies have brought new insights into et al. 2006). Moreover, the antidepressant activity the possible role of recently discovered serotonin of an atypical antipsychotic, known to be a potent

5-HT6 receptors (5-HT6Rs) in depression. EMDT, 5-HT7R antagonist, proposed the idea that block- WAY-181187, and WAY-208466, the 5-HT6R ade of 5-HT7Rs might represent a key determinant agonists, reduced immobility in the mouse TST for antidepressant therapy. More direct evidence, and rat-modified FST, a behavior produced by such as antidepressant-like behavioral activity several antidepressant drugs (Carr et al. 2011; exhibited by 5-HT7R knockout mice (Hedlund Svenningsson et al. 2007). In contrast, antagonists et al. 2005; Guscott et al. 2005), downregulation of have also been reported to produce similar effects 5-HT7Rs in hypothalamus after chronic treatment in animal models for depression (Wesolowska with antidepressants (Sleight et al. 1995), and anti- and Nikiforuk 2007). SB-399885, a 5-HT6R depressant-like effects produced by selective antagonist, reduced immobility time and aug- 5-HT7R antagonists (such as SB-269970) mented the anti-immobility effects of antidepres- (Hedlund et al. 2005) strengthen this hypothesis. sants in rat during FST (Wesolowska 2007; Furthermore, the potent antidepressant profile Wesolowska and Nikiforuk 2008). of amisulpride (Montgomery 2002), aripiprazole It is well established that the reduction in immo- (Berman et al. 2009), or lurasidone (Loebel et al. bility time depends on the enhancement of central 2014), most likely mediated by the blockade of 5-HT and catecholamine neurotransmission 5-HT7Rs, provides clinical relevance of this tar- (Borsini 1995; Cryan et al. 2005). Although the get. However, a recent clinical trial showed that effect of EMDT on the levels of serotonin and cat- JNJ-18038683, a selective antagonist of echolamines is not reported yet, a recent study has 5-HT7Rs, had no statistically significant improve- shown that the partial 5-HT6R agonist, ment over a placebo on the Montgomery-Åsberg EMD386088, produced anti-immobility effects in Depression Rating Scale (MADRS). Besides, in rat FST by activation of dopaminergic system, this study, the ineffective response of escitalo- while noradrenergic and serotonergic systems pram administration (as that of JNJ-18038683) remained unaltered (Jastrzębska-Więsek et al. indicates the lack of assay sensitivity, and hence 2016). Furthermore, a microdialysis study has only the interpretation of these results is inconclusive. shown that selective 5-HT6R agonist WAY-181187 decreased the basal release of 5-HT, DA, and NE in 17.2.1.5 Other Neurotransmitter frontal cortex, striatum, and amygdala of freely Modulators moving rats (Schechter et al. 2008). In contrast, Emerging evidence has proved that depression is studies have shown that 5-HT6R antagonists (such not only associated with the monoaminergic but as SB-271046 and SB-399885) produced a signifi- also with other non-monoaminergic neurotrans- cant increase in extracellular levels of DA and NE mitter (such as GABA and glutamate) alterations without altering 5-HT neurotransmission (Lacroix (Krystal et al. 2002). Accordingly, researchers et al. 2004; Li et al. 2007). Altogether, it suggests have investigated the antidepressant potential of the role of 5-HT6Rs in the pathogenesis of depres- several new candidates with GABA and/or gluta- sion. However, extensive research investigating the mate modulatory effects. exact receptor signaling pathways is required to In view of the findings that depression and anx- develop effective ligands of this receptor subtype iety disorders are often overlapping and may share for antidepressant strategy. a common pathophysiology, the neurophysiologi- 17 Antidepressant Therapy for Depression: An Update 241 cal deficits of GABA is speculated to be related to glutamatergic signaling, a number of existing depression. Subsequently, the importance of both drugs and novel compounds have been investi-

GABA receptors (GABAA and GABAB) has been gated for their antidepressant potential. Some of established in pathogenesis of depression. Initially these include ketamine, memantine, amantadine, identified antidepressant-like effects of selective tianeptine, pioglitazone, riluzole, lamotrigine,

GABAB receptor agonists in preclinical studies AZD6765, magnesium, zinc, guanosine, adenos- was later confirmed to be weak and inconsistent, ine aniracetam, traxoprodil (CP-101,606), relative to the effects observed by the GABAB MK-0657, GLYX-13, NRX-1047, Ro25-6981, receptor antagonists. Notably, it was found that the LY392098, LY341495, d-cycloserine, d-serine, antidepressant effect of selective GABAB receptor dextromethorphan, scopolamine, pomaglumetad antagonists was blocked by 5-HT depletion using methionil, LY2140023, LY404039, MGS0039, tryptophan hydroxylase inhibitor (para-MPEP, and 1-aminocyclopropanecarboxylic acid. chlorophenylalanine) pretreatment (Slattery et al. It is interesting to quote here that glutamate recep- 2005) and that antidepressants caused an upregu- tor modulators have shown to induce rapid and lation of GABAB receptor number and function long-lasting antidepressant effects in several clini- (Sands et al. 2004). Based on these results, it may cal trials (Berman et al. 2000; Brennan et al. 2010; be speculated that decrease in GABAB receptor Diazgranados et al. 2010; Teng and Demetrio tone secondary to a decrease in GABAergic activ- 2006; Valentine et al. 2011; Zarate et al. 2006), ity may result in prolonged activation of 5-HT sys- suggesting that glutamate system-based therapy tem, which may account the antidepressant-like may represent an effective alternative to biogenic- activity of GABAB receptor antagonists. amine-based agents for depression.

The significance of GABAA receptor modula- Other studies have shown acetylcholine receptors in depression came into existence from a tor modulators also influence neural processes study which reported that eszopiclone, a positive that mediate antidepressant effects of several allosteric modulator of GABAA receptor, potenti- drugs. The clinical efficacy of mecamylamine ated the antidepressant response of fluoxetine in (Shytle et al. 2002) and varenicline (Philip et al. patients with depressive symptomology (Fava 2009) (the antagonist and partial agonist of nico- et al. 2006; Snedecor et al. 2010). These initial tinic acetylcholine receptor (nAChR), respec- results warrant efforts to profile GABAergic tively) constitutes a compelling argument for modulators as novel antidepressants. further evaluation of the nAChR as a target for Moreover, compelling evidence from clinical novel antidepressant drug development. studies indicate that glutamate transmission is abnormally regulated in discrete brain areas of depressed individuals. Indeed, several postpartum 17.3 HPA-Axis-Targeted Therapy studies reported elevated tissue glutamate levels in and CRF Antagonists patients with major depressive and bipolar disorders (Frye et al. 2007; Hashimoto et al. 2007; Lan It is now well established that persistent HPA-axis et al. 2009). In line, chronic treatment with antide- hyperactivity, characterized by elevated circulat- pressants from different classes reduced presynap- ing glucocorticoid levels and impaired negative tic and stress-induced increase in glutamate release feedback mechanism, plays a key role in the devel- (Michael-Titus et al. 2000; Musazzi et al. 2010; opment of depression (Holsboer 2001; Pariante Reznikov et al. 2007). Accumulated evidence and Lightman 2008). Physiologically activated from previous findings indicates that N-methyl-d- corticotropin-releasing hormone (CRF) from the aspartate (NMDA) receptor antagonists, group 1 hypothalamus triggers the release of adrenocorti- metabotropic glutamate receptor antagonists cotrophic hormone (ACTH) from the anterior (mGlu), and α-amino-3-hydroxy-5-methyl-4- pituitary. ACTH traverses down the circulation isoxazolepropionic acid (AMPA) agonists have and increases release of glucocorticoids (GCs, cor- antidepressant properties. Consistently, based on ticosterone (CORT) in rodents and cortisol in 242 D. Gupta and R. Mahesh humans) from the adrenal medulla. The chain of interleukin-6 (IL-6), and tumor necrosis factor-α events then subside by the negative feedback sig- (TNF-α) (Penninx et al. 2003). Accordingly, anti- nals from GC to the CRF and ACTH releasing inflammatory strategies may be a promising centers. However, persistent triggering stimuli, as approach for the treatment of depression in in depression, impair the negative feedback inhibi- patients who do not respond to the current medi- tion that leads to consistent release of GCs into the cation. In support of this notion, separate studies circulation (Pariante and Lightman 2008). have reported that central administration of Depressed patients often exhibit high cortisol lev- TNF-α produced depressive-like behavior els and abnormal HPA-axis control (Holsboer (Moretti et al. 2015), whereas blocking of TNF-α 2001), whereas several antidepressants have been signaling using etanercept or infliximab pro- reported to alleviate depression with concomitant duced antidepressant-like effects in mice (Karson reduction in HPA-axis overactivity (Nikisch et al. et al. 2013; Krügel et al. 2013). In line, several 2005). Interestingly, a number of non-peptide mol- clinical trials consistently demonstrated the ecules with CRF1 receptor antagonistic action, potential antidepressant effects of a number of which suppress HPA-axis hyperactivity (such as TNF-α inhibitors, although reductions in depres- antalarmin, CP-154, CRA1000, 526, DMP904, sive symptomology was observed only in sub- DMP696, R121919/NBI-30775, R278995/ jects with higher baseline levels of inflammation CRA0450, LWH234, and SSR125543A), have (Maas et al. 2010; Raison et al. 2013; Weinberger shown to possess potential antidepressant effects et al. 2015). Other clinical studies have reported in preclinical animal models (Valdez 2009). cyclooxygenase (such as celecoxib and acetyl- However, the efficacy of CRF1 receptor antago- salicylic acid) and cytokine inhibitors (etaner- nists in controlled clinical trials with depressed cept, infliximab, ustekinumab, and adalimumab) patients was mostly negative (Binneman et al. as effective strategies with rapid onset of action 2008; Zobel et al. 2000). Moreover, the test drug (either alone or in combination with existing candidates were associated with several untoward medications) in patients who fail to respond to effects and worsening of depressive symptomol- the current therapies (Köhler et al. 2014; ogy after drug discontinuation. As a result, no Mendlewicz et al. 2006; Na et al. 2014). While CRF1 receptor antagonist has yet been approved the reduced depressive symptoms without for clinical use in patients with depression (Griebel increased risks of adverse effects, with these and Holsboer 2012). It could be due to the fact that agents, support the use of anti-inflammatory not all depressed patients exhibit hyperactivity of treatment in depression, identification of specific CRF and/or impaired stress response regulation subgroups that could benefit from such treatment and that all clinical trials with CRF1 receptor might be warranted. antagonists have so far been conducted in unselected patient samples. Accordingly, specific CRF1 antagonistic treatments are likely to be 17.5 Neurogenesis-Targeted effective only in patients with depression associ- Therapy ated with CRF-related abnormalities. Development of specific biomarkers for identifying such patients Although most antidepressants exert their initial and CRF1 receptor antagonists with high efficacy effects by interacting with one or more neu- and safety profiles may eventually lead to a more rotransmitter system in the brain, their clinical successful treatment of depression. antidepressant effects occur only after chronic administration (days to weeks). Therefore, it is speculated that a cascade of downstream path- 17.4 Inflammatory System- ways are ultimately responsible for their thera- Targeted Therapy peutic effects. These signaling pathways undoubtedly involved neurogenesis and neuro- Another major pathological concern in depressed plastic events that regulate complex psychologi- patients is increase in inflammatory biomarkers cal and emotional processes. Consequently, such as C-reactive protein (CRP), cytokines like considerable attention has been given to the alter- 17 Antidepressant Therapy for Depression: An Update 243 ations in neuroplasticity and cellular resilience have shown that depressed patients were associ- that might underlie the pathophysiology of ated with elevated prooxidant markers in both depression (Quiroz and Manji 2002). Extensive central and peripheral systems (Bilici et al. 2001; series of studies have demonstrated that an Michel et al. 2007) and reduced antioxidant important pathway involved in neurogenesis and enzyme activity (Stefanescu and Ciobica 2012). plasticity, the cyclic adenosine monophosphate In contrast, several antidepressants have shown (cAMP)–cyclic response element binding protein additional antioxidant effects associated with (CREB) cascade, is upregulated by chronic anti- amelioration of depressive symptoms in animals depressant treatment (Blendy 2006; Duman et al. as well as in humans (Bilici et al. 2001; Herken 2000). Antidepressant drugs increase the CREB et al. 2007). Alternatively, several antioxidants phosphorylation and the expression of brain- have reported antidepressant-like effects by them- derived neurotrophic factor (BDNF), a major selves or to improve effectiveness of current anti- protein involved in plasticity and neurogenesis. depressants. For example, a number of dietary Consistent with these findings, a variety of anti- antioxidants (such as ascorbic acid, vitamin E, depressants have been reported to increase hip- lipoic acid, rutin, caffeic acid, polyunsaturated pocampal neurogenesis and prevent fatty acids (PUFA), and rosmarinic acid) exhib- stress-induced atrophy of hippocampal neurons, ited antidepressant-like effects in animal models coupled with increased performance in behav- of depression (de Sousa et al. 2015; Manosso ioral models of depression (Blendy 2006; Duman et al. 2013; Venna et al. 2009; reviewed by et al. 2000). Therefore, a more direct approach Bouayed (2010)). Combination therapy with targeting critical molecules to enhance neuro- omega-3 fatty acid and vitamin C augmented the trophic factor signaling may hold considerable antidepressant activity of SSRIs (Amr et al. 2013; promise for the development of improved and Gertsik et al. 2012). Moreover, the antidepressant effective treatments. Some of these molecules are activity of the antioxidants was observed at rela- currently under development, which include tively lower doses (0.2–1 mg/kg) as compared to phosphodiesterase (PDE) inhibitors, glycogen the antidepressants such as imipramine or fluox- synthase kinase (GSK)-3β inhibitors, and mole- etine, which were active at higher doses (≥10 mg/ cules targeting MAP kinase cascades (Blendy kg) in animals (reviewed by Bouayed 2010). On 2006; Duman et al. 2000; Krishnan and Nestler the other hand, the combined therapy of currently 2008; Quiroz and Manji 2002), given that increas- prescribed antidepressants with some of these ing cAMP levels (by inhibiting negative regula- antioxidants indicated to be more effective than tors, PDE and GSK-3β) exert neurotrophic effects only antidepressant treatment in depressed patients via CREB-mediated upregulation of BDNF, anti- (Amr et al. 2013; Gertsik et al. 2012). apoptotic protein bcl-2 (Fig. 17.1). Conclusion Depression is a complex disorder, which is 17.6 Oxidative Stress likely to have multiple pathogenic pathways. and Antioxidants Although, a large array of antidepressants has been prescribed based on correction of mono- Past studies have shown that oxidative stress plays amine deficit, a significant portion of population a role in depression and that antidepressant activ- do not show therapeutic recovery and experi- ity may be mediated via improving oxidative ence several untoward effects. Over time, sev- stress/antioxidant function. The link between eral biological systems have been found to be depression and oxidative stress may arise from the involved in development of depression. Indeed, fact that brain is particularly vulnerable to oxida- impairment of neurotransmitter system, HPA- tive damage, due to large consumption of oxygen axis hyperactivity, stimulated inflammatory resulting in the production of free radicals, high activity, reduced neurogenesis, and enhanced amount of lipids as a substrate for oxidation, and oxidative stress has been implicated in the diminished antioxidant enzymatic activity pathogenesis of depression. Accordingly, sev- (Scapagnini et al. 2012). Several clinical reports eral monoaminergic and non-monoaminergic 244 D. Gupta and R. Mahesh

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Laura Orsolini, Federica Vellante, Alessandro Valchera, Michele Fornaro, Alessandro Carano, Maurizio Pompili, Giampaolo Perna, Gianluca Serafini, Marco Di Nicola, Giovanni Martinotti, Massimo Di Giannantonio, and Domenico De Berardis

L. Orsolini Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hatfield, Hatfield, Herts, UK Polyedra Research Group, Teramo, Italy Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, F. Vellante The Netherlands Polyedra Research Group, Teramo, Italy Department of Psychiatry and Behavioral Sciences, Department of Neurosciences and Imaging, Leonard Miller School of Medicine, University “G. d’Annunzio”, Chieti, Italy University of Miami, Miami, FL, USA A. Valchera G. Serafini Polyedra Research Group, Teramo, Italy Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health Villa S. Giuseppe, Hospital Hermanas Hospitalarias, (DINOGMI), Section of Psychiatry, University Ascoli Piceno, Italy of Genoa, IRCCS San Martino, Genoa, Italy M. Fornaro M. Di Nicola Laboratory of Molecular Psychiatry Institute of Psychiatry and Psychology, Fondazione and Psychopharmacotherapeutics, Unit of Psychiatry, Policlinico Universitario “A. Gemelli”, Università Department of Neuroscience, University School Cattolica del Sacro Cuore, Rome, Italy of Medicine “Federico II”, Naples, Italy G. Martinotti • M. Di Giannantonio A. Carano Department of Neurosciences and Imaging, Department of Mental Health, Psychiatric Service University “G. d’Annunzio”, of Diagnosis and Treatment, Hospital “Madonna Del Chieti, Italy Soccorso”, NHS, San Benedetto del Tronto, Ascoli Piceno, Italy D. De Berardis (*) Department of Neurosciences and Imaging, M. Pompili University “G. d’Annunzio”, Chieti, Italy Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Institute of Psychiatry and Psychology, Fondazione Sant’Andrea Hospital, Sapienza University of Rome, Policlinico Universitario “A. Gemelli”, Università Rome, Italy Cattolica del Sacro Cuore, Rome, Italy G. Perna National Health Service, Department of Mental Department of Clinical Neurosciences, Villa San Health, Psychiatric Service of Diagnosis and Benedetto Menni, Hermanas Hospitalarias, FoRiPsi, Treatment, Hospital “G. Mazzini”, Teramo, Italy Albese con Cassano, Como, Italy e-mail: [email protected]

18.1 Introduction mine in the prefrontal cortex, rather than the intake of a single antidepressant agent. At low Major depressive disorder (MDD) is a widespread doses, atypical APs enhanced the antidepressant disease, with a lifetime prevalence of 15% and an effect of ADs, mainly due to the activity at annual incidence of approximately 7%, which has 5-HT1A, 5-HT2A, and adrenergic α2-receptors, by been predicted to be the leading cause of disabil- hence showing a good efficacy and effectiveness ity among the Western countries by 2013, being as adjunctive therapy in TRD. The major con- associated with one of the highest risk of mortal- cern regards their side effects profile (especially, ity (odds ratio [OR] = 1.81), compared to general metabolic profile), being clozapine and olanzap- population (Gruenberg et al. 2008). Despite anti- ine at higher risk for weight gain and glucose depressants (ADs) representing the first-line treat- balance and aripiprazole, asenapine, lurasi- ment for MDD, approximately 10–15% of done, and ziprasidone at lower risk (Hasnain patients do not adequately respond to a pharmaco- et al. 2012; Orsolini et al. 2016). logical therapy, while around 30–40% of patients Nowadays, the Food and Drug Administration show only a partial remission of symptomatology (FDA) released the approval of aripiprazole as (Bromet et al. 2011). Treatment-resistant depres- augmentative drug in MDD and for autism spec- sion (TRD) is a condition characterized by a poor trum disorder; asenapine, clozapine, iloperidone, or an unsatisfactory response to at least two ade- and olanzapine have been approved in combina- quate (optimal dosage and duration) trials of two tion with fluoxetine for MDD and bipolar depres- different classes of ADs (Souery et al. 1999; Ward sion, while paliperidone and quetiapine (both as and Irazoqui 2010). Furthermore, it has been esti- extended-release and immediate-release formu- mated that around 10–30% of patients with MDD lation) have been described as effective in mono- do not respond to typical AD medications, and therapy in bipolar depression; extended-release this group of patients needs trials of a variety of quetiapine has been approved as augmentation treatment strategies (Joffe et al. 1996). Overall, strategy in MDD, whereas risperidone and zipra- literature data seems to support the beneficial sidone have been approved in autism spectrum effects of atypical antipsychotics (APs), as disorders (Gigante et al. 2012; Maher and adjunctive treatment to the ongoing antidepres- Theodore 2012). sants, particularly to the selective serotonin reup- Hence, it should be mandatory to furtherly take inhibitors (SSRIs), in ameliorating improve novel efficacious and effective agents or, drug-resistant forms of unipolar depression at least, combos for acute and residual depressive (Papakostas 2005; Shelton and Papakostas 2008; exacerbations, particularly in TRD (Muneer Rogóż 2013). Furthermore, as recently, the latest 2016). Among these potential strategies, atypical edition of the Diagnostic and Statistical Manual APs have been properly investigated as adjunc- (DSM-5) codified a new nosological entity tive drugs able to improve depressive symptom- characterized by subthreshold hypomanic or atology (Lin et al. 2014) or as first-line strategy in manic symptoms occurring during depressive major depressive episode with mixed characteris- episodes of either MDD or bipolar I or bipolar II tics (Fornaro et al. 2016; Stahl et al. 2017). The disorder (APA 2013). Hence, atypical APs have present chapter aims at reviewing the literature been as well suggested to be prescribed in the regarding the treatment of MDD with APs. treatment of mixed characteristics in a MDD (Stahl et al. 2017). Preclinical studies demonstrated how the aug- 18.1.1 Aripiprazole mentation of atypical APs (e.g., olanzapine, risperidone, clozapine, and quetiapine) to ADs Currently, aripiprazole has been approved for the (e.g., citalopram, fluoxetine, and fluvoxamine) treatment of bipolar disorder (mania and mixed would increase the extracellular level of dopa- episodes and as maintenance treatment) and 18 Atypical Antipsychotics in Major Depressive Disorder 253 represents the first atypical AP to be approved in significant greater mean change in MADRS the USA as adjunctive treatment in adult patients total score from baseline to endpoint with with MDD by the FDA in 2007 (Weber et al. 2–20 mg aripiprazole as adjunctive drug to 2008). Despite its antidepressant mechanism of SSRI/SNRI compared with placebo combined action remains still unclear, however, it has been with SSRI/SNRI (p < 0.01) (Chen et al. 2011). supposed a role as a partial agonist at D2, D3, and A meta-analysis evaluated the efficacy of

5-HT1A receptors and its antagonism at 5-HT2A adjunctive aripiprazole in patients with mini- receptors (Khan 2008; Pae et al. 2011). mal response to prior ADs, by pooling data A multicenter, randomized, double-blind, from three randomized, double-blind, placebo- placebo-controlled trial evaluated the efficacy controlled studies assessing the efficacy of and safety of aripiprazole vs placebo as adjunc- adjunctive aripiprazole to ADs in patients tive treatment to standard AD in patients with with MDD who had a minimal response (i.e., MDD who showed an incomplete response to <25% reduction on the Montgomery-Åsberg ADs, by showing promising results (Berman Depression Rating Scale [MADRS]) to an et al. 2007). A further multicenter, randomized, 8-week prospective AD treatment (Nelson et al. double-blind, placebo-controlled study, carried 2012). The post hoc analysis reported that out on a sample of MDD patients who showed an aripiprazole adjunctive to standard ADs is a inadequate response to at least one and up to clinically meaningful treatment option for three historical and one additional prospective patients who own a prior minimal response to AD treatment, reported a significantly greater antidepressant therapy. Patients statistically mean change in MADRS total score with adjunc- improved in their symptom scores and response tive aripiprazole vs placebo (p = 0.001) and a rates after the combination with aripiprazole greater significantly improvement in remission (Nelson et al. 2012). rates (p = 0.016) and response rates (p < 0.001) A dosage ranging 2–5 mg daily (starting (Marcus et al. 2008). In addition, a double-blind, dose), titrated until 5–10 mg/day or 15 mg/day, placebo-controlled study evaluating MDD has been recommended as adjunct to ADs for patients with inadequate response to ADs the treatment of MDD, while the treatment of reported a clinically significant improvement in manic/mixed episodes in bipolar disorder has MADRS total score from baseline to endpoint been recommended with a starting dose of (week 14) in aripiprazole vs placebo group 15 mg/day then titrated until 30 mg/day (Weber (p < 0.001). Remission rates were greater for et al. 2008). adjunctive aripiprazole vs placebo (p < 0.001) (Berman et al. 2009). A review and meta-analysis carried out on a 18.1.2 Asenapine pool of randomized placebo-controlled trials evaluating the efficacy of aripiprazole in treat- Asenapine belongs to the same class of clozap- ing both depression and manic phase of bipolar ine, olanzapine and quetiapine, sharing with disorder, both as monotherapy and adjunctive them a rather complex pharmacological binding therapy, with a placebo, included 9 RCTs profile. It has been approved for the acute treat- (n = 3046 patients). Aripiprazole was associ- ment of schizophrenia and manic/mixed episodes ated with a significant increase of response rate in 2009. Asenapine exhibits high affinity for in depressive patients (7.7%) and manic patients 5-HT1A (partial agonism), 5-HT1B, 5-HT2A,

(15.7%), compared to placebo. While there was 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 recep- no significant improvement of remission rate in tors (antagonism); dopamine receptors D2, D3, depressive patients between aripiprazole and D4, and D1; α1 (antagonism)- and α2-adrenergic placebo group (Arbaizar et al. 2009). A system- receptors; and H1 histamine receptors (antago- atic review reported in three studies statistically nism) and a moderate affinity for 2H receptors. 254 L. Orsolini et al.

Asenapine has been approved in the treatment of explain its antidepressant efficacy at low doses manic/mixed episodes in bipolar disorder (Azorin (Orsolini et al. 2016). It has been supposed its et al. 2013; Marazziti et al. 2016). antidepressant activity due to 5-HT7A antago- In vivo microdialysis in freely moving rats nism, independent of the dopamine receptor and in vitro intracellular recording of pyramidal (Abbas et al. 2009). At low doses (50 mg daily), cells of the medial prefrontal cortex (mPFC) of amisulpride preferentially blocks presynaptic rats evaluated how asenapine as adjunctive drug autoreceptors, producing an increase in dopa- to escitalopram may enhance catecholamine out- mine release, hence, by acting as a dopaminer- put in the prefrontal cortex and, hence, amelio- gic compound able to resolve the dopaminergic rate treatment-resistant depression (Björkholm hypoactivity that characterizes MDD; while at et al. 2014). In vivo electrophysiological and higher doses (400–1200 mg daily), it exerts its behavioral assays in rats reported that asenapine activity on postsynaptic D3/D2 receptors located failed to alter immobility time in the forced swim in the limbic region and prefrontal areas, by test, in the ACTH-treated rats, a model of producing selective dopaminergic inhibition, antidepressant-resistance (Delcourte et al. 2017). eliciting antipsychotic effects (Orsolini et al. A post hoc analysis carried out on two 3-week 2016). randomized, placebo- and olanzapine-controlled Recent reports support the role of amisulpride clinical trials demonstrated that asenapine may in the treatment of mood disorders, such as dys- significantly reduce depressive symptoms in thymia with or without MDD, or as add-on drug bipolar I disorder patients experiencing acute in the treatment of bipolar disorder (Montgomery manic or mixed episodes with clinically relevant 2002; Carta et al. 2006; Jarema 2007). A preclini- depressive symptoms at baseline; despite further cal study evaluating the antidepressant-like prop- studies should be properly integrated to confirm erty of amisulpride per se and its comparison with the generalizability of the current findings fluoxetine and olanzapine using forced swimming (Szegedi et al. 2011). A post hoc analysis evaluat- test in albino mice reported contrasting findings ing the effects of asenapine in bipolar I patients as there was no statistically significant difference with current moderate-to-severe mixed major between amisulpride and olanzapine in terms of depressive episodes reported that asenapine was immobility and swimming phases in mice associated to a significantly greater reduction in (p > 0.05) even though it was reported a greater depressive symptoms (p = 0.0195) (Berk et al. superiority of fluoxetine vs amisulpride and olan- 2015). zapine (p < 0.01) (Pawar et al. 2009). A trial carried out by Cassano and Jori (2002) reported a similar efficacy of low-dose amisul- 18.1.3 Amisulpride pride (50 mg/day) and low-dose antidepressant treatment with paroxetine (20 mg/day) in subjects Amisulpride is an alkylsulphone derivative of affected with TRD. A case report of a woman at the substituted benzamide, with a high affinity her first depressive episode reported a significant at pre/postsynaptic dopamine D2 and presynap- clinical improvement of depressive symptomatol- tic D3 receptors. At low dosages (100–300 mg ogy after the combination of low-dose amisul- daily), it preferentially binds to presynaptic pride with citalopram after a failure in remission autoreceptors D2/D3, raising the levels of dopa- (Carvalho et al. 2007). A prospective, intention to mine in the prefrontal cortex and showing a treat, 4-week study evaluated the efficacy of “disinhibiting and psychostimulant” profile. administration of amisulpride in the short-term While, at higher doses (400–800 mg daily), it treatment of depressive and physical symptom- displays its antagonistic activity at postsynaptic atology in cancer patients during chemotherapy,

D2 in the limbic areas, by exerting antipsychotic by showing a significant clinically improvement effects. Its antagonism at 5-HT7 receptors may (p < 0.002) (Torta et al. 2007). A study showed 18 Atypical Antipsychotics in Major Depressive Disorder 255 promising findings in the treatment of elderly 18.1.5 Cariprazine patients with psychotic depression by using amisulpride (75–100 mg daily) in combination with an Cariprazine is a novel antipsychotic drug that antidepressant therapy (Politis et al. 2008). A exerts partial agonism of dopamine D2/D3 recep- clinical trial carried out on 20 MDD women who tors with preferential binding to D3 receptor, were given fluvoxamine (100 mg daily) and amis- antagonism of 5HT2B receptors, and partial ago- ulpride (50 mg daily) throughout a 6-week period nism of 5HT1A. Currently, cariprazine is in late- reported a clear improvement of depressive symp- stage clinical development (phase III clinical tomatology in 19 out of 20 patients recruited trials) in patients with schizophrenia and in (p < 0.0001) (Hardoy and Carta 2010). A system- patients with bipolar disorder, as well as an atic review reported in only one study a statisti- adjunctive treatment in patients with MDD and cally significant greater mean change in the TRD. Cariprazine has completed phase III trials MADRS with 50 mg amisulpride compared to for the acute treatment of schizophrenia and placebo (p < 0.01) (Chen et al. 2011). A recent bipolar mania and phase II trials for the bipolar successful case report reported the efficacy of depression and MDD, while it is undergoing 100 mg/day of amisulpride in a patient with atypi- phase III trials as an adjunct to antidepressants. cal depression, who failed previous trials with flu- Preliminary animal models showed that low-dose voxamine, bupropion, fluoxetine, and valproate cariprazine exhibits antidepressant-like effects (Agarwal et al. 2012). (De Berardis et al. 2016). However, preliminary More evidence coming from studies carried out findings coming from studies evaluating the effi- on subjects affected by dysthymia show that amis- cacy of cariprazine as add-on therapy in MDD ulpride significantly improves depressive symp- patients with current depressive episode without tomatology, compared to placebo antidepressant psychotic symptoms but who previously failed to treatment (Lecrubier et al. 1997; Smeraldi 1998; respond to adequate trials of ADs do not seem to Amore and Jori 2001). Amisulpride was generally completely confirm previous antidepressant-like given in doses of 50 mg/day (Komossa et al. 2010). efficacy observed at low doses in animal models (Dimitrakopoulos and Konstantakopoulos 2015; De Berardis et al. 2016). Therefore, further stud- 18.1.4 Brexpiprazole ies are needed in order to draw up definitive and clear conclusions regarding its clinical and effi- Brexpiprazole is a serotonin-dopamine activity cacy profile as add-on treatment in TRD. modulator, acting as partial agonist at D2, as antagonist with a higher potency compared to aripiprazole regarding 5-HT2A, as agonist at 18.1.6 Clozapine 5-HT1A, and antagonist at α1B (Maeda et al. 2014; Rexulti 2015; Stahl 2016; Parikh et al. 2017). Adverse drug reactions of clozapine are com- Overall, data so far published (Citrome 2015; monly a factor discouraging clinicians from pre- Thase et al. 2015a, b; McIntyre et al. 2016; Davis scribing it (Li et al. 2015). By the way literature et al. 2015; Menard et al. 2015; Krystal et al. data reports that clozapine could have a role in 2015; Parikh et al. 2017) support the efficacy of psychotic mood disorders (Banov et al. 1994). brexpiprazole over placebo in MDD with NNT of Available case reports and retrospective studies 12 or response and 17–31 for remission. No stud- suggest that clozapine may be particularly effec- ies comparing brexpiprazole with aripiprazole or tive in the treatment of TRD and treatment- other antipsychotic augmenting agents in MDD resistant depressive phases of bipolar disorder exist although one trial comparing brexpiprazole (BD) (McElroy et al. 1991; Frakenburg 1993; Li with extended-release quetiapine in MDD is cur- et al. 2015.) Randomized clinical trials showed rently in the recruiting phase. that clozapine is an effective add-on treatment to 256 L. Orsolini et al. antidepressants for TRD (Yan 2001). Clozapine randomized, double-blind, placebo-controlled could be used as monotherapy or in combination study of adults with major depressive episodes with other treatments for treatment-resistant associated with bipolar I disorder, with or with- bipolar depression. It is associated with improve- out rapid cycling, and without psychotic symp- ment of mania, depression, rapid cycling, and toms. Lurasidone (20–60 mg/day or 80–120 mg/ psychotic symptoms (Li et al. 2015). day) has been demonstrated to be superior to placebo in reduction of MADRS and CGI-S scores at week 6. The high dosages did not provide 18.1.7 Iloperidone additional efficacy on average, compared to the low-dose range (20–60 mg/day). It has been as Iloperidone exerts a high affinity at serotonin well demonstrated to be efficacious as an adjunc-

5-HT2A and dopamine D2 and D3 receptors and a tive therapy with lithium or valproate (Loebel moderate affinity at 4D , 5-HT6, 5-HT7, and nor- et al. 2014; Muneer 2016). epinephrine NEα1 receptors (McDonagh et al. 2010). It has been approved only in the treatment of schizophrenia. No clinical trials have been 18.1.9 Quetiapine documented for the off-label use of iloperidone in MDD or TRD (Maher and Theodore 2012). Quetiapine is a dibenzothiazepine derivative Therefore, further studies should be carried out in which shows a greater in vitro binding affinity for order to better improve the knowledge and poten- 5-HT2 receptors than for dopamine D2 receptors tialities of iloperidone in the treatment of MDD and a high α1A-adrenoceptor and H1 receptor and/or TRD (Tarazi and Stahl 2012). antagonist activity. It shows a lower D2 and 5-HT2 receptor antagonism and a minimal antagonist activity at D1, D4, 5-HT2C, and α2A-adrenoceptors. 18.1.8 Lurasidone At therapeutic doses, it has been shown to occupy

approximately 30% of D2 receptors, as it has a Lurasidone hydrochloride, a benzisothiazol more rapid “runoff” or rapid dissociation (the so- derivative, is a second-generation (atypical) anti- called kiss and run hypothesis). Its partial agonis- psychotic agent that is approved for the treat- tic activity at 5-HT1A may explain its ment of schizophrenia in the USA, Canada, antidepressant effect (Orsolini et al. 2016). Europe, Switzerland, and Australia and also for Currently, quetiapine is available as an bipolar depression in the USA and Canada. In immediate-release (IR) and extended-released addition to its principal antagonist activity at (ER) quetiapine. It has been approved for the dopamine D2 and serotonin 5-HT2A receptors, treatment of manic (quetiapine IR in 2003 at the lurasidone exerts a distinctive 5-HT7 antagonis- dosage ranging 400–800 mg/day; quetiapine XR tic activity and displays a partial agonism at in 2008 at the dosage 400–800 mg/day, once a

5-HT1A receptors, as well as modest antagonism day) and depressive (quetiapine IR in 2006 at at noradrenergic α2A- and α2C-receptors (Orsolini dosages ranging 300–600 mg/day as monother- et al. 2016). Lurasidone is devoid of antihista- apy, quetiapine ER in 2008 at dosages ranging minic and anticholinergic activities. Its pharma- 300 mg/day as monotherapy) phases of bipolar cokinetic profile requires administration with disorder. Furthermore, it has been approved in food, and it is flexibly dosed 20–120 mg/day for the maintenance therapy of bipolar disorder (que- bipolar depression (Greenberg and Citrome tiapine IR and ER at dosages of 400–800 mg/day, 2017). Lurasidone has been approved for the as add-on drug to lithium or divalproex, in 2008). treatment of depressive episodes associated with In addition, quetiapine ER (150–300 mg/day) bipolar disorder type I (20 mg daily to 120 mg was approved in 2009 in the treatment of MDD daily). The efficacy of lurasidone as monother- as adjunct to ADs, while the FDA did not approve apy was established in a 6-week, multicenter, quetiapine IR (FDA 2009). 18 Atypical Antipsychotics in Major Depressive Disorder 257

Results from pivotal registration trails evalu- ence versus placebo in MADRS total score both ating the acute and maintenance efficacy and in anxious depressive and non-anxious depres- tolerability of quetiapine XR (as monotherapy sive patients, after the administration of que- and as adjunctive treatment) in MDD demon- tiapine XR 150 mg/day (p < 0.01) and 300 mg/ strated that quetiapine at dosages ranging day (p < 0.05) at week 6 (Thase et al. 2012). 50–300 mg/day provided rapid and sustained Another pooled analysis evaluating the efficacy symptomatic improvement in the acute and of quetiapine XR monotherapy in MDD from maintenance treatment of MDD (McIntyre et al. two 6-week, double-blind, placebo-controlled 2009). A systematic review reported two 8-week studies reported a significant improvement at placebo-controlled studies with a statistically week 6 at 150 mg/day (p < 0.001) and 300 mg/ significant greater mean change in MADRS day (p < 0.001) vs placebo. The response rates total score from baseline to endpoint with 50 mg (at week 6) were 52.7% (p < 0.001) quetiapine quetiapine in monotherapy (p < 0.05) and XR 150 mg/day and 49.5% (p < 0.001) quetiapine 150 mg (p < 0.01) and 300 mg (p < 0.01) of XR 300 mg/day vs placebo (33%). MADRS quetiapine extended release compared with pla- remission was significant only with quetiapine cebo (Chen et al. 2011), while one study in TRD XR 300 mg/day (28.8%) vs placebo (19.4%), at patients found a statistically significant greater week 6 (p < 0.01) (Weisler et al. 2012). mean change in MADRS total score with 150 and 300 mg extended-release quetiapine combined with ADs compared with placebo com- 18.1.10 Olanzapine bined with ADs (p < 0.01). Another study found a statistically significant greater mean change in Olanzapine is a thienobenzodiazepine derivative MADRS total score with 300 mg extended- which displays a significantly high in vitro inhib- release quetiapine combined with ADs com- itory activity at D1, D2, D4, 5-HT2A, 5-HT6, pared with placebo combined with ADs 5-HT2C, H1, and α1-adrenergic receptors. In addi- (p < 0.01), even though they did not found dif- tion, it shows a moderate affinity at 5-HT3 and ference between 150 mg extended-release que- M4, M5, M1, M2, and M3 muscarinic receptors tiapine combined with ADs and placebo (Orsolini et al. 2016). Currently, olanzapine has combined with ADs (Chen et al. 2011). been approved for the treatment of manic/mixed Quetiapine XR has been demonstrated to be episode (10–15 mg/day) of bipolar disorder I in effective at the dosage of 150–300 mg/day as monotherapy or as add-on therapy to lithium or adjunctive to ADs in MDD, with MDD response valproate. A combination of the antidepressant rates significantly higher with adjunctive que- fluoxetine and olanzapine (OFC, olanzapine/ tiapine XR 300 mg/day (but not 150 mg/day) fluoxetine combination) is also available in USA than with ADs plus placebo. The NNT to under the trade name Symbyax, and it has been achieve an additional response over ADs vs pla- approved for the treatment of depressive episodes cebo was 11–18 and 8–9 in the quetiapine XR associated with bipolar I disorder and TRD (5 mg 150 and 300 mg/day dosage groups, respec- of oral olanzapine and 20 mg/day of fluoxetine tively (Sanford 2011). A recent meta-analysis once daily). reported the efficacy of quetiapine as monother- A systematic review described one study evalu- apy, even though the authors described a high ating olanzapine in combination with fluoxetine dropout rate due to side effects and recom- which showed a statistically significant greater mended considering the risk vs benefit for an mean change in MADRS total score from baseline individual patient with MDD (Maneeton et al. to endpoint compared with olanzapine alone or 2012). A pooled analysis performed from two fluoxetine alone (p < 0.01). Furthermore, the sys- studies evaluating the efficacy of once-daily tematic review reports as well one RCT comparing quetiapine XR monotherapy for patients with olanzapine in combination with fluoxetine vs ven- MDD reported a statistically significant differ- lafaxine and one study evaluating olanzapine in 258 L. Orsolini et al. combination with fluoxetine vs nortriptyline show- double-blind, placebo-controlled, randomized ing a greater mean change in MADRS total score trial carried out on 274 subjects affected with during the trials but no difference by the endpoints MDD who were suboptimally responsive to (Chen et al. 2011). A recently published meta-anal- ADs and were randomly assigned to receive ris- ysis of RCT evaluating whether OFC is superior to peridone (1–2 mg/day) or placebo demonstrated olanzapine or fluoxetine monotherapy in TRD a statistically significant mean reduction in patients reported a greater change from baseline in depressive symptoms, a substantially increased MADRS (p < 0.001), HAM-A (p < 0.001), CGI-S remission and response, and a general improve- (p < 0.001), and BPRS (p < 0.001); a significant ment of other patient- and clinician-rated mea- higher response rate with OFC (RR = 1.25; sures (Mahmoud et al. 2007). A randomized, p = 0.001); and remission rate (RR = 1.71; placebo-controlled trial of risperidone augmen- p < 0.001) (Luan et al. 2017). tation for patients with difficult-to-treat unipolar, nonpsychotic MDD randomized subjects to risperidone (0.5–3 mg/day) or placebo augmen- 18.1.11 Paliperidone tation, demonstrating a significant more improvement in quality of life than patients in Paliperidone represents the major active metabo- the placebo group (Keitner et al. 2009). A sys- lite of risperidone. The actions of paliperidone tematic review reported one study that described are pharmacological like its precursor risperi- a statistically significant greater mean change done, displaying a high binding affinity at 2D and in the 17-item Hamilton Depression Rating

5-HT2A as antagonist. However, it differs from Scale with risperidone 1–2 mg combined with risperidone on its ability to block D2 receptors, antidepressants compared with placebo com- as it owns a D2 receptor affinity approximately bined with antidepressants (p < 0.01) (Chen three times lower than risperidone. The esti- et al. 2011). mated occupancy of D2 receptors at a dose of 6 mg/day is around 72%. It also binds to α1- and α2-adrenoceptors but less than risperidone. In 18.1.13 Ziprasidone addition, it binds less at H1 receptor than risperidone and does not block 5-HT2C receptors Ziprasidone possesses the highest 5-HT2A/D2 (Orsolini et al. 2016). It has been approved for receptor binding affinity ratio among all FDA- the treatment of schizophrenia and schizoaffec- approved APs. It acts as a 5-HT1A receptor partial tive disorder. Recent findings demonstrated its agonist (Papakostas et al. 2015; Richelson and efficacy as well in preventing depressive or Souder 2000; Tatsumi et al. 1999), and it has been manic episodes in schizoaffective and bipolar shown (in vitro) to be able to inhibit the neuronal disorder patients (Dimitrakopoulos and uptake of serotonin and norepinephrine, with a Konstantakopoulos 2015). However, a signifi- potency similar to ADs such as imipramine and cant improvement has been observed in the pre- desipramine (Schmidt et al. 2001). In an open- vention of manic (but not depressive) episodes label ziprasidone augmentation study for TRD, a (Keller and Nesse 2006). positive antidepressant response after 6 weeks of treatment with ziprasidone as add-on therapy to SSRI has been reported (Papakostas et al. 2004). 18.1.12 Risperidone Ziprasidone as an adjunct to escitalopram demonstrated an antidepressant efficacy in adult patients

Risperidone has high affinity to 5-HT2A, D2, with MDD experiencing persistent symptoms α1A-, and D4 receptors. It also binds with a mod- after 8 weeks of open-label treatment with escita- erate affinity toα 2A-, H1 and 5-HT2C receptors. lopram alone (Papakostas et al. 2015). Ziprasidone Risperidone displays a lower affinity to 1D and augmentation is equally efficacious in treating

5-HT1A (Orsolini et al. 2016). A multicenter, depression in patients with or without anxious 18 Atypical Antipsychotics in Major Depressive Disorder 259 depression (Ionescu et al. 2016; Heo et al. 2015). Banov MD, Zarate CA Jr, Tohen M, Scialabba D, Wines Furthermore, it has been documented to improve JD Jr, Kolbrener M, Kim JW, Cole JO. Clozapine therapy in refractory affective disorders: polarity predicts sleep continuity and sleep architecture among response in long-term follow-up. J Clin Psychiatry. MDD patients, after administering ziprasidone as 1994;55:295–300. add-on or in monotherapy (Monti 2016). Berk M, Tiller JW, Zhao J, Yatham LN, Malhi GS, Weiller E. Effects of asenapine in bipolar I patients meeting proxy criteria for moderate-to-severe mixed Conclusion major depressive episodes: a post hoc analysis. J Clin Although each possible AP agent may be use- Psychiatry. 2015;76:728–34. ful in the treatment of MDD, particularly TRD Berman RM, Marcus RN, Swanink R, McQuade RD, and mixed states associated with depressive Carson WH, Corey-Lisle PK, Khan A. The efficacy and safety of aripiprazole as adjunctive therapy in episodes, available evidence recommends pre- major depressive disorder: a multicenter, random- scribing aripiprazole (at low doses) as adjunc- ized, double-blind, placebo-controlled study. J Clin tive treatment; amisulpride (at low doses), Psychiatry. 2007;68(6):843–53. especially if associated with dysthymia; carip- Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, McQuade RD, Carson WH, Adson D, Taylor razine (at low doses), particularly if associated L, Hazel J, Marcus RN. 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Salih Selek and Jair C. Soares

19.1 Introduction anxiety, panic disorder, personality disorder, number of hospitalizations, number of previous Although the antidepressant era brought new episodes, onset of age before 18, melancholic hopes for treating depression with fewer side features, obstructive sleep apnea, and suicidality effects and better tolerability, at least one fifth of (Best et al. 2013; Gorwood et al. 2010; Souery the patients do not respond very well and about et al. 2007). Patients that have residual symptoms half of the patients experience a chronic or recur- of depression including poor concentration, rent course of illness (Lepine et al. 2012; Sackeim sleeping difficulties, low energy level, and minor 2001), and numerous definitions have been used persistent anxiety symptoms, concomitant sub- to describe resistance/refractoriness in depres- stance abuse, comorbid medical illnesses such as sion, and six different criteria were employed to diabetes mellitus, malignancies, or cardiovascu- define the categorical presence of TRD ranging lar disease are shown to be at higher risk of recur- from non-response to one antidepressant to non- rence and TRD (Hirschfeld 1994; Iosifescu et al. response to two or more antidepressants from dif- 2004; Nierenberg et al. 2003; Pollack 2005). A ferent pharmacological classes so far (Berlim and study in the adolescent TRD group showed phys- Turecki 2007). A research on US commercial ical abuse had significantly lower rate of response insurers database showed 6.6% of the treated to combination antidepressant therapy depression episodes met the criteria for TRD, and (Shamseddeen et al. 2011). On the other hand, a median time for an episode to evolve to TRD pseudo-resistance that is defined as inadequate was estimated about 1 year, resulting in increase treatment, misdiagnosis, or having unrecognized of average health costs about 3.72 times higher comorbid psychiatric or general medical condi- for TRD than non-TRD episodes (Kubitz et al. tions that contribute to treatment resistance is 2013). Potential risk factors contributing to treat- also common; thus, a comprehensive assessment ment resistance that have been reported as comor- including assessment of medical and psychiatric bid are other psychiatric disorders such as social comorbidities as well as personality features and psychosocial evaluation including evaluation of social support system is essential to rule out pseudo-resistance (Keitner and Mansfield 2012; Kornstein and Schneider 2001). A recent study S. Selek (*) • J.C. Soares showed that many patients still are not prescribed Department of Psychiatry, McGovern Medical an adequate antidepressant trial before switching School, University of Texas Health Science Center to a second-line treatment that is an indicator of at Houston, Houston, TX, USA e-mail: [email protected] pseudo-resistance problem (Hassan et al. 2016).

In addition to common known criteria of TRD potential antidepressants, but among the sug- described as failure to respond two adequate tri- gested molecules, only TNF-alpha antagonist has als, several authors also suggested “prophylaxis” been tried for TRD: 60 patients were given IV resistance in bipolar disorder that is defined as infusion of infliximab or place for 12 weeks, and experiencing five or more mood episodes, and there was no difference between groups accord- two of these episodes should occur in the past ing the depression scale scores. On the other 3 years despite two adequate medication trials hand, when the patients are grouped according to (Bauer and Ströhle 1999). their severity of inflammation based upon CRP In this current paper, we will review the cur- levels, those patients that had higher inflamma- rent treatment approaches based upon neurobiol- tory markers had better response to TNF-alpha ogy and evidence-based view. Regarding antagonist (Raison et al. 2013). pharmacological treatments, there are three Abnormal dexamethasone suppression test options: optimization, augmentation, and substi- findings in depressed patients that have been tution (Bauer et al. 2016). Substitution to another shown for decades suggested a deficit in HPA class of antidepressant, such as switching from axis; thus, several hormones including oxytocin SSRIs to SNRIs, which has been a common prac- were tried for depression but not for TRD tice before has shown not to improve response or (Coppen et al. 1983). Major depression trials had remission in TRD, and there is little data about different outcomes making an interpretation dif- how to switch to another class of antidepressant. ficult at this time regarding oxytocin (Sasaki (Souery et al. 2011). Pharmacogenetic testing for et al. 2016). rapid or poor metabolizers may be considered for pharmacotherapy-resistant patients, but there is 19.1.1.1 Ketamine currently no reliable basis for such testing Ketamine is an old NMDA receptor antagonist (Keitner and Mansfield 2012). anesthetic agent that has also been used in chronic pain as a low-dose infusion for at least two decades (Maher et al. 2017). Since NMDA recep- 19.1.1 Novel Treatments Based Upon tor antagonists have shown to be effective for New Neurobiological Findings depression in animal models, glutamate pathway gained interest of researchers in terms of enhanc- As an introduction to neurobiology, the classical ing dopamine neurotransmission. Although it has hypothesis of antidepressant efficacies has been been used as an anesthetic agent in ECT and in addressed through monoamine hypothesis for psychotherapy, using it in treatment-resistant years. In summary, deficiencies in monoaminer- depression is relatively new (Bryson and Kellner gic neurotransmitters have been strongly corre- 2014; Krupitsky et al. 2007). In a placebo- lated with depression, and antidepressants have controlled, double-blind, crossover study, rapid been believed to be exerting their effect through improvement of depressive symptoms after infu- monoaminergic pathways (Delgado 2000). sion and up to 3-day remittance were noted Although the link between inflammation and (Machado-Vieira et al. 2009). Several studies affective disorders has been suggested at the end used ketamine in unipolar depression either with of the nineteenth century, the phenomenon has single infusion or with repeated infusions and been revisited extensively based upon observa- most of them yielded more than half response tions that comorbidities of inflammatory disor- rates (DeWilde et al. 2015). A recent study indi- ders in depression. Moreover, shown alterations cated similar outcomes in twice weekly infusion in inflammatory cytokines in depression such as and thrice weekly infusion with 0.5 mg/kg dose TNF-alpha, IL-1B, and IL-6 brought the hope of and in both arms antidepressant activity extend- another target for treating depression (Liu et al. ing to 15 days (Singh et al. 2016). Growing off- 2014). Therefore, potential molecules targeting label use of ketamine also brought some concerns inflammatory pathway have been considered as that lack of long-term studies and deal with risk 19 Neurobiology and Evidence-Based Review on Novel Therapeutic Strategy for Treatment-Resistant 265 of dependency (Schatzberg 2014). A recent The guidelines, those without mention of treat- Cochrane database review found limited evi- ment resistance, were formularized according to dence for ketamine’s efficacy over placebo at their stepwise approach, and 3rd-line treatments time points up to 1 week in terms of the primary were accepted as interventions for treatment outcome and response rate, and the effects were resistance in bipolar depression (Selek et al. less certain at 2 week posttreatment (Caddy et al. 2017): American Psychiatric Association (APA), 2015). In order to balance the pros and cons cre- World Federation of Societies of Biological ation of a joint statement, formation of a registry Psychiatry (WFSBP) guidelines, and British of ketamine receiving patients and support of Association for Psychopharmacology (BAP) continued research is recommended by a group guidelines recommend ECT with substantial of ketamine researchers (Sanacora et al. 2017). In clinical confidence for treatment-resistant cases addition, there are some uncertainties about how (Goodwin et al. 2016; Grunze et al. 2010; any acute benefit from ketamine, which is often Hirschfeld et al. 2002). Although a revision of the clinically evident, can best be sustained (Goodwin APA guideline cited positive outcomes of the et al. 2016). There have been efforts of combina- preliminary study with Pramipexole, in one of tion of ketamine infusion (0.5 mg/kg) with ECT, latest trials, neither the response rates nor the but outcomes did not show substantial benefit remission rates were significantly different than (Anderson et al. 2017). placebo (Cusin et al. 2013; Hirschfeld 2005). Ketamine may have positive outcomes on sev- Canadian Network for Mood and Anxiety eral symptom clusters such as memory improve- Disorders (CANMAT) guidelines offer the fol- ment, anhedonia, or suicidality (Lally et al. 2015; lowing combinations if the third step is taken into Price et al. 2009; Shiroma et al. 2014). Despite account as treatment resistance: lithium with car- the concerns of ketamine abuse, it is addressed as bamazepine, pramipexole, MAOI, TCA, venla- “currently not appear to pose a sufficient public- faxine or SSRI (except paroxetine) and health risk of global scale to warrant scheduling” lamotrigine; divalproex with venlafaxine, TCA, in the 36th meeting of World Health Organization or SSRI (except paroxetine); and lamotrigine and Expert Committee on Drug Dependence (World quetiapine with lamotrigine (Yatham et al. 2013). Health and Dependence 2015). A new study con- Pacchiarotti et al. (2009) has described a ducted in mice pointed out the antidepressant stratified model of treatment resistance in bipo- effects of ketamine may be by one of its metabo- lar disorder: According to his definition, treat- lites, (2R,6R)-hydroxynorketamine (HNK) that ment-resistant bipolar depression is defined as has low affinity to NMDA receptors. In addition, failure to reach remission with adequate trials of this metabolite exerted its antidepressant effect lithium, combination of lamotrigine with an without dissociation, ataxia, and abuse liability ongoing mood stabilizer, or quetiapine mono- of ketamine in animal tests (Gould et al. 2017). therapy (over 600 mg per day) (Pacchiarotti et al. 2009). The author recommends olanzapine and fluoxetine combination or quetiapine or 19.1.2 Evidence-Based Treatments lamotrigine combination for the first step of treatment-resistant bipolar depression, and fail- Initially, we will review bipolar depression. ure to respond to this step is called as “refrac- Mainly depressive episodes predominate in the tory” bipolar I depression. The following course of bipolar disorder causing more func- suggestions are recommended for refractory tional impairment than other states (Birmaher depression: adjusting the olanzapine-fluoxetine et al. 2012). Although there are several treatment dose or starting of lithium and SSRI or bupropion guidelines available for bipolar disorder, little with therapeutic doses or quetiapine antidepres- attention is given to the management of treatment sant combination including SSRI and bupropion resistance. Recently, the authors reviewed several or novel agent trials. According to this approach, guidelines and summarized their suggestions: ECT is reserved for last treatment if the patients 266 S. Selek and J.C. Soares fail to respond what is called “involutional” Voineskos et al. 2016). Although Dr. Cerletti’s, depression. Pacchiarotti et al. (2009) also differ- who is the inventor of ECT, dream was also find- entiate treatments for bipolar I and II. Although a ing the substance, as defined by him acroagonine similar stepwise approach to bipolar II depres- that was supposed to be ECT’s effective “mole- sion is recommended, MAO inhibitors were sug- cule,” the exact mechanism is still remains elu- gested as combination instead of combination sive (Passione 2004). SSRI or bupropion in the second step of the Transcranial Magnetic Stimulation (TMS): treatment. TMS basically applies electromagnetic waves to generate an electric current in the brain with- 19.1.2.1 Electroconvulsive Therapy out direct contact. Since this treatment is more (ECT) and Other reimbursed by insurance companies, its use has Interventions recently increased in the United States. An add- Electroconvulsive therapy is recommended by on low-frequency TMS of the right dorsolateral most of the guidelines for treatment-resistant prefrontal cortex in treatment-resistant bipolar bipolar depression (Goodwin et al. 2016; Yatham depression patients was found to be effective. et al. 2013) including Canadian Network for However, in addition to small sample size, this Mood and Anxiety Disorders (CANMAT) guide- study excluded ECT non-responsive patients line that recommends ECT as a first-line treat- that may interfere with the findings. A recent ment for TRD (Milev et al. 2016). comparative study of TMS to ECT showed sig- However, a randomized controlled trial com- nificantly lower depression scale scores and pared the efficacy of ECT to an algorithm-based better effect size compared to those undergoing pharmacological treatment. Although the rTMS (Micallef-Trigona 2014). response rate was significantly higher in the ECT Vagus Nerve Stimulation (VNS): Few data (73.9% versus 35.0%), the remission rates were exist in TRB depression as discussed before similar (34.8% versus 30.0%) (Schoeyen et al. (Selek et al. 2017). Also, the limitations of this 2015). On the other hand, ECT has been consis- treatment including slow onset of antidepres- tently found effective short-term treatment for sant action and moderate response rates make depression and is probably more effective than conventional use difficult at this time. drug therapy (The UK ECT Review Group 2003). Even though the patients reach to remission with ECT, they need to be on maintenance treatment 19.1.3 Other Novel Treatment such as maintenance medications or maintenance Approaches ECT. Despite the little difference between maintenance and continuance ECT, they have been Deep Brain Stimulation (DBS): DBS has been interchangeably used and maintenance ECT has used for Parkinson’s disease more than 3 decades, been accepted as a more wide term. Data for but it is a new technique in treatment of TRD. In maintenance ECT (mECT) are few. Several stud- the first clinical trial, the electrodes were placed ies showed mECT’s efficacy in reducing the hos- in the subcallosal cingulate region (SCC), lead- pitalization for TRB patients both in unipolar and ing to a notable sustained antidepressant response bipolar depression (Vaidya et al. 2003). A recent (Mayberg et al. 2005). Despite promising out- German retrospective study including unipolar comes in open-label studies, a randomized sham depression cases also showed reduced hospital- controlled trial of DBS failed to show significant izations after mECT (Post et al. 2015; Vaidya improvement (Dougherty et al. 2015). Different et al. 2003). Numerous hypotheses have been outcomes raised the discussion of place of elec- proposed on how ECT works in depression trode targeting thus, subcallosal region, DR including anti-inflammatory effects, cortical nucleus, subgenual cingulate region have been inhibition, and pigment epithelium-derived factor tried with different outcomes (Torres-Sanchez (Jarventausta et al. 2017; Ryan et al. 2017; et al. 2017). Based upon electrophysiological 19 Neurobiology and Evidence-Based Review on Novel Therapeutic Strategy for Treatment-Resistant 267 studies in animal models and preliminary studies, Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa we suggest superolateral medial forebrain bundle TA, McShane R, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane (sl-MFB) as the primary site for DBS because sl- Database Syst Rev. 2015;9. MFB has more projections to the frontal cortex Conca A, König P, Hausmann A. 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Rafael C.R. Freire, Patricia C. Cirillo, and Antonio E. Nardi

20.1 Introduction to neurobiological changes from chemicals and drugs. Neurostimulation methods may be nonin- There is a growing interest in biological non- vasive, like transcranial direct current stimulation pharmacological treatments for depressive disor- (tDCS), repetitive transcranial magnetic stimula- ders, and this is probably due to the limitations of tion (TMS), electroconvulsive therapy (ECT), psychotherapies and psychopharmacological and magnetic seizure therapy (MST), or invasive, treatments. Many patients do not adhere to psy- such as vagus nerve stimulation (VNS) and deep chotherapies, and even for those who adhere, it brain stimulation (DBS) (Table 1.1). frequently takes a long time for the improve- As discussed in Chap. 15, the use of electrical ments to occur. A significant portion of patients charges in the brain has been studied since the does not respond or has a weak response to anti- classical antiquity, but the major turning point depressants and other pharmacological agents. was the invention of ECT in the 1930s. For many The side effects of these drugs are very common; decades, ECT was the most important treatment some patients do not tolerate them and abandon for depressive disorders, but the discovery and the treatment. Psychopharmacological agents are development of psychopharmacological agents, also contraindicated for special populations, such along with cultural and political influences, pro- as pregnant women, patients with liver failure, duced a decrease in the use of ECT. However, and other clinical conditions. ECT is still considered an invaluable treatment The terms neuromodulation and neurostimu- option for depressive disorders, especially for lation have been used to describe procedures that severe or treatment-resistant major depressive use magnetic or electrical stimulation on the disorder (MDD). On the one hand, there is abun- brain to treat psychiatric or neurological disor- dant evidence demonstrating the efficacy of ECT, ders through cortical activity modulation. The both as short-term and long-term treatment for term neurostimulation is more adequate for those MDD. On the other hand, studies also show that treatments, since neuromodulation is also applied the risks, side effects, and costs of ECT may become a problem in some cases. The TMS has been extensively studied since its discovery in the 1980s. Clinical trials indicate that magnetic stimulation is effective in the treat- R.C.R. Freire (*) • P.C. Cirillo • A.E. Nardi ment of depressive disorders, even in treatment- Laboratory of Panic and Respiration, Institute resistant disorders. Most of the studies with TMS of Psychiatry, Federal University of Rio de Janeiro, are short-term studies, but there are also a few Rua Venceslau Bras 71, Rio de Janeiro, RJ, Brazil e-mail: [email protected] long-term studies. TMS is associated with less

Table 1.1 Neurostimulation methods Modality Pretreatment Target region Mode of action Recommendation ECT Anesthesia and muscle Cerebral cortex Electrical current +++ relaxant produces seizure MST Anesthesia and muscle Cerebral cortex High-intensity magnetic + relaxant pulses produce seizure TMS – Cerebral cortex Low-intensity magnetic +++ pulses produce low electrical currents in the brain tDCS – Cerebral cortex Low-intensity ++ continuous electrical current VNS Implantation of pulse Vagus nerve Electrical pulses are ++ generator and transmitted to the brain electrode through the vagus nerve DBS Implantation of pulse Nucleus accumbens, Electrical pulses are + generator and ventral striatum, delivered to deep brain electrode inferior thalamic structures by electrodes nucleus, peduncle, lateral habenula, subgenual cingulate ECT electroconvulsive therapy, TMS repeated transcranial magnetic stimulation, MST magnetic seizure therapy, tDCS transcranial direct current stimulation, VNS vagus nerve stimulation, DBS deep brain stimulation (Milev et al. 2016; Akhtar et al. 2016) risks and side effects than ECT. Nevertheless, seen as a psychiatric asylum practice, and there magnetic stimulation seems to be less effective was an erroneous association with punishment and than electroconvulsive stimulation, especially in torture. The prejudice against this technique was the treatment of severe depressive disorders. probably due to ECT applications without the Both ECT and TMS are approved by the US patient’s consent and its indiscriminate use. Food and Drug Agency (FDA) and are widely Rudimentary ECT devices, lack of anesthesia, and used throughout the globe. lack of muscle relaxants were associated with MST, tDCS, DBS, and VNS are mainly exper- higher risks and side effects, reinforcing the nega- imental treatments for depressive disorders, and tive public perception of ECT. In the 1990s, a new the clinical trials with these techniques are scarce. interest on ECT emerged with a great increase of The FDA approved VNS vagus nerve stimulation clinical trials and publications. The efficacy of (VNS) only for adult patients with severe or ECT has been confirmed by several studies in the recurrent treatment-resistant depression; the last two decades. In addition, modern devices and other treatment modalities are not FDA approved. advanced anesthesia methods made ECT an extremely safe method that does not produce any discomfort for the patients. Despite all that, ECT is 20.2 Electroconvulsive Therapy frequently considered as the last therapeutic resource, reserved for very severe and refractory ECT is the oldest somatic treatment among those cases, demonstrating that the stigma about this currently used in psychiatric practice, and it is also method still exists (Mochcovitch et al. 2016). the most controversial. ECT was a popular treat- Recent studies indicate that methods used in ment for mental disorders between the 1940s and ECT applications, such as the position of the elec- 1960s. After the 1960s, the use of ECT met resis- trodes, current intensity, wavelength, frequency, tance, and it was no longer a treatment option for session duration, time between applications, and many psychiatrists and psychiatry services. It was number of sessions, may influence both positive 20 Clinical Application of Neurostimulation in Depression 273 and negative outcomes of this therapy. In order to disorder. Both unipolar and bipolar depressive produce effective seizures, unilateral ECT disorders are the main indications for ECT, requires higher electrical current doses, bifrontal accounting for 80–90% of them. This is probably ECT requires lower doses, and the lowest doses due to the superior efficacy of ECT in relation to are those applied in bitemporal ECT. This elec- pharmacotherapy. ECT is effective for patients trode placement is associated with more cognitive with or without psychotic symptoms, but the latter side effects, especially memory deficits, com- respond more rapidly to this treatment. It may be pared to unilateral and bifrontal positions. administered to pregnant or lactating women, However, it is still under debate if bifrontal and children, elderly people, or patients with severe right unilateral ECT are as effective as bitemporal clinical comorbidities, neuroleptic malignant syn- ECT. In right unilateral ECT, the application of drome, or Parkinson’s disease. Recent studies brief pulses (1.5 ms) was demonstrated to be more indicate that maintenance ECT is also effective, effective than ultrabrief pulses (0.3 ms), although and its efficacy is equivalent to the efficacy of the former is associated with more cognitive side continuation pharmacological treatment (Kellner effects than the latter. Ultrabrief pulses are not et al. 2006; Milev et al. 2016; Mochcovitch et al. effective in bitemporal ECT. Prolonged convul- 2016; Pastore et al. 2008). sions and poor ventilation were also correlated to Patients should receive ECT until there is cognitive deficits (Mochcovitch et al. 2016; remission of symptoms or the response reaches a Sackeim et al. 2008; Tor et al. 2015). The plateau. The clinical response should dictate Canadian Network for Mood and Anxiety how many sessions a patient should receive, usu- Treatments (CANMAT) classified right unilateral ally ranging from 6 to 15 sessions. Cognitive ECT and bifrontal ECT as a first-line treatment side effects are cumulative, and if they are too and bitemporal ECT as a second-line treatment, severe, the treatment should be abbreviated. On due to its cognitive side effects (Milev et al. 2016). the one hand, low charges are not effective; on the other hand, high charges produce more cognitive side effects. For this reason it is important 20.2.1 Short-Term Treatment to determine the adequate dose for each patient. The best method to find the correct dose is to The American Psychiatric Association (APA) and administer repeated stimuli with increasing the CANMAT consider ECT the most recom- loads until there is a generalized seizure, conse- mended treatment when there is a need for rapid quently establishing the seizure threshold. improvement, severe depression symptoms, high Typically, for bitemporal or bifrontal ECT, the risks related to drugs, lack of response to pharma- charge should be about 1.5 to 2 times the seizure cological agents, patient preference, pregnancy, threshold, whereas for unilateral ECT, the load or lactation. APA also points out that ECT should should equal 6 times the seizure threshold (Milev also be considered when the psychopharmaco- et al. 2016; Mochcovitch et al. 2016). logical treatment is only partially effective or pro- In the past, the occurrence of generalized sei- duces intolerable side effects. The World zures was considered necessary and sufficient to Psychiatric Association (WPA) also recommends produce the therapeutic effect of ECT. However, ECT as an early acute treatment for severe MDD, it is now clear that seizures can be ineffective, especially in depression with psychotic symptoms and this depends on the anatomical position of or at high risk of suicide. ECT is highly effective the electrodes, the dose of the electrical stimulus, in unipolar and bipolar depression, with remission and the patient’s seizure threshold. The minimum rates of 55, 61, and 64% for right unilateral, duration of the observed seizure should be 20 s or bifrontal, and bitemporal ECT, respectively. It is 25 s if measured with the electroencephalogram. also effective in the treatment of antidepressant- Studies have shown that the efficacy of ECT is resistant depression, rapid improvement of catato- correlated with a high ictal amplitude, especially nia symptoms, or prolonged severe manic in slow waves, and with great postictal suppres- 274 R.C.R. Freire et al. sion. Modern ECT devices allow quantitative tion. Other arrhythmias are secondary to the analysis of the ictal and postictal EEG, so that tachycardia observed during the seizure and may mathematical parameters (such as ictal power occur while the patient returns to consciousness. and coherence) can be calculated, helping to The short-term neurological side effects nor- determine if a seizure was effective or not. If the mally associated with ECT are mental confusion ictal power is low or there is no postictal suppres- and delirium, shortly after the seizure and anes- sion, the stimulus dose should be augmented. thesia recovery. Significant confusion may occur Increased blood pressure and heart rate just after in up to 10% of patients within the first hour the seizure are also associated with a greater effi- after the seizure. Delirium is usually more prom- cacy of ECT (Mochcovitch et al. 2016). inent after the first applications and in patients who received bilateral ECT or who have coexisting neurological disorders. Delirium typically 20.2.2 Long-Term Treatment disappears within days or a few weeks at most. The severity, type, and duration of cognitive dys- Maintenance ECT may be administered after the functions seem to be associated with the meth- remission of depressive symptoms for an indefi- odology of ECT administration, including nite period of time. The applications of mainte- electrode positioning, wave type, and frequency nance ECT usually occur two to four times per of procedure. Impairment of anterograde mem- month (Mochcovitch et al. 2016). ory is one of the most commonly observed short- A study with MDD patients (Kellner et al. term side effects, but it lasts only for a few days. 2006) compared maintenance ECT with the com- These side effects can be attenuated with the use bination of nortriptyline and lithium for 6 months. of ultrabrief pulses, unilateral electrode position, Differences regarding efficacy and tolerability and a larger interval between sessions (Milev between the two treatments were not observed. In et al. 2016; Mochcovitch et al. 2016). a clinical trial with elderly patients with psychotic Cognitive effects may be persistent, and its depression (Navarro et al. 2008), nortriptyline was intensity and duration are closely related to the compared to nortriptyline plus ECT for 2 years. In ECT parameters. Anterograde amnesia remits patients who received the combined treatment faster than retrograde amnesia, which may be (nortriptyline + ECT), the relapse rate was signifi- persistent in some patients. Apparently, cognitive cantly lower than in the nortriptyline group. impairments before ECT and postictal disorientation predict amnesia. Usually cognitive side effects improve after the end of the treatment, 20.2.3 Adverse Events and 6 months after the last treatment, there are no memory deficits anymore (Cohen et al. 2000; The most frequent immediate side effects of Ghaziuddin et al. 2000; Mochcovitch et al. 2016). ECT are headache, muscle soreness, nausea, and The mortality rate related to ECT is 2 in 10 per emesis, which vary depending on the anesthetic 100,000 patients, which is comparable to the risk used. More than 45% of patients report head- of death from anesthesia in general procedures. ache, which can be treated symptomatically with There is an increased risk of complications in the use of analgesics. Patients suffering from patients with arrhythmias, severe arterial hyper- migraine attacks are more predisposed to head- tension, congestive heart failure, large aneu- ache after ECT. Mild and transient cardiac rysms, insulin-dependent diabetes, brain tumors, arrhythmias may occur during ECT application, traumatic brain injury, cerebrovascular accident, especially in patients with prior heart disease. epilepsy, cerebrovascular malformations, and Arrhythmias result from brief postictal brady- narrow-angle glaucoma, but these are not abso- cardia and therefore can often be prevented by lute contraindications for ECT (Milev et al. 2016; increasing the dosage of anticholinergic medica- Mochcovitch et al. 2016). 20 Clinical Application of Neurostimulation in Depression 275

20.3 Repetitive Transcranial 110–120% of RMT in TMS and 70–80% for Magnetic Stimulation TBS. Less intense stimuli are not effective (Janicak and Dokucu 2015). In TMS, repetitive magnetic pulses are delivered Standard protocols for MDD consist of 20–30 over cortical areas through a coil positioned on daily sessions, over a course of 4–6 weeks. the scalp. The magnetic field produces electrical Clinical observations have shown that patients currents in the brain, stimulating or inhibiting must demonstrate some improvement within 20 brain structures. There are two types of TMS, one sessions. If not, they will probably not benefit is more superficial and the other is deeper. In con- from additional sessions. On the other hand, ventional TMS treatment, the electromagnetic improvement before 20 sessions predicts waves have a reach of 3 cm from que coil surface response and remission in a 30-session treatment to the cortex, while in deep TMS the reach is (Loo and Mitchell 2005; Milev et al. 2016). TMS approximately 5 cm. Several types of coils are treatments with three sessions per week (in dif- used in TMS, and they vary in size, format, focal- ferent days) have been reported, but the total ity, and reach. Theta burst (TBS) is a new form of number of sessions remains the same. In acceler- TMS, which consists of three bursts of pulses at ated protocols, the number of sessions is about 50 Hz every 200 ms. This form of TMS is as the same as in conventional protocols too. effective as TMS with 10 Hz, but the duration of Multiple TMS sessions (2–10) are administered the session decreases about 5 times, which allows in 1 day, producing quick results and decreasing services to treat a larger number of patients the duration of the treatment (Loo and Mitchell (Milev et al. 2016). 2005; Milev et al. 2016). All kinds of TMS can be inhibitory or excit- Frequencies of 1 Hz or less are considered inhib- atory. These treatments can be an add-on treat- itory and are applied to right DLPFC. Excitatory ment or monotherapy for depression. Commonly, frequencies, which are applied to the left DLPFC, psychotropic medications are maintained while range from 1 to 20 Hz. A 50 Hz excitatory fre- performing neurostimulation treatment. The quency is used in TBS. The number of stimuli per patient sits in an upright position and is conscious session ranges from 120 to 3000, and better results during the whole procedure, and there is no need were obtained with more than 1000 stimuli per ses- for anesthesia. sion (Lefaucheur et al. 2014). Usually the sites of stimulation are the left and TMS is already considered a first-line treat- right dorsolateral prefrontal cortex (DLPFC) and ment for patients with treatment-resistant depres- dorsomedial prefrontal cortex. Regarding sive disorder, who have not had a significant DLPFC, excitatory stimuli are applied on the left improvement to at least one antidepressant hemisphere, while inhibitory stimuli are applied (Milev et al. 2016). Several regulatory agencies on the right hemisphere. Some researchers had approved TMS for the treatment of MDD in attempted to combine both excitatory stimulation patients that have not responded to one antide- on the left DLPFC and inhibitory stimulation on pressant. Young patients, patients without psychi- the right DLPFC, but it did not show additional atric comorbidities, and those with few failures in benefits, compared to unilateral stimulation previous treatment attempts tend to respond bet- (Janicak and Dokucu 2015). ter to TMS, compared to those who do not have Stimulus intensity ranges from 1.5 to 3.0 tesla, these features (Lee et al. 2012). but intensity is based on resting motor threshold Due to its safety and efficacy in short-term (RMT), which is the minimum intensity to con- treatment, especially in patients with treatment- tract a patient’s thumb. Patients have their own resistant depression, TMS was considered by the RMT, and the stimulus intensity is calculated as a CANMAT a first-line treatment for MDD patients percentage of this RMT. The stimulus intensity who failed to respond to at least one trial with an applied to patients is predetermined, generally antidepressant (Milev et al. 2016). 276 R.C.R. Freire et al.

20.3.1 Short-Term Treatment cacy and tolerability of low-frequency unilateral TMS and bilateral TMS had better results than Several studies and meta-analyses showed similar other TMS modalities, especially new TMS efficacy of the right and left DLPFC TMS for methods for treatment-resistant depression, such MDD. Based on these evidences, it was hypothe- as accelerated protocols and deep TMS (Brunoni sized that bilateral stimulation, which is the com- et al. 2017). bination of inhibitory and excitatory TMS over ECT is the gold standard treatment for treatment- the right and left DLPFC, respectively, could have resistant MDD but requires anesthesia and fre- a better outcome, compared to unilateral stimula- quently causes cognitive side effects, while in the tion. However, the results did not show a signifi- treatment with TMS, there is no need of anesthesia, cant statistical difference (Milev et al. 2016). In a and cognitive side effects are not common. Six ran- meta-analyses with 34 TMS studies, patients who domized trials compared ECT (n = 102) and TMS received TMS (n = 751) had more significant (n = 113) and demonstrated the superiority of ECT improvements compared to those who received over TMS, with a mean weighted effect size of sham stimulation (n = 632), and the mean effect −0.47 (Slotema et al. 2010). size weighted to sample sizes was 0.55. The effect size of unilateral TMS in the left DLPFC was similar to the one of bilateral TMS. Unilateral 20.3.2 Long-Term Treatment TMS at the right DLPFC yielded a somewhat higher effect size (0.82) (Slotema et al. 2010). It is well established that depression relapse and The most widely used and studied magnetic recurrence are common after short-term pharma- stimulation technique is conventional TMS, but cological treatment. There is also a high risk of experience with TBS is increasing rapidly. TBS relapse from 2 to 12 months after acute treatment protocols over DLPFC have demonstrated positive with TMS. However, evidence also indicates that, results for the left intermittent TBS, which is excit- in patients with treatment-resistant MDD who atory, but not for the right continuous TBS, which achieved remission after acute treatment with is inhibitory. Bilateral TBS stimulation studies TMS, maintenance treatment with the same have shown mixed results (Milev et al. 2016). One neurostimulation method could prevent recur- study demonstrated that TBS in dorsomedial pre- rence. Nevertheless, there is no consensus on the frontal cortex was as effective as TMS in the left maintenance treatment protocols, and some DLPFC. The advantage of TBS was the reduced maintenance studies had positive results, but fur- session duration (6 min) compared to TMS ther clinical trials are needed (Loo and Mitchell (30 min). Some health-care systems are interested 2005; Milev et al. 2016). in treating larger numbers of patients, which is In some studies, patients were followed after easier with TBS, compared to conventional TMS acute treatment with TMS, and in those who pre- (Bakker et al. 2015). When a fast symptom sented a new depressive episode, TMS was improvement is needed, accelerated protocols resumed. These studies showed that 50–85% of using TBS could also be a good alternative to con- patients had benefited from additional TMS ses- ventional TMS, in which the sessions are much sions (Demirtas-Tatlidede et al. 2008; Fitzgerald longer (Loo and Mitchell 2005; Milev et al. 2016). et al. 2013). However, it is still important to Other TMS optimization strategies are accel- ascertain if a maintenance treatment could reduce erated protocols and extended number of pulses relapse rates. per session. Indeed, additional studies are necessary to evaluate the efficacy of these methods and to observe the occurrence of adverse events, 20.3.3 Adverse Events especially seizure (Lee et al. 2012). The meta-analyses of 81 randomized con- The most common adverse events are mild, and trolled trials (n = 4233) concluded that the effi- the patient can take symptomatic medications 20 Clinical Application of Neurostimulation in Depression 277 to relieve them. Those adverse events usually period of 4–6 weeks (Milev et al. 2016). The decrease in intensity or disappear during the “figure of 8” coil is not considered effective to treatment. Common adverse events are scalp dis- produce seizures, but the nonfocal round coil comfort or pain, headache, facial twitching, and and the double-cone coil are considered reliable local erythema. Drowsiness and tearfulness have to induce seizures. In MST, the stimulus inten- also been reported (Slotema et al. 2010). sity is always above the seizure threshold The most severe adverse events that can occur (Cretaz et al. 2015). are vasovagal syncope and seizure, but both are Currently, there are a few studies with small rare. Until now, fewer than 30 cases of seizure samples sizes evaluating the effectiveness of have been reported worldwide despite the large MST in treatment-resistant depression. In one of number of treatments that have been performed. the MST studies with a large sample (n = 13), In the current available literature, no cognitive three patients responded and two achieved impairment has been reported (Loo and Mitchell remission (Fitzgerald et al. 2013). In the largest 2005; Milev et al. 2016). In order to avoid or MST study (Kayser et al. 2015), 26 patients with minimize risks and adverse events related to treatment-resistant depression were enrolled in TMS, safety guidelines must be followed (Rossi an open-label clinical trial. The response rate et al. 2009). was 69%, and the remission rate was 46%. This study showed that MST was effective in the treatment of treatment-resistant depression and 20.4 Other Neurostimulation anxiety (Kayser et al. 2015). Both studies found Methods that MST is a safe and well-tolerated treatment. Overall, studies show response and remission 20.4.1 Magnetic Seizure Therapy rates similar to ECT (Milev et al. 2016). A systematic review of eight studies of MST treatment MST is a noninvasive convulsive technique that in patients with treatment-resistant MDD showed generates tonic-clonic seizures through a strong remission rates from 30 to 40% and less cogni- electromagnetic field. A coil positioned on the tive impairment, compared to ECT (Cretaz et al. skull produces this electromagnetic field in the 2015). There are no maintenance treatment stud- same way as in other magnetic neurostimulation ies following MDD patients after MST short- techniques (Milev et al. 2016). As in ECT, anes- term treatment. thesia and muscle relaxants are needed in One randomized within-patient study MST. Due to the loud clicking of the device, (Lisanby et al. 2003) compared MST to ECT in earplugs are also recommended (Engel and what regards adverse events and seizure charac- Kayser 2016). MST stimulates the superficial teristics. Ten inpatients in a major depressive cortex producing seizures, but there is no direct episode were directed to ECT. Then, they were electrical stimulation of the temporal cortex, randomized to receive two MST sessions in the which explains the absence of cognitive side first four ECT sessions. Side effects and cogni- effects in this treatment. Recent studies demon- tion were evaluated before and after sessions. strated that MST is effective for treatment-resis- MST seizures were shorter, with smaller ictal tant MDD, but it is not as effective as ECT amplitude, and patients showed faster poststimu- (Cretaz et al. 2015). lus reorientation. Still there is no consensus on the optimal The adverse events associated with MST are delivery parameters for MST, but most studies headache, muscle aches, disorientation after the have used a coil placement at the vertex with a procedure, and anterograde and retrograde amne- frequency of stimulation of 100 Hz, pulse width sia (Milev et al. 2016). Cognitive side effects are of 0.2–0.4 ms, and stimulation duration of 10 s. usually mild or absent (Cretaz et al. 2015). The schedule for MST is similar to the one for Due to the low level of evidence on MST, ECT, with a total of 12 sessions spread over a especially on maintenance treatment, the 278 R.C.R. Freire et al.

CANMAT rated this neurostimulation technique been evaluated as a cognitive improvement tool. as investigational (Milev et al. 2016). In a double-blind, randomized, controlled study (Fregni et al. 2006) with 18 outpatients with unipolar depression, patients showed working mem- 20.4.2 Transcranial Direct Current ory improvement after five tDCS sessions, even Stimulation without depression enhancement. In the CANMAT guidelines, tDCS is considered a third- tDCS is an electrical neurostimulation method line treatment for MDD, although it is not recom- with constant low-amplitude current focalized in mended for relapse prevention because there are specific cortical areas through electrodes placed no controlled studies on maintenance treatment on the scalp. This neurostimulation method (Milev et al. 2016). increases cortical excitability in cortical areas The most common adverse events of tDCS are under the anodal electrode, while it decreases cor- discomfort, itching, tingling, burning sensation, tical excitability where the cathodal electrode is and headache. Hypomania has also been reported placed. This effect is produced by the neuronal (Kalu et al. 2012). depolarization and hyperpolarization, respectively. There are basically two options of electrode plac- ing: (1) anodal electrode over the left DLPFC and 20.4.3 Deep Brain Stimulation cathodal electrode grounded in a noncortical area or (2) anodal electrode over the left DLPFC and DBS consists of neurosurgical implantation of the cathodal over the right DLPFC. The stimulus electrodes under magnetic resonance imaging intensity ranges from 1 to 2 mA, and the sessions (MRI) guidance in selected brain areas connected last for 30 min or more. Daily sessions for at least by a wire to a neurostimulator (NS) or an implant- 2 weeks are needed to obtain an antidepressant able pulse generator (IPG). The NS/IPG, usually effect. Six-week treatments were more effective placed into the right chest below the clavicle, than shorter treatments, and tDCS combined with sends electrical pulses to brain electrodes in order antidepressants was more effective than tDCS to modulate an adjacent neural network. DBS alone (Milev et al. 2016). parameters can be monitored and programmed Studies using tDCS to treat treatment-resistant remotely with a handheld device in a similar way MDD have shown mixed outcomes, with small to to pacemakers and VNS. There is also a patient moderate effect sizes of active treatment, when controller to turn it on and off, check battery sta- compared to sham (placebo). Two meta-analyses tus, and self-adjust parameters provided by the (Kalu et al. 2012; Shiozawa et al. 2014), which DBS programmer (Milev et al. 2016). included, respectively, six and seven randomized DBS is mainly used to improve motor symp- controlled trials (n = 259), concluded that active toms of Parkinson’s disease, but it is also been tDCS was more effective than sham (Kalu et al. studied in treatment-resistant depression, dysto- 2012; Shiozawa et al. 2014). On the other hand, nia, essential tremor, epilepsy, Alzheimer’s dis- the meta-analysis from Berlim et al. (Berlim et al. ease, and obsessive-compulsive disorder (OCD). 2013), which also included six randomized con- Studies using DBS to treat treatment-resistant trolled trials, did not find any significant differ- depression are increasing; but this technique still ence between both groups, even when analyzing needs to find more appropriate brain areas related only studies with at least 10 sessions and 2 mA. to this disorder for the implantation of electrodes In some studies, patients were followed for 1 to have more consistent results. The psychophar- month after the end of treatment to evaluate the macological and psychotherapeutic treatments sustained improvement of depression. In three of are usually performed in tandem with each other four studies, it was confirmed that patients who (Milev et al. 2016). received active tDCS maintained their levels of The main anatomical target for DBS in most improvement (Kalu et al. 2012). tDCS has also studies is the subcallosal cingulate (SCC) white 20 Clinical Application of Neurostimulation in Depression 279 matter, but also the ventral capsule/ventral stria- the follow-up. Eight of the eleven patients that tum (VC/VS), nucleus accumbens and medial responded were already responders at the first forebrain bundle (MFB), inferior thalamic year. Remission rates were 18.8% after 1 year, peduncle, lateral habenular complex, and rostral 15.4% after 2 years, 50% after 3 years, and 42.9% cingulate gyrus (Delaloye and Holtzheimer 2014; at the last follow-up visit. DBS was also well tol- Milev et al. 2016). erated in this study; however, two patients com- Currently there is no consensus on what the mitted suicide because of depressive relapse. optimal stimulation parameters are. However, tri- It is possible that some adverse events, such as als in animals concluded that some parameters intracranial hemorrhaging or infection, could result are more effective for the ventromedial prefrontal from the neurosurgery itself. Regarding adverse cortex/SCC such as high frequency (130 Hz) and psychiatric events, psychosis and hypomania were current intensity (100–300 mA). These studies reported after changes in stimulation parameters. also identified that prelimbic stimulation was Blurred vision and strabismus were also reported in more effective than infralimbic stimulation and patients after having increased the amplitude of the that left unilateral and bilateral stimulation had parameters. However, these events were reversible similar results (Milev et al. 2016). after an adjustment to the stimulation parameters DBS is indicated only when it is determined (Milev et al. 2016). No cognitive side effects were that other pharmacological and neurostimulation reported. Approximately 11% of the patients aban- treatments, like ECT, do not produce a clinical doned the treatment before the end. Patients had no response. Therefore, the patients submitted to cognitive impairment in long-term treatment DBS have ultra-resistant depression. Additionally, (Delaloye and Holtzheimer 2014). it is difficult to evaluate DBS effectiveness since The CANMAT considers DBS as an experi- the published literature is limited, and most stud- mental treatment because there are too few studies are noncontrolled, nonrandomized, and con- ies documenting its safety and efficacy (Milev sist of small sample sizes. Research shows that et al. 2016). response rates range from 30 to 60% and the remission rates range from 20 to 40% after 3–6 months of treatment with DBS. Only a small 20.4.4 Vagal Nerve Stimulation open-label study with DBS over MFB, with 7 patients, showed higher response (85.7%) and In VNS, an IPG is implanted subcutaneously in remission (57.1%) rates (Milev et al. 2016). the left chest, and the electrodes from the IPG Most studies followed up patients for 6–12 deliver low-frequency, intermittent pulses to the months, but one study (Malone et al. 2009) was left vagus nerve (Daban et al. 2008). VNS vagus able to follow up patients up to 51 months. In this nerve stimulation (VNS)demonstrated to be safe study, response and remission rates were, respec- in pregnant women. VNS can be used concomi- tively, 40% and 20% at 6 months and 53% and tantly with psychotropic drugs and electrocon- 40% in the last follow-up. In addition, DBS vulsive therapy (ECT) (Howland 2014). showed good tolerability. The electrical stimulation through the vagus In another study (Kennedy et al. 2011), MDD nerve provides stimulation to the nucleus tractus patients were followed for 3–6 years after DBS solitarius that modulates several subcortical and implantation to the subcallosal cingulate gyrus. cortical regions of the brain through the neural This study had the following response rates over networks (Milev et al. 2016). Treatment parame- the years: 62.5% after 1 year, 46.2% after 2 years, ters are similar to other devices which include the 75.0% after 3 years, and 64.3% at last follow-up intensity of the electrical stimulus (mA), pulse visit. It started with 20 patients, and at the end of width (microseconds), frequency (Hz), duration the first year, 16 patients were still in the study of the stimulus, and interval between them (sec- and at the end of 3 years 14 patients, and at the onds or minutes) (Howland 2014). There is still end of the fourth year, nine patients completed no consensus on what the optimal stimulation 280 R.C.R. Freire et al. parameters for MDD would be. Most studies events usually associated with the current inten- used the output current beginning at 0.25 mA, sity and usually improve with the reduction of 500-μs pulse width, and 20- or 30-Hz frequency current intensity. Other possible adverse events for 30 s of stimulation and a non-stimulation are headache, dysphagia, paresthesia, and pain interval of 5 min. In one long-term study, the (Howland 2014; Sackeim et al. 2001). electric current was increased to 1 mA (Daban Complications are expected in about 1% of sur- et al. 2008). There seems to be better response geries and may include wound infection and rates and decreased suicide attempts in VNS with hoarseness. Hoarseness may be the result of lim- higher electrical charges, compared to low ited or long-lasting vocal cord paralysis charges (Milev et al. 2016). (Howland 2014). Currently, there is only one randomized, con- Considering these factors, only ultra-treatment- trolled study with VNS to treat TRD (Rush et al. resistant depression patients are eligible for this 2005). This 10-week study evaluated 235 treatment. VNS is considered a third-line treat- patients, of whom 210 are with nonpsychotic ment for MDD in CANMAT and merits further treatment-resistant depression and 25 with bipo- study (Milev et al. 2016). lar depression. There were no statistically significant difference between VNS and sham in short Conclusion term. A meta-analysis of uncontrolled studies of All neurostimulation techniques discussed in VNS in the treatment of TRD (Martin and this chapter were beneficial to patients with Martin-Sanchez 2012) showed a significant MDD. In these treatments, the stimulation is improvement based on scale scores and response targeted to brain areas related to MDD, avoid- rates (31.8%, p < 0.0001). ing stimulation of peripheral areas, due to its Studies have shown that MDD patients potential side effects. Depending on the improve with VNS over a long time. The aver- method, neurostimulation can have a very fast age time necessary to show improvement was antidepressant effect, or it could take many approximately 3 months, but patients may need months for it to take effect. These non-phar- to wait for another 6 months to have a signifi- macological treatments may provide improve- cant improvement. The response and remission ment for a group of patients that have already rates vary significantly across studies. A meta- tried several psychopharmacological treat- analysis of six multicenter studies (Berry et al. ments and psychotherapy and did not achieve 2013), with a total sample size of 1035 patients remission. with treatment-resistant depression treated with Above all, benefits and risks should be VNS and 425 patients treated as usual, indi- weighed before indicating a neurostimulation cated a response rate of 32% for VNS and 14% treatment. Patients should receive information for treatment as usual after 96 weeks of treat- about the treatment and consent to it. Patients ment. The response rates for VNS and treat- and family members should know beforehand ment as usual after 48 weeks of treatment were that these treatments have risks of adverse similar. events and their efficacy is limited. The stronger predictor of bad response to VNS Neurostimulation is a field of psychiatry in patients with treatment-resistant depression that is in continuous development. Currently, (failure in at least two trials with antidepressants ECT and TMS are the most extensively stud- of different classes) is probably ultra-treatment- ied neurostimulation methods, while MST, resistant depression. In the study from Sackeim tDCS, VNS, and DBS have to be studied thor- et al. (Sackeim et al. 2001), patients who failed to oughly so that their efficacy and safety are respond to more than seven antidepressant trials evaluated. There is a substantial amount of or who have already been treated with ECT were evidence supporting ECT and TMS as routine unlikely to benefit from VNS. treatments for MDD; still technical refine- Voice changes, hoarseness, coughing, and ments are needed to improve the efficacy and dyspnea with physical exertion are adverse reduce adverse events. 20 Clinical Application of Neurostimulation in Depression 281

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Kwang-Yeon Choi and Yong-Ku Kim

21.1 Introduction In spite of these inherent limitations, a series of meta-analyses consistently support the superiority Both pharmacotherapy and psychotherapy are of a combination of psychotherapy and pharma- proven to be effective treatments for depression cotherapy compared to each therapy alone for the (Barth et al. 2013; Cuijpers et al. 2011). The ques- treatment of adult depression (Cuijpers et al. tion of whether combined therapy will show better 2009; de Maat et al. 2007; Khan et al. 2012). In efficacy than each therapy alone is the logical detail, not only robust acute symptom relief but treatment progression. Since the tricyclic antide- also relapse prevention effects were observed pressant era, this idea has been repeatedly explored (Oestergaard and Møldrup 2011; Schramm et al. by researchers. Innate difficulties exist to substan- 2007). Furthermore, the effects of combined ther- tiate this idea. First, double-blinded placebo-con- apy were prominent in severe, but non-chronic, trolled studies are lacking. Study design is forced depression (Hollon et al. 2014). Combined ther- to be open labeled or single blinded; thus esti- apy also has small benefits in cases of chronic mated effects were often exaggerated. Second, it is depression (Keller et al. 2000; Wolff et al. 2012). difficult to attain the sample sizes necessary to Regarding specific age groups, additional benefits detect a small effect size in a single placebo- of combined therapy seem to be questionable in controlled study. Third, in spite of a wave of efforts geriatric populations (Reynolds et al. 2010). to standardize procedures in psychotherapy, inter- Combined therapy has not been shown to be more therapist and interdisciplinary variations exist. effective than each therapy alone in cases of child and adolescent depression (Cox et al. 2014). Various psychotherapies, including cognitive K.-Y. Choi behavioral therapy (CBT) and interpersonal ther- Department of Psychiatry, College of Medicine, Chungnam National University, Daejeon, apy (IPT), similarly showed synergistic efficacy South Korea when combined with antidepressants (Palpacuer Department of Psychiatry, College of Medicine, et al. 2017; Schramm et al. 2007). Chungnam National University Hospital, Daejeon, Here, we provide a current overview of com- South Korea bined therapy from the perspective of learning Y.-K. Kim (*) theory and neuroplasticity. Memory reconsoli- Department of Psychiatry, College of Medicine, dation and its derivative, reconsolidation- Korea University, Seoul, South Korea updating, have clinical implications for Department of Psychiatry, Korea University Ansan improving the effectiveness of psychotherapy. Hospital, Ansan, Kyunggi Province, We review the mechanisms of antidepressant South Korea e-mail: [email protected] action regarding how non-pharmacological

© Springer Nature Singapore Pte Ltd. 2018 283 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_21 284 K.-Y. Choi and Y.-K. Kim interventions, including psychotherapeutic (Brunoni et al. 2009). Placebo effects of antide- interventions, can influence the effect of antidepressants are estimated to include up to 75% of pressants. Then we discuss the addition of the treatment response (Mora et al. 2011). The another drug (e.g., an HDAC inhibitor) to aug- placebo effects of antidepressant trials have ment the effectiveness of combined therapy. increased over the past 30 years (Rutherford Finally, we describe the future perspectives of and Roose 2013). The widespread belief in combined therapy. antidepressant efficacy strengthened participant expectations of obtaining positive effects. Positive public anticipation reinforces the pla- 21.2 The Effects of Combined cebo effect in clinical trials of antidepressants. Therapy This ironically contributes to the difficulties in demonstrating the efficacy of a new antidepres- 21.2.1 Placebo Response sant in clinical trials. of Combined Therapy Placebo effects were previously regarded as nonspecific effects. However, physiological and Therapy-specific effects were estimated to be neural responses accompanying positive expecta- surprisingly small (~10%) with the majority of tions identified these as placebo responses the effect attributed to nonspecific factors, such (Brunoni et al. 2009; Oken 2009; Peciña et al. as the therapeutic relationship and common 2015). If prior experience of benefits from a spe- factors (Ahn and Wampold 2001; Palpacuer cific treatment exists, a placebo response elicits et al. 2017; Wampold 2015). Among these non- more prominent conditioned physiological specific effects, patients’ expectations of responses (Porro 2009). The placebo response is improvement and therapists’ expectations for a explained from the perspective of classical condi- good therapeutic alliance constitute a large por- tioning and social learning (Colloca and Miller tion of the effects of psychotherapy. Leuchter 2011). Some may argue that it is better to com- et al. showed that these nonspecific effects also bine a placebo with psychotherapy in debates of contribute to the effects of combined therapy placebo as a first-line treatment for depression (Leuchter et al. 2014). Patients with depression (Brown 1994; Kelley et al. 2012; Kirsch 2014). were randomly assigned to three groups. All However, this approach is not sustainable, groups received supportive care during weekly because it will eventually weaken patients’ and visits. Additionally, antidepressants, a placebo, therapists’ expectations of recovery (Kelley et al. and no medication (control) were provided to 2012). each group during the 8-week study period. The placebo plus supportive care group showed a greater response than the supportive care only 21.2.2 Synergistic Effects group. However, the antidepressant plus sup- of Combined Therapy portive care group showed a better response than the supportive care only group, but not the Because psychotherapy cannot be blinded to cli- supportive care plus placebo group. A priori nicians and patients, the beneficial effect of com- anticipation of the effectiveness of antidepres- bined therapy can only be demonstrated by sants predicted these therapeutic responses. placebo-controlled randomized studies to Due to the small effect and sample size, the exclude the placebo response. The effectiveness effectiveness of combined therapy over placebo of combined therapy is inclined to be exagger- plus supportive care was not demonstrated. A ated by studies designed without the placebo substantial portion of the beneficial effect of plus psychotherapy comparison mentioned combined therapy comes from the placebo above. response, like the case of antidepressant treat- There are several studies that include a ment and other non-pharmacological treatment placebo-controlled psychotherapy group as a 21 Is a Combination of Pharmacotherapy and Psychotherapy Superior to Each Alone? 285 control. A meta-analysis of 12 studies revealed esis. Impairing or blocking adult neurogenesis that the effect of active medication is small but does not necessarily cause depression or alleviate significant (effect size = 0.25) over placebo psy- the effect of antidepressants (Hanson et al. 2011). chotherapy (Cuijpers et al. 2010). Neuroplasticity is implicated in depression and Despite these small effects, we may wonder if the therapeutic action of antidepressants (Duman we should pursue combined therapy for depressed et al. 2016). Antidepressants, electroconvulsive patients. Is it better to recommend moderate therapy (ECT), and exercise enhance synaptic exercise as an adjuvant therapy, for its cost- plasticity (Alme et al. 2007; Nordgren et al. 2013; effectiveness? Exercise shows moderate efficacy Patten et al. 2013). Moreover, direct targeting of as an adjunct to antidepressant medications, as synaptic plasticity sufficiently showed rapid anti- well as to monotherapy for mild to moderate depressant effects (Kanzari et al. 2017). Brain- depression (Kvam et al. 2016; Schuch et al. derived neurotrophic factor (BDNF) plays a 2016). Otherwise, we will need to find the clini- critical role in antidepressant-induced enhance- cal characteristics or biomarkers that predict ment of synaptic plasticity, but not all (Alme et al. better response to combined therapy to maxi- 2007). Serotonin activates the transcription factor, mize their cost-effectiveness (Dunlop et al. cAMP response element (CREB), via intracellu- 2017). Currently, one meta-analysis the proj- lar signaling pathways (PKA-cAMP-CREB). ect is examining clinical elements that predict CREB turns on various plasticity-related genes, better improvement with combined therapy including BDNF. BDNF is involved in not only (Weitz et al. 2017). adult neurogenesis but also new dendritic spine formation. It is well known that BDNF plays a key role in neural plasticity, such as functional 21.2.3 Mechanisms and structural plasticity (Alme et al. 2007; Leal of Antidepressant Drugs et al. 2014; Tanaka et al. 2008). Downstream of BDNF, the TrkB-p11-SMARCA3 signaling path- In the 1950s, a serendipitous discovery from an way is necessary for antidepressant effects (Oh antituberculosis drug, iproniazid (MAO-A inhib- et al. 2013; Seo et al. 2016; Svenningsson et al. itor), opened the era of pharmacotherapy in the 2013). treatment of depression. Since then, antidepres- The rapid antidepressant effect of ketamine sants such as tricyclic antidepressants (TCAs) gives us new insight into the pathophysiology of and selective serotonin uptake inhibitors (SSRIs) depression and antidepressant effects. The neuro- have been developed. These drugs stem from the plasticity hypothesis of depression also explains monoamine hypothesis of depression. However, the mechanism of the rapid-onset antidepressant it is doubtful whether this explains the etiology of effect of low-dose ketamine infusion (Browne depression. A 2–3 week gap occurs between neu- and Lucki 2013). NMDA antagonism showed a rotransmitter elevation and clinical response. rapid increase in the density of dendritic spines. Moreover, while tryptophan depletion, a precur- NMDA antagonism inhibits tonic GABAergic sor of serotonin, can cause depression (Young interneurons that disinhibit glutamatergic trans- 2013), patients with depression do not necessar- mission (Kavalali and Monteggia 2012). ily have a serotonin deficiency in their brains Increased AMPA transmission results in the acti- (Gryglewski et al. 2014). vation of the BDNF-TrkB-Akt-mTORC1 path- Newer hypotheses arrived with the discovery way to increase local protein synthesis supporting of adult neurogenesis. Depressed patients show synaptic plasticity (Yoshii and Constantine-Paton diminished neurogenesis in the hippocampus, 2010). The fact that TrkB blockade abolishes the and chronic antidepressant treatment reverses antidepressant effect of ketamine indicates that this decreased neurogenesis, which correlates BDNF is a common convergent pathway of anti- with clinical response (Perera et al. 2011). depressant action (Autry et al. 2011; Lepack However, there also are limitations to this hypoth- et al. 2014). 286 K.-Y. Choi and Y.-K. Kim

21.2.4 Antidepressant-Environment Taken together, the interaction between anti- Interaction depressants and environment explains the effectiveness of combined therapy over nonspecific Antidepressants do not merely elevate mood in effects, such as the placebo response. To induce patients with depression. This is supported by the optimal recovery from depression, enhanced neu- fact that antidepressants don’t affect mood in roplasticity by antidepressant treatment is neces- healthy non-depressed individuals (Gelfin et al. sary, but not sufficient. With non-pharmacologic 1998). The neuroplasticity hypothesis posits new intervention, the effectiveness of antidepressants expectations about the effect of antidepressants. can be improved. Like a double-edged sword, enhanced neural plasticity by antidepressant treatment makes patients more susceptible to influences in their 21.3 The Mechanism environment. The effect of antidepressants can of Psychotherapy make depression worse, as well as recovering mood symptoms, depending on the context in 21.3.1 Mechanism of Psychotherapy which treatment occurs. This issue was compre- from the Perspective hensively reviewed in recent articles (Choi and of Learning Theory Kim 2016; Rief et al. 2016). Epidemiological studies indicate that depressed There have been efforts to explain the effect of patients with low socioeconomic status show a psychotherapy from the perspective of learning diminished treatment response to antidepressants and memory. More specifically, memory recon- relative to patients with high socioeconomic sta- solidation theory has received considerable atten- tus (SES) (Cohen et al. 2006; Trivedi et al. 2006). tion from psychotherapists. Memory types have In a rodent model of depression, antidepressants been divided into implicit and explicit memory. reversed depression-like symptoms in an enriched Explicit memory encompasses episodic memory environment. In contrast, antidepressants wors- (autobiographical memory) and semantic mem- ened depression-like symptoms in a stressful situ- ory. Implicit memory is divided into associative ation (Alboni et al. 2015; Branchi et al. 2013). memory (emotional memory), procedural mem- Reevaluation of Sequenced Treatment ory, and priming memory. During early life, Alternatives to Relieve Depression (STAR*D) social reciprocal interactions between infants and also revealed that, when treated with a high dose parents form long-lasting procedural memories, (citalopram 40 mg), depressed patients with high which function as a framework which determines SES showed a significantly higher response rate how a person interacts with others over the course than did low SES patients (Chiarotti et al. 2017). of his or her life. This is called attachment or self- This evidence supports the new expectation posed schema depending on psychotherapy disciplines. by the neuroplasticity hypothesis. Once negative automatic thoughts (which derived There is evidence that the anxiolytic effect of from negative self-schema), which cognitive antidepressants, as well as the antidepressant therapy targets, are formed, patients habitually effect, is strongly influenced by the therapeutic repeat the way they think in ambiguous situa- environment. A combination of antidepressants tions. Mindfulness-based cognitive therapy and extinction training (comparable to cognitive (MBCT) also aims to reduce these negative auto- behavioral therapy) successfully attenuated a matic thoughts (Frewen et al. 2007). Many learned fear response, without relapse, in a rodent patients with depression use maladaptive coping model of fear conditioning (model of anxiety dis- strategies, such as avoidance, to alleviate emo- orders) (Karpova et al. 2011). However, neither tional suffering. Because avoidance helps to alle- antidepressants nor extinction training alone viate symptoms in the short term, avoidance showed the robust and sustainable effects shown coping continues to be negatively reinforced. in their combination. However, in the long term, avoidance leads to 21 Is a Combination of Pharmacotherapy and Psychotherapy Superior to Each Alone? 287 detrimental consequences. Both an individual’s 2010). Memory can be strengthened and weak- mood and the situation get worse. Acceptance- ened, according to the environment. After the commitment therapy (ACT) and behavioral acti- reconsolidation process, memory restabilizes. Ten vation therapy (BA) target this avoidance coping minutes to 6 h after memory recall is the reconsoli- strategies in the treatment of depression (Chawla dation window. During this period, disrupting the and Ostafin 2007; Jacobson et al. 2001). reconsolidation process with drugs (e.g., a protein Psychodynamic psychotherapy addresses the synthesis inhibitor) or interfering with learning can recollection of remote memory as an important dramatically attenuate the physical response to therapeutic process. Not addressing simple episodic memory (Nader and Einarsson 2010). This method memory, therapists try to remind patients of implicit works well with procedural memory (Walker et al. memories, such as emotional memory and transfer- 2003), operant conditioning (Goltseker et al. 2017; ence (procedural memory), and then respond to Tedesco et al. 2014), and classical conditioning patients in a different way than the patients experi- (Björkstrand et al. 2017). There have been efforts enced with their parents. This therapeutic concept to translate reconsolidation into the clinical setting. was called working through by Freud and correc- This concept has been applicable to behavioral tive emotional experience by Alexander. This con- therapy for anxiety disorders and substance use cept also is regarded as reconsolidation-updating, as disorders (Chiamulera et al. 2014). described below. Exposure therapy for a specific phobia and exposure and response prevention (ERP) therapy for obsessive-compulsive disorder 21.3.3 Reconsolidation-Updating modify habitual responses after the initial recollection of memory. Reconsolidation and extinction are The memory reconsolidation process is distinct based on these behavioral therapies. from the extinction process in that it directly modi- fies memory per se. In contrast, extinction is regarded as new learning that suppress the original 21.3.2 Memory Reconsolidation memory. What happens if these two processes are combined? It has been shown that fear memory is The concept of memory reconsolidation plays a successfully suppressed to the erasure level if pivotal role in explaining the therapeutic effect of extinction learning happens during the psychotherapy (Lane et al. 2015). Before mention- reconsolidation window in which plasticity is ing memory reconsolidation, it is necessary to enhanced (Monfils et al. 2009). This paradigm is understand memory consolidation. The most called reconsolidation-updating or reconsolidation- important discovery of memory research is that, extinction. In general, after extinction, a fear mem- once formed, a memory is not stable through the ory can reappear spontaneously (spontaneous acquisition, maintenance, and recall processes. recovery) in different contexts than where the Rather, it is a dynamic process. Memory consolida- extinction training occurred (renewal) and with a tion is the process of transforming short-term foot shock alone (reinstatement). However, recon- memory into long-term memory. During consoli- solidation-updating successfully suppressed a fear dation, memories get destabilized and are suscep- response in the condition of rejuvenating a con- tible to external stimuli. Three to six hours after cealed fear memory. This phenomenon has been memory acquisition is called the consolidation demonstrated to be effective in humans (Agren window (Nader and Einarsson 2010). During this et al. 2012; Björkstrand et al. 2015; Schiller et al. period, new protein synthesis occurs. After the con- 2010). Recently, not only fear memory but also solidation window, memory again becomes stable. craving related to nicotine addiction memory Memory reconsolidation mimics memory consoli- could be successfully attenuated by using this dation. After memory recall, stable memory again approach (Germeroth et al. 2017; Xue et al. 2017). becomes destabilized, malleable, and vulnerable to The reconsolidation phenomenon is observed the external environment (Nader and Einarsson in other forms of memory. Procedural memory 288 K.-Y. Choi and Y.-K. Kim can be diminished by interfering with learning reconsolidation-updating as a therapeutic target, during reconsolidation (Walker et al. 2003). because maladaptive memories, which psycho- Episodic memory can be also distorted by cues therapy targets, are usually formed a long time presented after memory reactivation (Scully et al. before the first psychotherapy visit. Fortunately, 2016). Negative automatic thoughts, attachment, it was revealed that an epigenetic drug (HDAC2 and transference can be categorized into implicit inhibitor; CI-994) enables remote memory to be memory, such as procedural memory and emo- modified by the reconsolidation-updating para- tional memory. If so, this reconsolidation- digm (Gräff et al. 2014). Compared to recent updating explains the effect of psychotherapy. As memory recall, after retrieval of remote memory, psychodynamic psychotherapists expected, the hippocampus is less activated and less acety- reconsolidation-updating might be central to the lated. HDAC2 inhibition restored acetylation and effect of psychotherapy. We can optimize the cur- activation levels in the hippocampus during rent procedures of psychotherapy. remote memory retrieval. Combined therapy in depression has been primarily restricted to the combination of antidepres- 21.4 How to Improve Combined sants and psychotherapy. In the treatment of anxiety Therapy disorders, combining d-cycloserine (a dopamine partial agonist) with exposure-based therapy has Depression is a chronic and relapsing disease with been well studied during the last decade. A recent a great socioeconomic burden. More major depres- meta-analysis reported that d-cycloserine augmen- sive episodes make the disease more intractable. tation has a small but significant benefit (Mataix- Early identification and a complete recovery with Cols et al. 2017). Moreover, d-cycloserine showed no remaining symptoms are essential to prevent a significant augmentation effect on virtual reality illness progression (Hetrick et al. 2008). Combined (VR)-based exposure therapy over an active pla- therapy shows efficacy in cases of mild-to-severe cebo (Rothbaum et al. 2014). depression and in both chronic and non-chronic depression. In particular, combined therapy dem- 21.4.1.2 Beyond Antidepressants: onstrated better efficacy in preventing relapse than HDAC Inhibitors as a New pharmacotherapy or psychotherapy alone. Thus, Augmentation Strategy combined therapy deserves to be recommended as HDAC detaches an acetyl marker located on his- a first-line treatment for depression, although it tone tails. HDAC1-11 isoforms are classified into remains a second-line treatment because of its classes I, IIA, IIB, III, and IV. Valproate and CI-994 cost-effectiveness, practicality, and the limited are designated as class I HDAC inhibitors. Class I availability of psychotherapy (Parikh et al. 2009). HDAC consists of HDAC1, HDAC2, and HDAC3. Eventually, more patients will benefit from com- Isoforms perform diverse functions in cell-type- bined therapy if we improve its effectiveness and specific manners. Regarding learning, HDAC2 the availability of psychotherapy. functions as a molecular brake, preventing aberrant expression of plasticity-related genes at baseline. Upon learning (neural activation), HDAC2 21.4.1 How to Improve Combined detaches from the histone tails wrapping target Therapy in Pharmacotherapy genes. The histone tail is now allowed to be acety- lated by histone acetyltransferase (HAT). Closed 21.4.1.1 Pharmacological chromatin (heterochromatin) turns into loose chro- Augmentation matin (euchromatin), which allows RNA poly- of Reconsolidation-Updating merase and transcription factors to approach Although reconsolidation-updating can attenuate promoters of target genes. HDAC2 inhibition or recent memory, remote memory (>1 month) is genetic knockout of HDAC2 showed a cognitive not modified by this paradigm (Costanzi et al. enhancing effect via facilitating expression of neu- 2011). This limits the usefulness of roplasticity-related genes (Guan et al. 2009). 21 Is a Combination of Pharmacotherapy and Psychotherapy Superior to Each Alone? 289

Fig. 21.1 Synergistic effect of combined therapy. An psychotherapy, memory retrieval-induced reconsolidation antidepressant enhances BDNF expression. An HDAC can be modified by the interactions between patient and inhibitor further augments this expression. Enhanced neu- therapist roplasticity facilitates the effect of psychotherapy. During

The beneficial effect of an HDAC inhibitor on (Ohira et al. 2013). Targeting PNNs with antide- the combination of psychotherapy and antidepressants or directly with HDACs showed prom- pressants will be the next big question to be ising results in boosting the effects of behavioral answered (Fig. 21.1) (Choi and Kim 2016). interventions, such as fear extinction (Karpova HDAC inhibitors showed promising results in a et al. 2011; Yang et al. 2016). HDAC inhibitors, rodent model of depression. HDAC inhibitors as well as antidepressants (Vetencourt et al. showed an antidepressant effect with local infu- 2008), can restore critical period plasticity, which sion (Covington et al. 2015, 2009, 2011) in the has been translated into the treatment of amblyo- nucleus accumbens, medial prefrontal cortex, pia (Lennartsson et al. 2015; Silingardi et al. hippocampus and amygdala, as well as systemic 2010). Antidepressants show hope in facilitating infusion (Schroeder et al. 2007; Tsankova et al. rehabilitation after strokes via elongating the crit- 2006) in a rodent model of depression. In addi- ical period of recovery (Ng et al. 2015). tion, HDAC inhibitors augmented the effect of antidepressants in rodents (Schmauss 2015). The 21.4.1.3 Avoid Benzodiazepine Use underlying mechanism is that HDAC inhibitors Benzodiazepines are widely prescribed with anti- facilitate BDNF gene expression by increasing depressants to manage anxiety symptoms in H4 acetylation at promoter III of the BDNF gene depressed patients (Furukawa et al. 2001). (Schmauss 2015). However, there is concern that concurrent benzo- In particular, HDAC inhibitors and antidepres- diazepine use might ameliorate the beneficial sants can restore immature neuron-like plasticity. effects of combined therapy. Antidepressant-induced juvenile-like, critical Benzodiazepine has been shown to downregu- period-like plasticity is mediated by reducing late enhanced neurogenesis by antidepressants in perineuronal nets (PNNs). PNNs, extracellular rodents and humans (Boldrini et al. 2014; Sun matrix surrounding preferentially GABAergic et al. 2013). Furthermore, benzodiazepine interneurons, are lacking during critical periods. decreased the behavioral effects of antidepres- It appears that when a critical period is closed, sants in an animal model of depression (Sun et al. synaptic connections prevent robust activity- 2013). Benzodiazepine impedes functional dependent changes (Berardi et al. 2004). recovery during rehabilitation after a cerebral Antidepressants reduce PNN-like juvenile states infarct (Schwitzguébel et al. 2016). Currently, 290 K.-Y. Choi and Y.-K. Kim benzodiazepine is no longer recommended for 21.4.2.2 How to Innovate use in patients with PTSD (post-traumatic stress a Psychotherapy-Providing disorder) or recent trauma (Jeffreys et al. 2012), Platform because it increases the risk of developing PTSD A barrier to the widespread use of combined ther- and worsens psychotherapy outcomes (Guina apy is the accessibility of psychotherapy. Patients et al. 2015). Direct clinical evidence addressing have the right to access various non- this issue in the combined therapy of depression pharmacological treatment options, from exer- is lacking. However, it is prudent to avoid benzo- cise and nondirective supportive psychotherapy diazepine use in combined therapy. Concurrent to more specialized therapies, such as interper- use of benzodiazepines should be regarded as a sonal psychotherapy and cognitive behavioral major confounding factor in future research on therapy. Many patients prefer to attend psycho- combination therapy. therapy rather than taking medication (McHugh et al. 2013; van Schaik et al. 2004). However, complex factors, including financial and time 21.4.2 How to Improve Combined costs, lack of information about the nearby vali- Therapy in Psychotherapy dated therapists, and the health-care system, hinder patients/clinicians from choosing psycho- 21.4.2.1 Education System vs. therapy alone or combined therapy. Psychotherapy Practice There is a move to improve the mismatch No one contradicts the evidence that education problem between clients and providers, just as changes people’s brains and their life. Good nur- Uber and AirBnB connect consumers and poten- turing during early life helps people engage in tial providers. In the near future, it may be popu- good psychosocial relationships and maintain lar to use a new platform service connecting physical and mental health throughout their life- clients with nearby therapists (Baumel 2015). time. Mental health-care professionals are also This has the potential to innovate current psycho- expected to reshape one’s life. However, relative therapeutic practice. Patients save on effort to to parents and teachers, mental health practitio- find a nearby therapist providing a particular ners are placed in disadvantageous situations form of psychotherapy. The platform should have while public expectation is high. an apparatus to validate providers’ proficiency During school age, individuals spend 3~8 h and certificates before enrollment, and then ther- per day at school for many years until gradua- apists will be further evaluated on their reputa- tion. In addition, students participate in 45–50- tion. This information will help clients to choose min tutoring sessions into a subject during each therapists. From the therapists’ perspective, they semester at least once per week. Only after save the time they would have spent rescheduling entering graduate school can interactions with a a client’s request. The missed session fee will be supervising professor be reduced to approxi- automatically paid. And this system will provide mately 1 h per week. Only this small amount of clients with a more flexible reservation schedule interaction is the time allowed for psychothera- while minimizing default/empty reservations. pists to positively influence patients’ lives. Computerized CBT reduces the need for face- Postdoc fellows who are preparing their inde- to-face sessions and extends coverage to people pendent research need far less time than once a who need CBT but can not actually apply it. If week interactions with their advisors to achieve therapists combine internet-based apps with cog- their purpose of achieving independence. By nitive behavioral therapy, more intensive monitor- analogue, psychotherapists treat all students as ing or feedback will be provided. Behavioral graduate students, regardless of middle school, therapy using a mobile application showed initial high school, and university achievement. A promising effectiveness in the management of more flexible health-care system is needed to obesity (Chin et al. 2016; Kim et al. 2017). meet the wide spectrum of patients’ and clini- Recently, a computerized CBT-insomnia (CBT-i) cians’ needs. program showed efficacy compared to a conven- 21 Is a Combination of Pharmacotherapy and Psychotherapy Superior to Each Alone? 291 tional CBT-i program (Cheng and Dizon 2012). At reconsolidation window (10 min to 6 h) as much a minimum, guided self-help intervention is also as possible. effective for subthreshold and mild-to-moderate Active engagement of memory retrieval is depression (Fledderus et al. 2012) (Buntrock et al. already applied to the treatment of anxiety disor- 2016; Gellatly et al. 2007). ders (exposure-based therapy for PTSD and acro- These approaches will be helpful for patients phobia). Facilitating recollection of emotional who have subthreshold depression, who are seek- memory engaged with unresolved interpersonal ing something more than self-help, and who want conflict is used in the psychodrama technique. interactive experiences while they are not in the For a more immersive experience, a virtual real- therapist’s office. In particular, early intervention ity device is being developed (Coelho et al. 2009; for subthreshold depression is important to pre- Shapiro et al. 2005). If we can simulate the inter- vent the development of depression (Buntrock personal relationship in virtual reality, the direct et al. 2016; Beardslee et al. 2013; Brent et al. experimental approach used in psychodrama 2015). Primary prevention for an individual at risk based on individual therapy will be possible. This for depression might be an effective strategy to will help the depressed patient who will benefit reduce the socioeconomic burden of depression, from interpersonal therapy. considering that experiencing a single major Simple recall of a memory is not enough to depressive episode is associated with a 60% recur- cause reconsolidation-updating. Prediction error rence and that pharmacologic treatment only is an indispensable component. Reconsolidation- reduces recurrence by 10–30% (Hirschfeld 2001). updating occurs only when patients experience a In the future, face-to-face sessions would be different outcome than expected (Ecker et al. partially replaced with video calls (Corruble 2012). Psychoanalytic psychotherapy and et al. 2016; van der Vaart et al. 2014). This will cognitive-behavioral therapy utilize this factor. increase the accessibility of psychotherapy and Empiricism is based on a patient’s subjective combined therapy. Preferences of the clinician experience. Clinicians encourage patients to will- and patient, validation of effectiveness, and legal ingly experience repeated failures of their expec- and institutional issues remain to be resolved. tations about the self, others, and the environment. More studies validating their effectiveness com- Without these elements, psychotherapy would not pared to face-to-face treatment are needed (Bee differ from self-help books or psychoeducation. et al. 2008; Dagöö et al. 2014; Thorp et al. 2012; Watkins et al. 2016). 21.5 Maintenance Strategies 21.4.2.3 How to Maximize the Effect for Combined Therapy of Reconsolidation-Updating Accessing the process of recall requires waiting If patients respond well to combined therapy, it is until it appears naturally, although there are direct recommended they maintain the combined ther- interventions, such as psychodrama or exposure apy during the continuation phase. Combined during cognitive-behavioral therapy. Before the therapy showed a superior relapse-free ratio to formation of the therapeutic alliance, it is better to antidepressants alone and psychotherapy alone wait until patients autonomously engage in mem- (Oestergaard and Møldrup 2011; Reynolds et al. ory recollection. We wonder whether this strategy 1999). However, for patients who need mainte- is still the best if months or years have elapsed. nance treatment to prevent recurrence, it remains Assuming that reconsolidation-updating is an unclear which strategy is the best (Huijbers et al. active ingredient to achieve psychotherapeutic 2012). There are three maintenance options: anti- effectiveness, maximizing therapeutic compo- depressant maintenance, maintenance psycho- nents during each session will shorten treatment therapy, and slowly tapering antidepressants with duration and improve outcomes. Facilitating the psychotherapy maintenance. In the case of panic recollection of a maladaptive memory in the early disorder, CBT therapy combined with antide- half of a session will be helpful to utilize the pressants showed a worse relapse prevention 292 K.-Y. Choi and Y.-K. 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Jennifer Apolinário-Hagen and Christel Salewski

22.1 Introduction United States), and its occurrence throughout regional, sociodemographic, or economic back- Depression is one of the leading causes of chronic grounds (Kessler and Bromet 2013). According illness and disability worldwide (Gotink et al. to the Diagnostic and Statistical Manual (DSM) 2015; Kessler and Bromet 2013). World Health V (American Psychiatric Association; APA Organization (WHO) estimates accounted to 300 2013), MDD is characterized by depressed mood million people living with depression, with an or a loss of interest or pleasure in everyday activi- increase of 18% within the past decade (2005 to ties, with an unceasing or almost daily presence 2015). Consequently, “Depression: Let’s Talk” for 2 weeks or more, resulting in substantial psy- was chosen as the campaign motto of the WHO chological strain and impaired psychosocial, World Health Day 2017.1 The aim of this self- occupational, social, and educational functioning help campaign was to engage more persons with (Box 22.1). depression to seek and get help. According to the Global Burden of Disease Study 2015, the incidence rates for depressive disorders ranged from 2.9% (Solomon Islands) to 5.9% (Australia), Box 22.1: DSM V Symptoms of MDD with an estimation of 4.4% of the global popula- MDD diagnosis requires at least five of the tion suffering from depressive disorders (WHO following nine complaints: 2017). Among the different types of depressive disor- (1) Depressed or nervous mood ders, major depressive disorder (MDD) is an (2) Reduced interest or pleasure in most ongoing global burden because of the relatively activities high lifetime prevalence (e.g., 16.9% in the (3) Significant changes in weight or appetite, (4) sleep patterns, and/or (5) in psychomotor activity 1 WHO International (2017). Depression: Let’s Talk. Last (6) Emotional fatigue or loss of energy accessed on 10 April 2017 under http://www.who.int/ campaigns/world-health-day/2017/toolkit.pdf?ua=1. (7) Feelings of worthlessness and/or exces- Archived under http://www.webcitation.org/6plZia43b. sive or inappropriate guilt (8) Diminished concentration or increased indecisiveness J. Apolinário-Hagen (*) • C. Salewski Department of Health Psychology, Institute for (9) Thoughts, intentions, or plans related to Psychology, University of Hagen, Hagen, Germany suicidality e-mail: [email protected]

Treatment as usual (TAU) for MDD includes 22.2 Mindfulness-Based different types of antidepressant pharmacother- Cognitive Therapy apy and psychological interventions, such as cog- for Depression Relapse nitive behavior therapy (CBT). Considering Prevention potential side effects of antidepressants as the main reason for nonadherence in the longer-term Learning the skill of mindfulness (or awareness maintenance therapy and relapse prevention of at the present moment) is a key strategy in the recurrent MDD, psychological interventions have relapse prevention of MDD in MBCT (Box 22.2). been endorsed as noninvasive, effective alternative. Mindfulness-based cognitive therapy (MBCT) has been developed as specialized group program for the relapse prevention of MDD Box 22.2: Defining Mindfulness as Multi- (Teasdale et al. 2000; Segal et al. 2002). Systematic facet Construct in the Context of MBCT reviews and meta-analyses of randomized con- Mindfulness is widely defined as “…the trolled trials (RCTs) have confirmed MBCT as awareness that emerges through paying atten- effective compared to active and waiting list con- tion on purpose, in the present moment, and trol groups in face-to-face settings in persons with nonjudgmentally to the unfolding of experi- current or past depression (MacKenzie and ence moment by moment” (Kabat-Zinn Kocovski 2016). However, several drawbacks can 2003, p. 145). hamper the adherence to treatment or the longer- In addition to this definition, Bishop term maintenance of treatment effects, such as et al. (2004, p. 234) understand “… mind- perceived inflexibility of group programs or high fulness as a process or regulating attention time constraints when implementing mindfulness in order to bring a quality of nonelaborative practice into everyday routines (Kvillemo et al. awareness to current experience and a qual- 2016; Wahbeh et al. 2014). To overcome some of ity of relating to one’s experience within an the obstacles of face-to-face group-based MBCT, orientation of curiosity, experiential open- web-based mindfulness-based interventions have ness, and acceptance.” been suggested as suitable self-help options in the Concerning MBCT: “(1) Mindfulness adjunctive treatment and prevention of depression is a generic skill and so it can be praticised (Brown et al. 2016; Spijkerman et al. 2016). The on many aspects of experience in many interventions are delivered by computer, tablet, or situations (…) (2) (…). Mindfulness train- smartphone and, in the latter case, via mobile ing aims to make individuals fully aware health applications (mHealth apps). Due to the of their thoughts and feelings, from novelty of these developments, patients as well as moment to moment, whether those experi- health professionals require evidence-based rec- ences are pleasant, unpleasant, or neutral ommendations regarding the usefulness of web- (…) (3). The mindfulness state is charac- based mindfulness programs and apps. terised by direct experience of current To derive such recommendations for health reality in the moment, rather than elabora- professionals in practice and research, the tive, ruminative thinking about one’s situ- purpose of this chapter is to provide a short ation, and its origins, implications and overview of the evidence base on the efficacy associations. Mindfulness training appears of web-delivered MCBT self-help formats in to be associated with a reduction in the the prevention or prophylaxis of MDD relapse tendency to ‘float away’ into ruminative, in public health, based on the current state of elaborative thoughts throughout streams knowledge about traditional face-to-face (…)” (Teasdale et al. 1995, p. 34). MBCT. 22 Internet-Based Mindfulness-Based Cognitive Therapy for the Adjunctive Treatment of Major… 301

Mindfulness skills are taught in manualized tude toward oneself (Keng et al. 2011). In prac- 8-week group programs under supervision of an tice, however, many mindfulness programs expert instructor. Regarding the course contents, combine components of MBSR, MBCT, and mindfulness courses vary across three main orien- ACT. Nonetheless, each mindfulness program tations: mindfulness-based stress reduction starts from the premise that it is mandatory to (MBSR), mindfulness-based cognitive therapy develop and promote mindfulness systematically (MBCT), and acceptance and commitment ther- through regular practice in both the course group apy (ACT) (Kabat-Zinn 2003). In general, setting and in daily life (Kabat-Zinn 2003). mindfulness-based interventions aim to change Regarding therapeutic indications, MBCT the function and context of maladaptive inner pro- has a clear focus on MDD and related mental or cesses, such as negative feelings and automated somatic illnesses, whereas MBSR is applied to a thoughts (Hofmann et al. 2010; Kabat-Zinn 2003). broader spectrum of mental health conditions Grounded on mindfulness meditation practice and and populations (Cavanagh et al. 2014; Khoury tailored from Buddhist to Western culture, Kabat- et al. 2013). In some indications, such as bipolar Zinn developed MBSR as the first mindfulness- disorder, acute depression, and social phobia, based training for patients with chronic pain in the preliminary evidence suggested that MBCT late 1970s (Kabat-Zinn 2003). MBCT was devel- may be even more effective than TAU (Keng oped by Segal in the 1990s for depressive patients et al. 2011). Contraindications for MBCT as manualized 8-week group course (Strauss et al. involve persons who are not capable of or will- 2014; van der Velden et al. 2015). ing to attending group programs and persons MBCT was first termed by Teasdale et al. (1995) suffering from acute psychotic symptoms, sui- as attentional control (mindfulness) Training that cidality, or a current life crisis (Keng et al. 2011; was based on information-process ing analyses Meibert 2016). conducted to explain the mechanisms of action of Regarding its content and structure, MBCT cognitive therapy for effective prevention of MDD is designed as an 8-week group course, with a (see Teasdale et al. 1995). MBCT is based on both maximal number of 12–14 participants. Since the principles of MBSR and CBT (Segal et al. the first four of the eight modules of MBCT 2002, 2012). Although MBSR and MBCT share courses (i.e., lessons 1–4) are based on exer- their grounding and mediation exercises, their con- cises to learn mindfulness meditation in the tents, targeted health conditions, and populations course setting and daily life, the second four differ substantially. Since MBCT was designed as a (i.e., lessons 5–8) focus on the management of specific mindfulness intervention for the relapse future negative or depressed mood on the basis prevention of MDD (Teasdale et al. 2000), it is usu- of mindfulness (Meibert 2016). As mentioned ally provided in homogenous group settings con- above, MBCT usually consists of similar basic sisting of participants with similar health conditions training components as MBSR. These elements (Meibert 2016), which is different from MBSR. The can be differentiated in formal and informal aim of MBCT training is to learn and regulate con- mindfulness exercises. Formal mindfulness trast between attention in the autopilot mode and exercises include structured workouts like body mindfulness in daily activities (Teasdale et al. scan, sitting meditation, and mindfulness body 1995). Another derivate of MBSR and CBT is ACT work or yoga exercises. Mindfulness exercises that has been developed by Hayes et al. (2006). comprise a broad number of informal mindful- While MBSR scopes on mindfulness-based medi- ness practices aiming to bring awareness or tation practice, MBCT has an additional focus on “inner presence” to daily routines, such as CBT exercises for depression, and ACT puts breathing, eating, or walking. Informal exer- emphasis on experience-orientated techniques to cises can be easily applied in everyday life train self-acceptance and a nonjudgmental atti- (Meibert 2016). 302 J. Apolinário-Hagen and C. Salewski

22.3 Mechanisms of Change Intention in MBCT

To understand why and how MBCT works, Mindfulness mechanisms of change have been investigated to identify who is most likely to benefit from MBCT Attention Attitude (MacKenzie and Kocovski 2016). The theoretical model behind MBCT describes the impact of Fig. 22.1 The three axioms of mindfulness: intention, attention, and attitude. Adapted from Shapiro et al. (2006), cognitive vulnerability on repetitive automated, p. 375. According to Shapiro et al. (2006), these aspects negative thoughts in the relapse of MDD represent no separate stages; instead they are intercon- (MacKenzie and Kocovski 2016). According to nected aspects of a single cyclic process. They occur this cognitive vulnerability model, repeated auto- simultaneously. Mindfulness reflects this type of moment- to-moment process mated negative thoughts become associated with the depressed state. In turn, the number of depressive episodes increases the risk of depression (III) “in a particular way” (attitude toward mind- relapse through the easier reactivation of implicit fulness qualities) (Fig. 22.1). These aspects rep- response patterns (Teasdale et al. 1995). In line resent interconnected stages of a cyclic process with the diathesis-stress model, cognitive reactiv- that occur simultaneously. Mindfulness is ity or vulnerability to stress is crucial for the assumed to reflect this type of moment-to- onset, relapse, and recurrence of MDD symp- moment process. These components appear to be toms. Therefore, cognitive reactivity is a central relevant to understand mechanisms of change in concept in MBCT that explains the frequent MBCT. recurrence of MDD even after successful antide- Several predictors and mediators for the effec- pressant therapy—at least in persons who are tiveness of MBCT are discussed in the literature. For vulnerable during stressful situations (Scher et al. instance, in treatment-resistant MDD, Eisendrath 2005). Within the process of internal mainte- et al. (2011) identified four mediators for the effec- nance of depression, so-called depressogenetic tiveness of face-to-face MBCT: lower rumination, schematic models (cognitions that advance increased self-compassion, improved acceptance, depressive thoughts and feelings) are synthe- and reduced avoidance. These and other factors have sized. These emotional patterns of responses been investigated in several RCTs on the effective- result in the “establishment of self-perpetuating ness of traditional MBCT group formats. Other processing configuration that continue to regen- studies suggest that MCBT is most likely to be effec- erate depressogenetic schematic models” tive (in terms of reduced relapse risk) in patients with (Teasdale et al. 1995, p. 28). three or more previous depressive episodes, child- Bishop et al. (2004) assume that two pro- hood adversity (i.e., dysfunctional parenting), and cesses are involved in the training of mindful- earlier onset of the first MDD episode (Ma and ness: (1) regulation of mindfulness at the present Teasdale 2004). However, empirical evidence also moment and (2) orientation to the experience suggests that two or more previous episodes increase within daily activities. According to Shapiro the effectiveness of MBCT in the prevention of et al. (2006), further elements are vital, namely, MDD relapse (Clarke et al. 2015). intention to practice and attitudes that affect meditation practice. These authors also state that multiple mechanisms may enable behavior 22.4 Evidence Base for Face-to- changes in mindfulness interventions, namely, Face MBCT self-regulation, values clarification, cognitive behavioral flexibility, and exposure. They pro- In face-to-face settings, mindfulness-based inter- pose three axioms of mindfulness: (I) “on pur- ventions have been shown to be as effective as pose” (intention), (II) “paying attention,” and CBT in reducing depression, stress, and anxiety 22 Internet-Based Mindfulness-Based Cognitive Therapy for the Adjunctive Treatment of Major… 303 in different groups of patients (Hofmann et al. symptoms are most likely to benefit from 2010; Khoury et al. 2013, Khoury et al. 2015). A MBCT. In other words, more severe depressive systematic review by Fjorback et al. (2011) on symptoms at baseline were associated with larger five included reviews revealed that MBCT is effects of MBCT compared to other active treat- effective in the relapse prevention of MDD. There ments across RCTs (Kuyken et al. 2016). is also evidence that MBCT is as effective as Regarding mechanisms of change, a system- pharmacotherapy in the maintenance treatment atic review (Keng et al. 2011) identified increases of MDD (Clarke et al. 2015). Teasdale et al. in mindfulness, metacognitive awareness, accep- (2000) investigated the effectiveness of MCBT tance, and behavioral self-regulation as important (TAU provided by the family doctor versus TAU factors for the effectiveness of MBCT. In addi- plus MBCT training) in 145 patients with two tion, a systematic review (van der Velden et al. previous episodes of depression and found that 2015) on 23 studies identified that changes in TAU and MBCT were equally effective. mindfulness, rumination, worry, compassion, and Additionally, a first meta-analytic review by meta-awareness were associated (in some studies Strauss et al. (2014) on 12 RCTs targeting the with mediating effects) with improvements in effectiveness of MBIs in the relapse prevention depression-related outcomes. of MDD showed significant effects in terms of Regardless of these promising findings on reduced depressive symptom severity in patients MBCT efficacy, empirical evidence further indi- with current MDD. Another review on 15 RCTs cated that the therapeutic success of mindfulness- investigating mindfulness-based interventions based trainings depends on active participant (Cavanagh et al. 2014) identified small to medium engagement and regular exercises of acquired effect sizes for depression outcomes. According mindfulness techniques in daily life (Cavanagh to a systematic review of 23 reviews and meta- et al. 2013). Implementing mindfulness practice analyses (Gotink et al. 2015), data on 115 RCTs into daily life can be challenging for persons with with 8683 participants confirmed that both recurrent depressive episodes. A potential solu- MBCT and MBSR significantly improved tion to facilitate the access to mindfulness inter- depressive symptoms compared to TAU (i.e., ventions could be the provision of web-based help patients receive from a family doctor or mindfulness interventions for adults with mental other sources depressed patients usually seek health issues (Mak et al. 2015). help from) and waiting list control groups. In this review of reviews, three included reviews scoping on 17 RCTs on MBCT for depression (Chiesa 22.5 Internet-Based MBCT and Serretti 2011; Coelho et al. 2007; Piet and as Novel Strategy Hougaard 2011) positive, but not significantly higher effects of MBCT compared to TAU were Mindfulness-based and acceptance-based treat- identified. Moreover, in an individual patient data ments face a growing interest in patients and meta-analysis (Kuyken et al. 2016), the efficacy policy makers in general. There is also a recent of MBCT in the prevention of MDD relapse expansion of web-delivered mindfulness-based across ten included RCTs was confirmed. Patients interventions for depression (Brown et al. 2016). receiving MBCT showed a reduced risk of MDE Web-based mindfulness interventions have been relapse within a 60-week follow-up period com- suggested as a further opportunity to enlarge self- pared to the non-MBCT condition. Since there help options (Spijkerman et al. 2016). The were no significant interaction effects between Internet provides additional pathways for the dis- MBCT outcomes and individual characteristics semination of evidence-based mindfulness-based (sociodemographic and illness-related variables), interventions to a broader range of individuals at least some evidence was found for the assump- (Kvillemo et al. 2016). Potential key advantages tion that especially patients suffering from recur- of Internet-based mindfulness interventions rent depressives episodes or profound residual include the easy access and cost-effectiveness 304 J. Apolinário-Hagen and C. Salewski

(Brown et al. 2016). Preferred delivery modes of automated feedback via reminders or a system, interventions should therefore be considered in others provided professional guidance from a the treatment and the relapse prevention of trained psychologist or psychology graduate stu- MDD. In a survey by Wahbeh et al. (2014), the dents. Clinical support was mostly delivered via majority of the 500 respondents preferred the email or telephone and could include the person- Internet over traditional group courses as deliv- alized feedback on the progress or completion of ery mode for mindfulness interventions, because tasks, for instance, regarding tasks in an addi- web-based programs can be attended with more tional workbook targeting strategies to inform convenience than face-to-face group formats. about mindfulness skills and self-acceptance in Most of clinically tested web-based mindful- everyday life. Taken together, web-based mind- ness interventions follow the structure of 8-week fulness programs have become increasingly MBSR courses, and many provide at least a mini- interesting for healthcare, and thus health profes- mal professional support, including therapist sional should be informed about its chances and assistance, individualized feedback, or coaching risks for patients with recurrent MDD. (Spijkerman et al. 2016). Examples for such web- delivered mindfulness programs and apps are the “Mindfulness” app from Sweden (Ly et al. 2014), 22.6 Evidence Base for Internet- “Mindfulness online” from the United Kingdom Based MBCT (Krusche et al. 2013), “iMind” from China (Mak et al. 2017), or “Mindful Mood Balance” from In summary, preliminary evidence from RCTs North America (MMB, Boggs et al. 2014). An suggested that Internet-based mindfulness inter- example for a multicomponent nine-module pro- ventions such as MBCT are effective in depres- gram is “Deprexis” (Meyer et al. 2009) from sion treatment across different populations (Fish Germany. This program combines CBT with et al. 2016; Jayewardene et al. 2017; Spijkerman acceptance-based and mindfulness-based mod- et al. 2016). For instance, first evidence has dem- ules for the self-help treatment of mild to moder- onstrated that hybrid group online mindfulness ate depressive symptoms. “Deprexis” uses group programs with peer support are feasible behavioral activation, cognitive restructuring, alternatives to rather inconvenient and costly tra- mindfulness or acceptance, and social skill ditional group courses with expert teachers (see training. Kemper and Yun 2015). Most studies focused on Although 8 weeks is the standard duration nonclinical populations, but reported improve- time for MBSR and MBCT in face-to-face group ments in depressive symptoms after web-based formats, a review on 15 web-based mindfulness or app-based mindfulness-based interventions interventions has shown that their time span nonetheless (e.g., Ly et al. 2014). In addition, ranged from 2 to 12 weeks (Spijkerman et al. brief online mindfulness-based interventions 2016). According to a systematic review with ten (shorter than 7 weeks) have also proved to be RCTs on the efficacy of eHealth versions of effective in reducing depressive symptoms in mindfulness-based ACT programs for mood and nonclinical populations (e.g., Cavanagh et al. anxiety disorders (Brown et al. 2016), the 2013; Krusche et al. 2013; Mak et al. 2015). intended duration time of web-delivered ACT However, the number of RCTs on web-based programs ranged between 3 and 12 weeks. The mindfulness interventions is still small, and most number of sessions varied between 2 and 9 mod- interventions use mild to moderate depressive ules. Design features appeared to be associated symptoms and not relapse prevention of MDD as with engagement and adherence to a program. primary outcome. Often the scope is on MBCT Included web-based ACT interventions used dif- for nonclinical populations (e.g., Ly et al. 2014) ferent levels of mostly asynchronous communi- or on the effectiveness of other intervention types cation and clinical assistance: While some like ACT (e.g., Levin et al. 2014; Pots et al. interventions provided no human guidance or 2016; Wolever et al. 2012) or MBSR (Kvillemo 22 Internet-Based Mindfulness-Based Cognitive Therapy for the Adjunctive Treatment of Major… 305 et al. 2016; Mak et al. 2015) in nonclinical popu- ety, and distress ranged between 39.5% and 92% lations such as students and employees. One across programs with an intended course length exception is a qualitative study conducted by of 6–8 weeks. According to another systematic Boggs et al. (2014) on the web-based MBCT pro- review on web-delivered ACT interventions gram “Mindful Mood Balance” that proved to be (Brown et al. 2016) with 10 RCTs (n = 5 RCTs effective in reducing residual symptoms of MDD targeting depression), adherence rates ranged and was endorsed as suitable for relapse prophy- from 48 to 100% across included studies. laxis. A study (Meyer et al. 2009) on the program Improved adherence in guided interventions may “Deprexis” found significant improvements of imply that guidance is one or even the core com- current depressive symptoms at the 6-month fol- ponent of the effectiveness of web-delivered low-up assessment. Another web-based mindful- mindfulness interventions, but more research is ness intervention was also found to be effective needed to support this assumption (Brown et al. in reducing residual symptoms of MDD 2016; Spijkerman et al. 2016). In addition, stud- (Dimidjian et al. 2014). ies on web-based mindfulness interventions In addition to computerized programs, apps reveal severe differences in the construction, are a potential means to ease the implementation length, and delivery modes (Fish et al. 2016). of mindfulness practice in daily life and to match Finally, application-oriented issues like imple- habits and preferences of younger adults better mentation of web-based interventions into than traditional programs. Different smartphone healthcare settings need to be discussed more apps conveying MBCT and MBSR to depressed detailed. populations might also serve as useful self-help tools. In a study by Ly et al. (2014), an 8-week smartphone-delivered mindfulness app turned 22.7 Implementation of Internet- out to be as effective as a behavioral activation Based MBCT app in 40 middle-aged patients with symptoms of depression. This is an important finding because Currently, the process of disseminating and patient preferences to physical activity or mind- implementing web-based mindfulness-based fulness may differ. Thus, more options such as interventions successfully into public health set- different types of effective apps can be provided tings is a key challenge in this developing field. for patients with depression. Although mHealth Regarding the implementation into care, a meta- apps may provide an easily accessible delivery analytic review on the efficacy of mindfulness- mode for mindfulness interventions, the useful- based interventions in primary care (Demarzo ness of numerous services that are currently et al. 2015) with six trials suggests that the inter- freely available in app stores can be considered as ventions can be effectively provided in healthcare questionable. In line with a previous review and can help to improve mental health and qual- (Plaza et al. 2013), Mani et al. (2015) confirmed ity of life in patients. However, as a scoping in a systematic review of 23 iPhone apps a lack of review (Drozd et al. 2016) revealed, little atten- evidence for the content quality and usefulness of tion has been placed so far the (both successful the (mostly not evaluated) mindfulness apps to and unsuccessful) implementation of web-based develop mindfulness. Likewise, many apps mis- interventions for depressive disorders. leadingly suggested to target, but were only Different barriers and facilitators related to the guided, meditation apps, timers, or reminders. implementation of web-based intervention are Adherence rates vary largely across web- discussed (Hennemann et al. 2016). For instance, based mindfulness interventions. According to a in an 8-week web-based self-administered mind- systematic review by Spijkerman et al. (2016), fulness intervention using automated reminders adherence (i.e., completion of five or more les- from Sweden (Kvillemo et al. 2016), the pro- sons) for the 15 included RCTs on web-based gram’s anonymity and flexibility in terms of time mindfulness interventions for depression, anxi- and location were endorsed as advantageous 306 J. Apolinário-Hagen and C. Salewski

program features by the participating students. tions for different populations (Spijkerman et al. Positive attitude to mindfulness practice and per- 2016). In addition, most web-based interventions ceiving the program as helpful and meaningful report high attrition rates (e.g., Dimidjian et al. improved the likelihood for completion. In a 2014; Mak et al. 2015). It must also be considered qualitative study on the web-based MBCT pro- that several RCTs on MBCT involve limitations, gram “Mindful Mood Balance” for relapse pro- such as heterogeneous patient groups, publication phylaxis, participants’ comments indicated some bias, and a lack of studies on long-term effects other important topics, such as time management and follow-up periods (Fish et al. 2016; Gotink as challenge for program completion and home et al. 2015). Due to the lack of high-quality and practice of mindfulness and flexibility and longitudinal studies, more research is needed to reduced time commitment as benefits of the derive recommendations for the use of MBCT in Internet delivery mode (Boggs et al. 2014). Both different populations with past or current depres- less time commitment and more flexibility appear sive symptoms. Open questions include the clari- to be important benefits of brief web-based mind- fication of mechanisms of change and the fulness interventions. As some pilot studies have cost-effectiveness of MBCT programs in mental indicated, brief web-based mindfulness interven- healthcare (Gotink et al. 2015). Therefore, deter- tions (7 weeks or less) have been shown to be minants of the effectiveness or mechanisms of effective, although it should be noted that some change need to be explored for different delivery nonclinical prevention studies involved high modes of MBCT. There is a lack of mediation attrition rates (see Cavanagh et al. 2013; Kvillemo model analyses in the MBCT effectiveness et al. 2016; Mak et al. 2015, 2017). research literature to identify pathways of change in mindfulness interventions (Gu et al. 2015; Shapiro et al. 2006; van der Velden et al. 2015) 22.8 Implications for Practice that needs to be addressed in future studies. and Research Available evidence also suggests the need for research to determine effective motivational fea- Overall, the evidence base on the effectiveness tures in online self-help, such as the application of and acceptability of face-to-face MBCT group persuasive design (Kelders et al. 2012, 2013). formats in MDD relapse prevention is promising More studies using mixed methods, including in- (Fjorback et al. 2011; Hofmann et al. 2010; depth interviews and participatory approaches Khoury et al. 2013; Strauss et al. 2014). going beyond the exploration of the effectiveness, Mindfulness-based group interventions have are required to identify important features in web- proved to be effective as adjunctive treatment and based programs (Yardley et al. 2015). prevention options across different conditions, Theory-driven strategies are needed to generate populations, and primary care settings (Demarzo meaningful contents of motivational messages et al. 2015). Concerning the relapse prevention of based on health behavior change models and to MDD, regular home meditation practice can turn improve adherence in web-based mindfulness out as challenge for some patients (Crane et al. interventions subsequently (Mak et al. 2015). 2014). Thus, web-based interventions could be a However, poor eHealth literacy or e-awareness, convenient alternative for hard-to-reach popula- low technology acceptance, and negative attitudes tions such as young adults and males who are toward web-based self-help treatments can turn unlikely to attend face-to-face group courses out as obstacle to use such services (Hennemann (Jayewardene et al. 2017; Khoury et al. 2013, et al. 2016). To understand the conditions for an Khoury et al. 2015). effective dissemination of MBCT, differences in However, to date the evidence base for web- delivery modes as well as contextual and individ- based delivery of MBCT is still insufficient to ual factor need to be studied in more depth, espe- derive comprehensive or definitive conclusions on cially before implementing innovative strategies the helpfulness of online mindfulness interven- into primary care. It should also be considered 22 Internet-Based Mindfulness-Based Cognitive Therapy for the Adjunctive Treatment of Major… 307 that, outside of clinical trials, evidence-based web- Boggs JM, Beck A, Felder JN, Dimidjian S, Metcalf CA, based mindfulness interventions are currently Segal ZV. Web-based intervention in mindfulness meditation for reducing residual depressive symptoms inaccessible for the public in various countries and relapse prophylaxis: a qualitative study. J Med (Kvillemo et al. 2016). Furthermore, it should be Internet Res. 2014;16(3):e87. noted that the helpfulness of mindfulness apps Brown M, Glendenning A, Hoon AE, John A. Effectiveness remains unclear at present (Mani et al. 2015; Plaza of web-delivered acceptance and commitment therapy in relation to mental health and well-being: a system- et al. 2013). The role of system features like auto- atic review and meta-analysis. J Med Internet Res. mated reminders with regard to the effectiveness 2016;18(8):e221. of web-delivered mindfulness-based or accep- Cavanagh K, Strauss C, Cicconi F, Griffiths N, Wyper A, tance-based interventions appears still unclear Jones F. A randomised controlled trial of a brief online mindfulness-based intervention. Behav Res Ther. (Brown et al. 2016). Finally, there is an overall 2013;51(9):573–8. scarcity of RCTs on web-based mindfulness inter- Cavanagh K, Strauss C, Forder L, Jones F. Can mind- ventions in clinical populations (Fish et al. 2016). fulness and acceptance be learnt by self-help?: a Future studies should aim to fill these research systematic review and meta-analysis of mindfulness and acceptance-based self-help interventions. Clin gaps, especially in terms of web-based and app- Psychol Rev. 2014;34(2):118–29. delivered MBCT formats in different populations Chiesa A, Serretti A. Mindfulness based cogni- worldwide. Fish et al. (2016) recommended a tive therapy for psychiatric disorders: a system- number of components to standardization of mind- atic review and meta-analysis. Psychiatry Res. 2011;187(3):441–53. fulness interventions delivered by technology: Clarke K, Mayo-Wilson E, Kenny J, Pilling S. Can non- They should last at least 4 weeks, contain 30 min pharmacological interventions prevent relapse in adults of practice for 6 days per week, and use a different who have recovered from depression? 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Demarzo MMP, Montero-Marin J, Cuijpers P, et al. although data on the role of different factors such The efficacy of mindfulness-based interventions in as guidance and delivery modes is still not suffi- primary care: a meta-analytic review. Ann Family cient to derive definitive conclusions. To provide Med. 2015;13(6):573–82. support for informed decisions, health profes- Dimidjian S, Beck A, Felder JN, Boggs JM, Gallop R, Segal ZV. Web-based mindfulness-based cognitive sional can assist patients to find appropriate therapy for reducing residual depressive symptoms: mindfulness programs. However, several chal- an open trial and quasi-experimental comparison to lenges for the successful implementation of propensity score matched controls. Behav Res Ther. web-delivered MBCT programs remained open 2014;63:83–9. Drozd F, Vaskinn L, Bergsund HB, Haga SM, Slinning that need to be addressed in the future. K, Bjorkli CA. 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Karen Pilkington

23.1 Introduction out this disorder (Unützer et al. 2000). While over 50% of those with severe depression reported using Complementary and alternative medicine (CAM) CAM to treat their condition, less than 20% visited is the term used to describe a range of treatments, a CAM therapist, suggesting a high proportion of therapies and practices that are not considered self-diagnosis and self-treatment (Kessler et al. part of conventional medicine. These approaches 2001). In an Australian survey, participants reported are used alongside conventional treatment (com- using CAM less frequently than prescription medi- plementary use) or, in some cases, in place of this cations to treat depressive symptoms (Parslow and (alternative use). While certain practices and Jorm 2004). CAM users suffered from worse men- treatments are part of medical practice in some tal health including more depressive and anxiety countries, they may be classed as CAM in other symptoms than those who took neither CAM nor countries. For example, acupuncture traditionally prescribed medication. In Europe, 18% of people used in East Asian countries and widely used in with anxiety/depression consulted a CAM provider standard care is viewed as CAM in Western at least once in the previous 12 months, while 12% healthcare contexts. Similarly, views on practices had attended psychiatric outpatient services, and change over time so that herbal medicine, a part of 2.5% visited both (Hansen and Kristoffersen 2016). traditional medicine in many countries, is gener- Women and those with higher levels of education ally considered to be CAM in Western contexts. were more likely to visit CAM providers compared Nevertheless, the use of CAM is widespread. with men and those with lower educational achievement, but severity of depression did not predict extent of use. 23.2 Use of CAM for Depression Frequent use of CAM has also been identified in Asian populations although few studies have Surveys of CAM use have consistently revealed been published. A small survey of adult inpa- frequent use by those with depression. In a study in tients in Taiwan found that nearly 70% of those the United States (USA), people meeting the crite- with depression reported using at least one form ria for major depression were significantly more of CAM in the past 12 months (Hsu et al. 2008). likely to use alternative medicine than those with- Herbal medicines, spiritual healing and folk remedies were used most frequently, and mild to moderate depression was a stronger predictor of K. Pilkington use than severe depression. As is common with School of Health Sciences and Social Work, CAM, only 35% had discussed CAM use with University of Portsmouth, Portsmouth, UK e-mail: [email protected] their psychiatrist. CAM use, most frequently

© Springer Nature Singapore Pte Ltd. 2018 311 Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_23 312 K. Pilkington involving Chinese herbal medicines, was also because expectations of and preference for CAM reported by over 40% of a nationally representa- may influence results of clinical trials. tive sample of older adults in Singapore (Feng et al. 2010). Forty-five surveys of CAM use for depressive 23.4 Approach to the Literature disorders have been collated (Solomon and Adams 2015). Twenty-three studies were con- In the following sections, brief summaries are ducted in the United States, five in Australia and presented of the evidence from research on each at least one from each of 14 other countries. of the therapies. The focus is on providing an Prevalence varied significantly due to variation in overview of the ‘best available evidence’ which is study methodology, population and the definition primarily based on systematic reviews and ran- of CAM used. A wide range of therapies are domised controlled trials (RCTs). These were reported to be used for depression, but those that identified through searches of the Cochrane are self-directed including herbal medicine and Library including the Cochrane Database of dietary supplements were most prevalent. Other Systematic Reviews for ‘gold’ standard system- self-prescribed therapies that are sought include atic reviews, the Database of Abstracts of Reviews aromatherapy and mind-body approaches such as of Effects for quality appraised reviews and the meditation, relaxation and yoga. Therapies pro- Cochrane Central Register of Controlled Trials. In vided by practitioners such as acupuncture, addition, searches were carried out on PubMed. homeopathy, massage and Chinese medicine are Many trials use depression as an outcome mea- also popular (Solomon and Adams 2015). sure whether the condition being treated is psy- In general, typical CAM users appeared to be chological, physical or medical. In cases of 40–59 years of age with medium-level education comorbidity, it is possible that any effect on and a higher income and socioeconomic status than depression is indirect. For example, chronic pain non-users. Comorbidity is common with greater may be relieved by treatment and, thus, depres- perceived mental health needs than non-CAM users sion due to the pain may also be relieved. (Solomon and Adams 2015). Therefore, the focus in the summaries is on trials in depressive disorder as the primary condition. Those in which depression was measured as one 23.3 General Comments About of a whole range of outcomes, and where the main Research on CAM target for treatment was a medical or physical for Depression condition, were excluded. The therapies addressed include those most fre- Clinical trials of various forms of CAM have quently used or researched: acupuncture, aroma- been conducted, and these have been compared therapy and massage, dietary supplements, herbal with trials of antidepressants (Freeman et al. medicines, homeopathy, hypnotherapy, medita- 2010). Participants in CAM trials were more tion, relaxation, yoga and other mindful exercises. likely to be female and lower placebo response rates were seen compared with those in the antidepressant trials (Freeman et al. 2010). 23.5 Evidence on Specific Depression severity was, however, similar. For Therapies therapies that require considerable interaction between the practitioner and patient and where 23.5.1 Acupuncture placebo controls are not feasible, selection of appropriate control interventions is challenging. Acupuncture involves the stimulation of specific The fact that blinding in clinical trials is not pos- points of the body usually by inserting fine nee- sible for most complementary therapies is a point dles. Points may be stimulated manually or by of particular significance when assessing an out- the application of a small electric current (elec- come such as depression which is subjective and troacupuncture). The selection of points depends based on self-assessment. It is also relevant on a number of factors including the training and 23 Current Research on Complementary and Alternative Medicine (CAM) in the Treatment 313 background of the acupuncturist and the condi- inhaled, applied to the skin or used in combination tion being treated. There are two main approaches: with massage. In most cases, dilution of the oils is traditional Chinese and ‘Western’ or ‘medical’ required prior to use. Effects of aromatherapy are acupuncture. In traditional Chinese medicine, thought to be due to psychological responses to the acupuncture is often used in conjunction with odour and the effects of inhaled volatile compounds other therapies such as herbs. The diagnostic sys- on the limbic system (Cavanagh and Wilkinson tem is different from that used in conventional 2002). Few trials have been carried out into the medicine. Disease is considered to result from effects of essential oils in depression. One small imbalance of a vital force or energy known as study compared aromatherapy massage with mas- ‘qi’. Acupuncture points are considered to lie sage alone in 32 inpatients and outpatients at a UK along energy channels called meridians through hospital suffering from depression and/or anxiety which qi flows. In contrast, Western or medical (Lemon 2004). The oils were selected according to acupuncture is based on conventional anatomy physical and psychological symptoms. The control and physiology and often focused on pain relief. group received massage without the essential oils A large number of trials have been conducted of in an identical environment to the test group. acupuncture in depression, many of which have Aromatherapy massage was found to have greater been carried out in China. Thirty clinical trials are effects, but a lack of blinding may have influenced included in the Cochrane systematic review (Smith the results. Citrus fragrance by inhalation has also et al. 2010). Acupuncture delivered in the trials var- been investigated with positive results reported ied in terms of point selection, frequency of treat- (Komori et al. 1995) as has aromatherapy massage ments and total number of treatments administered. with oils including sweet orange, geranium and Most trials compared acupuncture with drug treat- basil (Okamoto et al. 2005). Both trials were small ment, and, consequently, there was a high risk of and uncontrolled so the findings can be considered bias due to lack of blinding. In addition, the quality preliminary at best. of reporting was poor with limited data on adverse The effects of inhalation aromatherapy have effects. Trials in post-stroke depression were been compared with aromatherapy massage. included, in which it is possible that stimulation Twelve RCTs were located, five involving inhaled had an effect on stroke-related dysfunction and, aromatherapy and seven massage aromatherapy thus, indirectly relieved depression. (Sánchez-Vidaña et al. 2017). Seven studies More recently, beneficial effects were reported showed improvement in depressive symptoms, but in a systematic review of acupuncture as an the study populations were varied and not all were adjunctive treatment based on the standardised depressed. Of those studies using aromatherapy mean difference (SMD) in scores on the 17-item inhalation, only two involved participants who Hamilton Rating Scale for Depression (HAMD) were actually depressed—one in cancer patients (−2.52; 95% CI, −4.12 to −0.92; p < 0.01) in and one in postnatal depression—and the results week 6 (Chan et al. 2015). The treatment was were contradictory. The trials focused on aroma- found to be well tolerated, but the lack of a pla- therapy massage involved diverse populations. cebo control means that the findings are not con- This, together with the varied administration clusive. The most recent review included 18 methods and outcome measures, complicated studies: 11 as monotherapy and 7 as adjunct interpretation. The authors concluded that the evi- treatment (Sorbero et al. 2016). As with previous dence on aromatherapy massage was stronger than reviews, interventions and comparators varied that for aromatherapy inhalation. and the evidence was judged to be weak and These findings suggest that it is the massage inconclusive. component from which those treated derive the most benefit. Four trials in depression or dysthymia were included in a systematic review of massage in 23.5.2 Aromatherapy and Massage depression (Coelho et al. 2008). In three trials, massage was compared with relaxation, but the Oils extracted from various parts of plants are used evidence was judged to be inconclusive. A subse- in aromatherapy. These ‘essential oils’ may be quent meta-analysis included 17 trials involving 314 K. Pilkington participants with differing conditions and ages Substantial heterogeneity was present, but the (Hou et al. 2010). Significant differences between evidence indicated a potential benefit of zinc sup- massage and control treatments were reported. plementation either as a stand-alone or adjunctive Trials were reported to be of moderate quality, but treatment. A subsequent trial illustrated the com- quality scores did not appear consistent with the plexity of interpreting the findings of such studies assessment tool used. This causes some uncertainty as baseline levels, intake of zinc and other nutri- as to the reliability of the conclusions. ents and antidepressants may all influence results (Ranjbar et al. 2013). Further research is needed to fully confirm the role of both minerals. 23.5.3 Dietary Supplements 23.5.3.3 5-HT (Hydroxytryptophan)/ Several vitamins and minerals and the dietary supple- Tryptophan ments, inositol, tryptophan and 5-hydroxytryptophan, Tryptophan, an amino acid and component of a omega-3 fatty acids, S-adenosylmethionine (SAMe) normal diet, is converted to 5-HT in the body and turmeric, have all been assessed as potential (Shaw et al. 2002). Tryptophan and 5-HT can treatments in depression. cross the blood-brain barrier where conversion to the neurotransmitter, serotonin, takes place. 23.5.3.1 Vitamins (Folate/Folic Acid/ Thus, there has been interest in a potential antide- Vitamin B9 and Vitamin D) pressant effect. A large number of trials were A Cochrane review based on three RCTs, two of located for a Cochrane review in 2002, but only which assessed folate as an adjunctive treatment, two (64 participants) were of sufficient quality concluded that the ‘limited available evidence for inclusion (Shaw et al. 2002). Very little subse- suggests folate may have a potential role as a sup- quent research activity has taken place, possibly plement to other treatment for depression’ (Taylor because of an outbreak of eosinophilia-myalgia et al. 2003). There was insufficient evidence to syndrome linked to the supplement but which confirm whether this was true for those with nor- was subsequently found to be due to contami- mal levels and with folate deficiency. Few trials nated batches of L-tryptophan. have been published subsequently, but a subsequent meta-analysis reported a non-significant 23.5.3.4 Inositol difference from placebo (Sarris et al. 2016). Inositol, a naturally occurring isomer of glucose, Vitamin D deficiency has been associated with is consumed in many foods but is also available depression, but several systematic reviews of its as a dietary supplement. It is involved in cell sig- therapeutic use have produced mixed conclusions. nalling via neurotransmitters including serotonin The most recent review focused specifically on (Taylor et al. 2004). The Cochrane review in adjunctive use and, based on two trials, suggested 2004, which included four short-term trials with there was supportive evidence for the use of vita- a total of 141 participants, did not show ‘clear min D with antidepressants (Sarris et al. 2016). As evidence of a therapeutic benefit’. Little research with folate, it is unclear whether this is true regard- interest has been shown subsequently. less of physiological levels in the body. 23.5.3.5 Omega-3 Fatty Acids (n-3 23.5.3.2 Minerals (Magnesium Polyunsaturated Fatty Acids) and Zinc) An increasing prevalence of depressive disorders While there have been investigations into a pos- combined with reduced dietary intake of omega-3 sible correlation between magnesium levels and/ fatty acids suggested a possible link between the or intake and depressive disorders (e.g. Yary two (Appleton et al. 2015). Consequently, large et al. 2016), only zinc has undergone a series of numbers of trials of omega-3 fatty acids have clinical trials for depressive disorders. Four small been conducted. Twenty-six trials, of which 25 trials examined the effects of zinc supplementa- (1438 participants) were placebo controlled, were tion on depressive symptoms (Lai et al. 2012). included in a Cochrane review (Appleton et al. 23 Current Research on Complementary and Alternative Medicine (CAM) in the Treatment 315

2015). A ‘small-to-modest’ benefit was shown for found in Europe and Asia, it is widely used in the supplement, but the evidence was judged to be Europe and prescribed in countries such as very low quality. Additionally, the effect did not Germany. Extracts of the plant, a member of the appear to be clinically significant as the difference Hypericaceae family, have been shown to contain was equivalent to 2.1 points on the Hamilton constituents with actions relevant to depression. Rating Scale for Depression with a 95% confi- Reuptake of several neurotransmitters including dence interval of 0.7–3.5. Thus, as with other serotonin, dopamine and gamma-aminobutyric supplements, further research was recommended acid (GABA) is inhibited by extracts and specifi- to fully assess effects, both positive and negative. cally by one constituent, hyperforin (Russo et al. Other reviews have, however, provided more pos- 2014). However, clinical efficacy has also been itive interpretations (e.g. Sarris et al. 2016). reported when hyperforin is absent (Schrader 2000), and a single mechanism of action has not 23.5.3.6 SAMe (S-Adenosylmethionine) been determined. SAMe is an active cofactor of methylation Thirty-seven trials were included in a involved in the synthesis and metabolism of neu- Cochrane systematic review (Linde et al. 2005). rotransmitters (Galizia et al. 2016). It is synthe- Subsequently, the inclusion criteria were adjusted sised from adenosine triphosphate and the amino resulting in the exclusion of nearly half of these acid, methionine. It is in clinical use in some trials when the review was updated 3 years later. European countries and available as a dietary The current version includes 29 trials involving a supplement in others. A Cochrane review in 2016 total of 5489 patients (Linde et al. 2008). included eight trials of SAMe as monotherapy or Hypericum has been compared with placebo and as add-on therapy to SSRIs. No differences were standard antidepressants and shown to have mod- found between SAMe and placebo or antidepres- est effects over placebo and comparable effects to sants, and based on the absence of high-quality antidepressants with fewer adverse effects. Most evidence, it was not possible to draw firm conclu- trials (19) addressed mild to moderate rather sions as to its effectiveness. severe depression, but few included long-term follow-up with a maximum duration of 12 weeks. While rigorously conducted, the review revealed 23.5.4 Herbal Medicine marked heterogeneity between placebo- controlled trials and more favourable findings in Various plant-based treatments have been used as trials from German-speaking countries. The lat- part of traditional medicine on a global basis and ter was not readily explained and thus compli- over millennia. Several of these have been investi- cated the interpretation of the findings. gated for measurable effects in depression based Subsequent systematic reviews have reported on reported psychopharmacological actions such similar findings: a meta-analysis of 27 trials as inhibition of monoamine reuptake and break- (3808 patients) comparing hypericum with selec- down, effects on serotonin receptors and tive serotonin reuptake inhibitors (SSRIs) found GABAergic effects (Sarris et al. 2011). Those that comparable response and remission rates and a have received particular attention include Crocus lower rate of discontinuation with hypericum (Ng sativus (saffron), Echium amoenum (borage), et al. 2017). Evidence on long-term outcomes Hypericum perforatum (St John’s wort), and in severe depression was still insufficient. A Lavandula angustifolia (lavender), Panax ginseng systematic review including 35 studies and 6993 and Rhodiola rosea (roseroot). patients also reached similar conclusions (Apaydin et al. 2016). Systematic differences 23.5.4.1 Hypericum perforatum were not found in outcomes based on the extract (St John’s Wort) used, and an extract containing 0.3% hypericin One herb that has generated a significant amount and 1–4% hyperforin was used in the highest of research attention is Hypericum perforatum number of trials. Economic evaluation indicates (St John’s wort). A small, herbaceous perennial that it is a cost-effective option (Solomon et al. 316 K. Pilkington

2013). Hypericum extracts, however, have an depression. To date there has only been limited effect on the cytochrome P450 system, inducing research. A small, preliminary RCT found tinc- metabolism and, hence, reducing the plasma lev- ture prepared from lavender flowers to be less els of a wide range of clinically important drugs effective than imipramine in the treatment of (Henderson et al. 2002). Concerns regarding mild to moderate depression although patients in potential interactions have affected recommenda- both groups improved from baseline tions on use in some countries. (Akhondzadeh et al. 2003). A combination of imipramine and tincture was more effective than 23.5.4.2 Crocus sativus (Saffron) imipramine alone (P < 0.0001) possibly due to a Saffron, the dried stigma from Crocus sativus, synergistic effect or a result of the lack of blind- has been used in many cultures as a spice and ing. Lavender oil capsules have been tested more medicine. Many medicinal properties including recently: eight patients with major depressive serotonergic and hypothalamus-pituitary-adrenal disorder and symptoms of anxiety, insomnia and (HPA) axis-modulating effects have been psychomotor agitation were included in a case observed. The dried stigmas have been used in series (Fißler and Quante 2014). Six cases clinical trials as have a less expensive product, responded to a combination of lavender and anti- the dried petals. Lopresti and Drummond (2014) depressant. An oral form of lavender was also identified six trials, two placebo-controlled and tested against placebo in mixed anxiety and four versus antidepressants, while the meta- depression (Kasper et al. 2016). The trial analysis by Hausenblas et al. (2013) included five recruited 318 adult outpatients based on ICD-10 trials. Both came to positive conclusions: ‘initial criteria. Significantly greater reductions in anxi- support for the use of saffron for the treatment of ety and depression were recorded with lavender. mild-to-moderate depression’ (Lopresti and Further replication is needed to confirm these Drummond 2014) and ‘saffron may improve the findings. symptoms and the effects of depression’ (Hausenblas et al. 2013). A series of clinical tri- 23.5.4.5 Panax ginseng (Asian, als has followed all conducted by research teams Chinese, Korean Ginseng) in Iran and investigating different patient popula- Ginseng, traditionally used in Asia for a range of tions. The small sample size of many has been medical conditions, was tested as an adjuvant identified as a limitation with recommendations treatment for women with residual depression for large, well-powered trials to confirm results. symptoms. After 8 weeks, reduced depressive symptoms were reported, but, as no control group 23.5.4.3 Echium amoenum (Borage) was included, it is not clear whether the improve- Dried flowers from this plant are used in Iran to ment was due solely to the herbal treatment make a tea for use as an anxiolytic and mood (Jeong et al. 2015). enhancer (Sayyah et al. 2006). A preliminary, randomised, placebo-controlled trial (35 patients 23.5.4.6 Rhodiola rosea (Roseroot or with mild to moderate depression) suggested Goldenroot) some beneficial effects after 4 weeks in reducing Rhodiola has traditionally been used in Russia depression symptoms. However, the effects were and Scandinavia for various indications includ- not maintained at 6 weeks. Further studies con- ing depression and fatigue (Dwyer et al. 2011). firming these findings are not available. Two RCTs investigated the effects of rhodiola in depression. Both were three-arm trials: one com- 23.5.4.4 Lavandula angustifolia pared two different doses of a standardised Miller (Lavender) extract of rhodiola rhizome against placebo Lavender is widely promoted for use in insomnia, (Darbinyan et al. 2007), and the other compared but other uses have been investigated. In particu- rhodiola with sertraline and placebo (Mao et al. lar, there had been interest in lavender used orally 2015). According to the first trial, rhodiola perfor major depression and mixed anxiety and formed significantly better than placebo in reduc- 23 Current Research on Complementary and Alternative Medicine (CAM) in the Treatment 317 ing mild to moderate depression after 6 weeks of and Pilkington 2013). Positive results were treatment. Improvements in insomnia, emotional reported including no significant differences instability and somatisation were also reported. compared with medication, greater effect than In contrast, the second trial demonstrated modest medication or placebo and reduction in adverse but non-significant reductions in depression event rates when used as additive therapy. scores with no significant differences between Limitations in reporting and in methodology, and groups. Both trials were blinded, but different differing formulae and control interventions, pre- antidepressants were used, and the second trial vented any reliable conclusions being presented. was not powered to detect small differences A subsequent review attempted to assess which between groups which may explain the contrast- herbal formulae were most frequently used for ing results. Less adverse effects were reported the ‘patterns’ matching a diagnosis of depression with rhodiola leading the researchers to conclude (Yeung et al. 2015). This confirmed that Xiaoyao that, though less effective than sertraline, rhodi- decoction and Chaihu Shugan were the two for- ola may provide a better risk-to-benefit ratio in mulae most frequently used, while Bai Shao mild to moderate depression. (Paeonia lactiflora Pall.) and Chai Hu (Bupleurum chinense DC.) were the most commonly used 23.5.4.7 Curcuma longa (Turmeric) individual herbs. The rationale underlying herb Turmeric, a member of the ginger family, is a selection was seldom provided, and comparative commonly used spice containing curcuminoids efficacy could not be assessed due to the small which are yellow chemicals used as food colou- number of good-quality studies. rants. Used in Indian Ayurvedic medicine for various health conditions, curcumin had been reported to increase serotonin and dopamine lev- 23.5.5 Homeopathy els while inhibiting monoamine oxidase enzymes (Kulkarni et al. 2008). Several clinical trials fol- Homeopathy is a system of medicine based on lowed which were collated in a systematic review the principle of similia similibus curentur or ‘let (Al-Karawi 2016). Trials originated from several like be treated by like’. Homeopathic remedies countries and treatment was for a maximum of 8 are prepared from various substances—animal, weeks. Reduction in depression was seen in com- mineral and plant derived—in extremely dilute parison with placebo. Statistically significant dif- (ultramolecular) solutions. Interventions investi- ferences between curcumin and placebo were gated in clinical trials of homeopathy may involve also reported in the second meta-analysis (Ng the whole system including a consultation with et al. 2017). The clinical significance is not prescription of individualised remedies or involve entirely clear. only the remedies. Few RCTs have been carried out on homeopathy or homeopathic remedies for 23.5.4.8 Chinese Herbal Medicine depressive disorders (Pilkington et al. 2005). The ‘herbs’ used in traditional medical systems in While uncontrolled and observational studies Asia, such as Chinese herbal medicine, include have reported positive results including high lev- animal and mineral substances in additional to els of patient satisfaction and response, these those sourced from plants. These are usually used results have not been replicated in rigorous RCTs. in various combinations (or formulae) which are One trial in Brazil involving 91 outpatients with prescribed on an individual basis based on diag- DSM-IV diagnosis of moderate to severe depres- nostic ‘patterns’. Certain formulae have been sion reported non-inferiority of individualised promoted at being particularly suitable for homeopathy compared with fluoxetine (Adler depression, one of which Xiao Yao San and a et al. 2011). Further investigation of these modification of this, Free and Easy Wanderer reported results in Europe was not successful. Plus. An overview of the evidence on Chinese The aim was to assess the specific clinical benefit medicine for depression found that most clinical of the homeopathic consultation in addition to research had focused on these formulae (Butler that of homeopathic remedies in depression 318 K. Pilkington

(Adler et al. 2013). Recruitment problems were wave’ cognitive and behavioural therapies widely encountered with only 44 from 228 planned used in the treatment of psychological problems patients randomised. Thus the trial was under- (Churchill et al. 2013). Evidence of its effects in powered, and no consistent or clinically relevant acute depressive episodes is still required. results were observed for comparisons between homeopathic remedies and placebo or between homeopathic and conventional consultations. 23.5.8 Relaxation Therapies

Progressive muscle relaxation, relaxation imag- 23.5.6 Hypnosis/Hypnotherapy ery and autogenic training are all forms of relaxation therapy. Fifteen trials involving people Hypnosis has received relatively limited attention diagnosed with depression or symptoms of in terms of research on its effects in depressive depression were analysed and collated for a disorders. A review of the research included six Cochrane review (Jorm et al. 2008). These tech- trials (258 participants) (Shih et al. 2009). The niques were found to be more effective than no or control conditions were not reported and all trials minimal treatment, but only when symptoms were categorised as poor quality. Considerable were self-rated: effects based on clinician ratings heterogeneity was apparent in the participants were less conclusive. (cancer patients, postnatal women, students and volunteers) and interventions. Thus, the authors’ conclusion that hypnosis ‘appears to be a viable 23.5.9 Yoga nonpharmacologic intervention for depression’ appears to be premature. Yoga, a traditional Indian practice comprising spiritual, moral and physical practices, became popular in the West in the 1960s. Yoga, as prac- 23.5.7 Meditation and Mindfulness tised in the West, generally involves the asanas (postures and stretches), breathing techniques and Meditation refers to practices that involve training meditation. The practice is intended to improve and regulating the attention and encompasses a physical aspects such as flexibility, strength and range of practices including concentrative meth- balance while also helping to focus the mind. ods, transcendental meditation and mindfulness Effects on the autonomic nervous system and techniques. While little research exists on prac- relaxation response are proposed as the main tices such as transcendental meditation, there has mechanisms of action (Riley 2004). The clinical been considerable clinical and research interest in research on yoga for depression was first reviewed mindfulness techniques. This is confirmed by a in 2005, at which point five RCTs (n = 183) were review in 2015 which identified 18 studies relat- identified (Pilkington et al. 2005). Further research ing to 7 distinct techniques of which mindfulness- was recommended and, by 2013, 12 RCTs were based cognitive therapy (MBCT) comprised the located (n = 619) (Cramer et al. 2013). These largest proportion of studies (Jain et al. 2015). In included patients with depressive disorders and fact, the other studies included in this review rep- those with raised levels of depression. Moderate resented meditation as part of practices such as evidence was found for short-term effects of yoga yoga and tai chi, and only one trial was of medita- compared to usual care but limited evidence com- tion per se. Mindfulness when combined with pared to relaxation and aerobic exercise. Data on cognitive behavioural therapy as MBCT has been long-term and adverse effects were insufficient for the subject of a large number of rigorous RCTs analysis although a review of safety indicates that prompted by a trial in 2000 reporting successful exercise is similar in this respect to usual care and prevention of recurrence/relapse (Teasdale et al. exercise (Cramer et al. 2015). When trials were 2000). It is currently seen as one of the ‘third restricted to those diagnosed with major depres- 23 Current Research on Complementary and Alternative Medicine (CAM) in the Treatment 319 sive disorder, no differences were found in the series of systematic reviews have been pub- short term between yoga and aerobic exercise and lished on each, but conclusions vary, possibly antidepressants (Cramer et al. 2017). The risk of due to differences in inclusion criteria. For bias was unclear for the majority of trials, but there example, one review concluded qigong was some evidence of effects beyond placebo and appeared beneficial in reducing depressive comparable to standard treatments. symptom severity (Liu et al. 2015), while another reported inconclusive results (Oh et al. 2013). Both included two trials in 23.5.10 Qigong and Tai Chi depressive disorder. A summary of key results from all the rele- Other mindful forms of exercise that have vant Cochrane reviews is presented in generated interest are qigong and tai chi. A Table 23.1.

Table 23.1 Cochrane reviews of complementary and alternative (CAM) for depression Results of meta-analysis No. trials (no. (SMD [95%CI] unless Author, year Therapy patients) Main comparisons stated) Smith 2010 Acupuncture 1–3 Manual vs Non-significant (NS) (41–175) • Wait list control differences except for wait • Sham acupuncture list control −0.73 • Non-specific [−1.18, –0.29] acupuncture SSRIs (add-on) −1.06 • Amitriptyline [−1.69, −0.43] • SSRI (monotherapy) • SSRI (add-on) 1–6 Electroacupuncture vs NS except for SSRIs (add (42–853) • Amitriptyline on) −0.70 [−1.32, −0.07] • SSRIs (monotherapy) • SSRI (add-on) 1 (26) Laser acupuncture vs sham MD −7.3 [−12.68, −1.92] Taylor 2003 Folate 2 (151) Placebo (add-on) MD −2.65 [−0.38, −4.93] 1 (96) Trazodone – Taylor 2004 Inositol 1 (28) Placebo (monotherapy) −0.71 [−1.48, 0.06] 3 (85) Placebo (add-on) 0.12 [−0.31, 0.55] Appleton Omega-3 fatty acids 25 (1373) Placebo −0.30 [−0.10, −0.50] 2015 1 (40) Fluoxetine – Joyce 2015 Reiki 2 (84) Wait list control – 1 (40) Relaxation – Jorm 2008 Relaxation 5 (136) Wait list, minimal or no −0.59 [−0.94, −0.24] treatment 9 (286) Psychological (CBT) 0.38 [0.14, 0.62] Galizia 2016 S-Adenosylmethionine 2 (142) Placebo (monotherapy) −0.54 [−1.54, 0.46] 4 (619) Imipramine −0.04 [−0.34, 0.27] 1 (129) Escitalopram MD 0.12 [−2.75, 2.99] 1 (73) Placebo (add-on) MD −3.90 [−6.93, −0.87] Linde 2008 St John’s wort 18 (3064) Placebo RR 1.48 [1.23, 1.77] 17 (2810) Antidepressants RR 1.01 [0.93, 1.09] Shaw 2002 Tryptophan and 2 (46) Placebo OR 4.10 [1.28, 13.15] 5-hydroxytryptophan 320 K. Pilkington

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A Biological markers, 36, 44, 54, 56–61, 69, 113, Acceptance and commitment therapy (ACT), 172, 291, 119, 165, 239 305, 308, 309 Biological mechanism, 36, 113, 114, 177, 216 Acupuncture, 315–317, 324 Biological rhythms, 124 Adiponectin, 209, 212 Biomarkers, 31, 35, 53, 56–62, 69, 70, 72, 73, 76, 77, 83, Adrenaline, 127, 145, 167, 168, 229, 239 90, 99, 101, 115, 116, 184, 214, 216, 233, 246 Aggressiveness, 125, 144 Bipolar disorder (BD), 4, 9, 15, 17, 24, 54, 56, 69, 74, Agomelatine, 108, 117, 127, 128, 133, 135, 228 93, 102, 124, 128, 130, 131, 133, 135, 245, Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 256–262, 268, 269, 305 acid (AMPA), 146, 167, 245, 248 BLT, see Bright light therapy (BLT) Amisulpride, 244, 258, 259, 263 Borderline personality disorder, 7, 8, 17, 143 Amygdala, 18, 19, 38–40, 57, 60, 61, 71–77, 102, 109, Brain-derived neurotrophic factor (BDNF), 19, 21, 26, 156, 157, 167–169, 213, 215, 293 36, 39, 40, 58, 61, 76, 90, 165–167, 199, 213, Amyloid positron emission tomography, 157, 158, 160 215, 247, 289, 293 Anhedonia, 35, 36, 75, 99, 101–109, 168, 169, 178, 179, Brexpiprazole, 26, 28, 259, 263 182, 193, 194, 210, 228, 231, 269 Bright light therapy (BLT), 124–126, 128–130, 133–135 Anticipation, 99–102, 105, 106, 109, 169, 288 Burnout, 189–200 Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS), 104 Antidepressant, 7, 17, 38, 55, 74, 107, 123, 144, 159, C 167, 177, 210, 227, 239, 256, 267, 287, 304, Cancer, 133, 166, 179, 182, 184, 258, 317, 322 316 Cariprazine, 26, 259, 263 Antioxidants, 26, 180, 215, 216, 247, 248 Carolina Premenstrual Assessment Scoring System Antipsychotics, 26–29, 31, 160, 244 (C-PASS), 5 Apathy Evaluation Scale (AES), 108 CBT, see Cognitive behavioural therapy (CBT) Aquaporin-4, 59 CBT-I, see Cognitive behavioral therapy for insomnia Aripiprazole, 26, 28, 29, 244, 256, 257, 259, 263 (CBT-I) Aromatherapy, 316–318 Cerebrovascular disease (CVD), 183 Assessment, 8, 10, 39, 54, 56, 103–107, 130, 153, 172, Cerebrovascular risk factors, 159 181, 182, 184, 185, 190–193, 197, 267, 318 Chapman Social Anhedonia Scale (CSAS), 104 Atypical antipsychotics, 26, 27, 30, 160, 244, 256–263 Chronic obstructive pulmonary disease (COPD), 183, Autoimmune disorders, 179–182 184 Chronic pain, 133, 165–172, 184, 268, 305, 316 Chronic renal failure (CRF), 60, 183 B antagonists, 245 Basal ganglia, 38, 60, 74, 169 Chronic stress, 24, 38, 39, 127, 177, 178, 210, 228, BDNF, see Brain-derived neurotrophic factor 230–232 (BDNF) Chronobiology, 135 Behavioral activation therapy (BA), 291 Chronotherapy, 134 Bereavement, 3, 6, 55, 61 Cingulate cortex, 58, 60, 61, 74, 157, 158

Cingulotomy, 76 Dimensional Anhedonia Rating Scale (DARS), 105 Circadian rhythms, 41, 115, 123, 124, 126, 128–134, 181 Dimensional ratings, 55–56 Classification, 9, 10, 15, 30, 53–56, 69, 72, 75, 77, 178 Dopamine, 21, 26, 27, 37, 38, 53, 57, 58, 61, 73, Clinical trials, 76, 77, 217, 233, 241, 244, 246, 258–260, 101–103, 106–109, 116, 117, 126, 127, 147, 270, 275, 276, 278, 280, 288, 311, 316–318, 165, 166, 169, 211, 213, 215, 239, 256–260, 320, 321, 324 268, 319, 321 CLOCK genes, 114 Dorsal prefrontal cortex, 57, 102 Clozapine, 26, 256, 257, 259, 260, 263 Drug development, 233, 245 Cognition, 9, 35, 36, 42, 71, 72, 102, 154, 159, 180, DST, see Dexamethasone suppression test (DST) 213, 241, 281, 306 DTI, see Diffusion tensor imaging (DTI) Cognitive behavioral social rhythm therapy Duloxetine, 117, 169–171 (CBSRT), 118 Dysthymic disorder, 3, 5, 6 Cognitive behavioral therapy for insomnia (CBT-I), 118, 119, 132, 133, 135, 294 Cognitive behavioural therapy (CBT), 29, 73–77, E 131–133, 185, 287, 295, 304–306, 322 Early-onset depression (EOD), 155, 160 Cognitive biological model, 156–157 Echium amoenum (Borage), 320 Cognitive impairment, 54, 145, 153–160, 180, 182–184, Effort, 16, 18, 61, 83, 84, 99, 100, 102–105, 107, 109, 278, 281, 283 200, 227, 239, 245, 269, 290, 294, 324 Cognitive rigidity, 144, 145, 147 eHealth, 308, 310 Cognitive therapy, 290 Electroconvulsive therapy (ECT), 8, 17, 185, 268–271, Combined therapy, 247, 287–290, 292–296 275–277, 280, 281, 283, 284, 289 Comorbidity, 6, 15, 17, 23, 24, 54, 113, 116, 130, Electroencephalography (EEG), 42–44, 114, 116, 144, 147, 165, 168, 169, 184, 267, 268, 118, 278 277, 279, 316 Emotion recognition, 84, 85, 93 Complementary and alternative medicine (CAM), Endocrine, 59–61, 168, 178, 184, 199, 209 315–324 Endocrine disorders, 180–182 Complementary therapies, 316 Endophenotypes, 36, 37 Congestive heart failure, 182, 278 Etiology, 3, 6, 16, 18–22, 36, 58, 59, 114, 116, 165, 181, Connexin 43, 59 193, 194, 232 Consortium for Reliability and Reproducibility Expectation, 72, 99, 100, 102, 106, 172, 190, 191, 194, (CoRR), 77 228, 230, 288, 290, 295, 316, 324 Construct proliferation, 200 Exposure and response prevention (ERP) therapy, 291 Cortico-limbic structures, 53, 61 C-reactive protein (CRP), 22, 42, 59, 213, 214, 246, 268 Crocus sativus, 319, 320 F Cytokines, 22–24, 36, 42, 59, 146, 165, 166, 178, Fawcett-Clark Pleasure Capacity Scale 213–215, 246 (FCPCS), 103, 104 FDA, see Food and Drug Administration (FDA) Feedback integration, 100, 107 D Fibroblast growth factor (FGF), 58, 59, 61

Deep brain stimulation (DBS), 76, 108, 109, 270, 271, 5-HT3 receptors (5-HT3Rs), 241–243 275, 276, 282–284 5-HT4 receptors (5-HT4Rs), 243 Dementia, 35, 93, 181, 183, 184 5-HT6 receptors (5-HT6Rs), 244 Depressed brain, 72–74, 76 FKBP5, 41, 42 Depression, 3–10, 15, 35–51, 53, 83, 113–119, 123–135, Food and Drug Administration (FDA), 26, 28, 30, 31, 143, 153, 165, 177–185, 189, 205, 227, 256, 257, 260 239–248, 256, 267, 287, 303, 315 Functional connectivity, 43, 61, 75, 76, 102, 156 Depressive disorders, 3, 38, 72, 113, 143, 171, 194, Functional magnetic resonance imaging (fMRI), 19, 60, 227–234, 275, 316 61, 71, 72, 74–77, 84, 153, 156, 169 Deprexis, 308, 309 Fundamental frequency, 83 Dexamethasone suppression test (DST), 41, 145, 268 non-suppression, 146 Diagnosis, 4–6, 10, 16, 36, 37, 40, 44, 53, 69, 70, 72, 77, G

83–93, 99, 116, 148, 155, 157, 181, 183, 184, GABAA agonists, 248 192, 193, 198, 303, 321 GABAB antagonists, 248 Diagnostic and Statistical Manual of Mental Disorders, Gabapentin, 160, 170 fifth edition (DSM-5), 3, 54, 61, 143, 192, γ-aminobutyric acid (GABA), 39, 53, 57, 61, 102, 243, 227, 256 245, 319 Dietary supplements, 316, 318, 319 Generalized anxiety disorder (GAD), 5, 7, 9 Diffusion tensor imaging (DTI), 60, 71, 72, 75 Gene set, 19, 20 Index 325

Genetics, 6, 148, 229 L Genetic variants, 41 Late-onset depression (LOD), 155, 158 Gene x environment diseases, 15 Lavandula angustifolia Miller (Lavender), 320 Glial cell, 59, 146, 215 Leptin, 60, 208–212, 214, 216 Glial cell line-derived neurotrophic factor Leptin hypothesis of depression, 211 (GDNF), 40, 59 Light therapy, 114, 118, 119, 125, 129, 133, 134 Glial fibrillary acidic protein (GFAP), 59 Lurasidone, 7, 244, 256, 260, 263 Glucocorticoid, 38, 41, 42, 60, 165, 177, 178, 181, 208–211, 215, 216, 229, 245, 246 Glutamate, 27, 38, 39, 53, 57, 58, 61, 102, 114, 165, 167, M 178, 215, 245, 268 Magnetic resonance imaging (MRI), 60, 70–72, 74, 76, Glutathione (GSH), 216 159, 282 Magnetic seizure therapy (MST), 271, 275, 276, 281, 282, 284 H Major depressive disorder (MDD), 4, 15–36, 42, 53–69, Herb, 317, 319–321, 324 73, 99, 113, 123, 143, 166, 179, 182, 211, 227, High-density lipoprotein (HDL) cholesterol, 60 229, 256–263, 275, 303, 320, 322 Hippocampus, 37–40, 57, 58, 71, 74, 75, 157, MAOIs, see Monoamine oxidase inhibitors (MAOIs) 158, 178, 180, 181, 210–214, 243, 289, Maslach Burnout Inventory, 190 292, 293 Massage, 316, 317 Histone deacetylase (HDAC) inhibitor, 293, 296 MBCT, see Mindfulness-based cognitive therapy (MBCT) Homeopathy, 316, 321, 322 Medical illness, 177, 267 Hopelessness, 3, 4, 10, 35, 55, 61, 144, 145, 147, 194 Meditation, 306, 310, 316, 322 Humanistic approach, 10 Melatonin, 108, 117, 124–128, 135 Hypericum perforatum (St John’s wort), 319, 320 Memory reconsolidation, 287, 290, 291 Hypersomnia, 9, 35, 54, 113–116, 118, 199 Mental health, 6, 85, 87, 99, 177, 205, 294, 307, 309, Hypersomnolence, 116, 118 310, 315, 316 Hypnosis/hypnotherapy, 316, 322 Metabolic endotoxemia, 214 Hypothalamic–pituitary–adrenal (HPA) axis, 18, 26, 36, Metabotropic glutamate receptor antagonists (mGlu), 40–42, 59, 60, 114, 145, 146, 158, 165, 177, 245, 248 178, 181, 185, 209–211, 214–216, 228, 229, Methodology, 10, 18, 59, 71, 74, 77, 278, 316, 321 239, 243, 245–247, 268, 320 Mindful Mood Balance, 308–310 Mindfulness, 304–308, 310, 311, 322, 324 Mindfulness-based cognitive therapy (MBCT), 290, I 303–311, 322 Iloperidone, 256, 260, 263 Mindfulness-based stress reduction (MBSR), 172, 305 Immune, 22, 23, 26, 36, 41, 42, 59, 165, 166, 168, 178, Mind Monitoring System (MIMOSYS), 87–93 199, 213, 215 Minerals, 318, 321 Impulsivity, 102, 144, 145 Monoamine oxidase A gene, 114 Inflammasome, 23, 24 Monoamine oxidase inhibitors (MAOIs), 227, 240, Inflammation, 42, 59, 146, 165, 177–180, 184, 213–216, 241, 269 246, 268 Mood disorder, 3–5, 15–18, 22, 23, 30, 31, 57, 72, Inflammatory markers, 42, 59, 128, 268 85, 93, 115, 130, 131, 133, 179–181, 227, Inositol, 318 258, 259 Insomnia, 9, 28, 35, 54, 113–119, 127, 128, 132, 133, Motivation, 23, 35, 75, 99–106, 109, 119, 153, 168, 169, 135, 320, 321 179, 231 Insula, 58, 61, 73–76, 101–103, 158, 169 MRI, see Magnetic resonance imaging (MRI) Insulin, 181, 208–214, 216 Myocardial disease, 182 Insulin-like growth factor-1 (IGF-1), 59, 213 International Classification of Disease, 10th revision (ICD-10), 4, 54, 69, 192, 320 N Internet-based MBCT, 307–311 Neopterin, 215 Interpersonal and social rhythm therapy (IPSRT), 130, Nerve growth factor (NGF), 39, 40, 58, 59 131, 133, 135 Neurobiology, 16, 22, 76, 77, 99, 101–103, 105, 109, “Involutional” depression, 270 153–160, 184, 228, 230, 267–271 Neurocognitive function, 153, 155, 160 Neurogenesis, 39, 212, 213, 215, 239, 246–248, 289, 293 K Neuroimaging, 5, 6, 36, 37, 44, 53, 58, 61, 69, 102, 106, Ketamine, 38, 146, 167, 245, 268, 271, 289 109, 148, 168, 169, 184 Kraepelinian dichotomy, 4, 6, 9 Neuroimaging-based biomarkers, 60–62 Kynurenine pathway, 24, 146, 165 Neuroimaging biomarkers, 70–72, 76 326 Index

Neuroinflammation, 23, 24, 146, 178, 214, 215 Prefrontal cortex (PFC), 146, 147, 156, 157, 211 Neuropathic pain, 166, 170 Pregabalin, 170 Neuroprogression, 15, 17 Primary sleep disorders, 113, 116–119 Neurostimulation, 275–284 Prognosis, 17, 57, 77, 184, 185 Neurotransmitter modulators, 241–245, 248 Pro-inflammatory cytokines, 22, 23, 36, 42, 59, 165, 178, Neurotransmitters, 24, 26, 36–39, 53, 57, 58, 61, 71, 101, 181, 213–216 102, 107, 108, 114, 126, 147, 165–168, 184, Psychodynamic psychotherapy, 291 185, 215, 228, 239, 243, 244, 246, 247, 268, Psychotherapy, 74, 115, 123, 128, 130–133, 135, 268, 289, 318, 319 275, 284, 290–293 Neurotrophins, 19, 36, 39, 40, 58, 59 Nitric oxide (NO), 38 Nitrosative stress, 180, 215, 216 Q N-methyl-d-aspartate (NMDA) receptor, 38, 58, 146, Qigong, 323 148, 167, 215, 245, 268, 269 Quetiapine, 29, 30, 131, 160, 256, 257, 259–261, 263, 269 Norepinephrine, 20, 26, 27, 38, 53, 57, 58, 61, 107, 108, 117, 147, 213, 260, 262 Nosology, 6, 143 R Randomized controlled trials (RCTs), 28, 29, 124, 132, 261, 262, 270, 280, 282, 304, 320 O Rapid eye movement (REM) Obesity, 17, 23, 42, 90, 205–217 density, 43, 113–116 Obstructive sleep apnea (OSA), 113, 116, 118, 119, 267 sleep, 43, 114, 115, 117 Olanzapine, 30, 160, 256–258, 261–263, 269 Reactive nitrogen species (RNS), 215, 216 Operational diagnosis, 6 Reactive oxygen species (ROS), 23, 38, 213–216 Opioids, 102 Reconsolidation, 293, 295 Orbitofrontal cortex, 58–60, 74, 75, 101 Refractory depression, 269 OSA, see Obstructive sleep apnea (OSA) Relapse prevention, 282, 295, 304, 305, 307, 310, 311 Osmotic-release methylphenidate (OROS), 108 Relaxation therapies, 118, 322 Oxidative stress, 36, 42, 59, 166, 178, 180, 209, 215, REM sleep behavior disorder (RBD), 116, 117, 119 216, 239, 243, 247 Research domain criteria (RDoC), 10, 37, 77, 99 Resistin, 209, 212 Restless legs syndrome (RLS), 17, 113, 116, 117, 119 P Revised Chapman Physical Anhedonia Pain, 102, 108, 165–172, 178, 179, 281, 284, 316, 317 Scale (CPAS), 104 Pain matrix, 168 Reward association, 105 Paliperidone, 256, 262, 263 Reward processing, 75, 99–103, 105–107, 109, 168 Panax ginseng, 319, 320 Reward valuation, 101, 106 Parkinson’s disease, 35, 93, 154, 168, 169, 179, 183, Rhodiola rosea, 319–321 184, 270, 277, 282 Risperidone, 160, 256, 262, 263 Pathogenesis, 16, 22, 23, 57, 114, 147, 155, 165, 168, RLS, see Restless legs syndrome (RLS) 180, 200, 211, 212, 241, 243, 245, 247 ROS, see Reactive oxygen species (ROS) Pathophysiology, 6, 22, 27, 37–40, 53, 55, 58–60, 126, 158, 159, 165, 209–212, 216, 227–233, 239, 247 S Periodic limb movements during sleep (PLMS), 116, 117 S-adenosyl methionine (SAMe), 318, 319 Pessimism, 4, 73, 144, 145, 147 Schizophrenia, 4, 8, 9, 26, 28, 30, 54, 102, 104, 106, 195, PET, see Positron emission tomography (PET) 257, 259, 260, 262 PFC, see Prefrontal cortex (PFC) Seasonal depression, 20 Pharmacological treatment, 7, 129–131, 133–135, 170, Selective serotonin reuptake inhibitors (SSRIs), 69, 107, 268, 270, 277, 280, 283 117, 124, 129, 159, 169–171, 227, 228, 233, Pharmacotherapy, 69, 72–75, 108, 115–118, 124, 239, 240, 256, 319 268, 277, 289, 307 Serotonin (5-HT), 37, 57, 168 Placebo effects, 288 Serotonin-norepinephrine reuptake inhibitors (SNRIs), Polysomnography (PSG), 113–115 107, 108, 117, 170, 171, 228, 233, 241 Polythetic diagnostic criteria, 9, 10 Serotonin transporter gene, 18, 19, 114 Positron emission tomography (PET), 60, 61, 70–73, Shirom-Melamed Burnout Measure (SMBM), 192, 75–77, 169 196–199 Pramipexole, 269 Sleep Prefrontal cortex, 18, 21, 26, 36–39, 43, 57–59, 73–76, deprivation, 75, 115, 118, 119, 124, 128–130, 84, 101, 103, 109, 145, 168, 169, 213, 215, 132–135 256, 258 electroencephalography (EEG), 113–114 Index 327

Slow-wave sleep (SWS), 114, 115, 117 Tricyclic antidepressants (TCAs), 117, 159, 184, 227, Snaith-Hamilton Pleasure Scale (SHAPS), 103 240, 289 SNRIs, see Serotonin-norepinephrine reuptake Tryptophan, 24, 126, 146, 165, 180, 181, 215, 289, 318 inhibitors (SNRIs) Turmeric (Curcuma longa), 318, 321 Specifiers, 3, 6–8, 10, 29, 56, 61 SSRIs, see Selective serotonin reuptake inhibitors (SSRIs) U Sterile inflammation, 22–24 Unresolvable stress, 193, 194, 200 Structural connectivity, 71, 75 Substance P, 165, 167, 168 Subtypes, 41, 44, 54, 60, 70, 75, 101, 105, 135, V 199, 233 Vagus nerve stimulation (VNS), 270, 275, 282 Suicidal behavior, 35, 36, 40, 143–148 Valproate, 259–261, 292 Suicide, 17, 36, 37, 39, 40, 53–55, 57, 70, 113, 143–148, Vascular endothelial growth factor (VEGF), 58, 61, 90, 213 194, 277, 283 Vascular pathology, 159 Suicide risk, 147, 148 Vitamins, 318 Voice analysis, 83

T Tai chi, 322, 323 W TCAs, see Tricyclic antidepressants (TCAs) White matter signal hyperintensities, 76 Temporal Experience of Pleasure Scale (TEPS), 104 World Health Organization (WHO), 69, 99, 170, 192, TNF-α inhibitors, 246 205, 227, 239, 269, 303 Transcranial direct current stimulation (tDCS), 275, 276, 282 Transcranial magnetic stimulation (TMS), 129, 270, Y 271, 275 Yoga, 305, 316, 322–324 Transnosological specifiers, 10 Treatment-resistant depression (TRD), 27, 30, 107, 256, 258, 279–282, 284 Z Treatment-selection biomarker (TSB), 70 Ziprasidone, 27, 256, 262, 263