1521-0081/70/3/475–504$35.00 https://doi.org/10.1124/pr.117.014977 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:475–504, July 2018 Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets F. Caraci, F. Calabrese, R. Molteni, L. Bartova, M. Dold, G. M. Leggio, C. Fabbri, J. Mendlewicz, G. Racagni, S. Kasper, M. A. Riva,1 and F. Drago1 Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite’ Libre de Bruxelles, Bruxelles, Belgium (J.M.) Abstract ...................................................................................476 I. Introduction . ..............................................................................476 Downloaded from II. The New Neuroscience-Based Nomenclature and the Classification of Antidepressant Drugs: Implications for Drug Discovery and Clinical Practice ...............................476 III. Clinical Phenotypes of Treatment-resistant Depression .....................................478 A. Definition of Treatment Resistance and Staging Models. ...............................478 B. Features Contributing to Treatment Resistance.........................................478 by guest on May 19, 2020 IV. Genetics of Treatment-resistant Depression ................................................480 V. From the Neurobiology of Depression to Treatment Resistance..............................481 A. Etiological Mechanisms of Major Depression . ..........................................481 B. The Glutamatergic System . ............................................................482 C. Synaptic Plasticity and Neurotrophic Mechanisms . .....................................484 D. Hypothalamic-Pituitary-Adrenal Axis Dysfunction . .....................................485 E. Immune System Dysregulation and Neuroinflammation. ...............................486 F. Epigenetic Mechanisms ................................................................487 VI. Current Therapeutic Strategies for Treatment-resistant Depression.........................489 A. Dose Increase . ........................................................................489 B. Switch of the Antidepressant Drug .....................................................489 C. Antidepressant Combination Medication................................................490 D. Augmentation Strategies . ............................................................490 VII. Drug Discovery in Treatment-resistant Depression .........................................491 A. Animal Models or Treatment-resistant Depression . .....................................491 B. Pharmacological Strategies in Treatment-resistant Depression . .........................491 1. Glutamatergic System . ............................................................491 Address correspondence to: M. A. Riva, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail: [email protected] F.Car. received compensation as speaker/consultant from Eli Lilly, Lundbeck, Otzuka, Janssen-Cilag, Grunenthal and he has received research grants from Lundbeck. M.D. has received a travel grant from Janssen-Cilag. J.M. is a member of the Faculty of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. G.R. has received consulting fees and/or honoraria from Indena, Servier, and Recordati. S.K. received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe, and Servier. M.A.R. has received compensation as speaker/consultant from Lundbeck, Otzuka, Sumitomo Dainippon Pharma, and Sunovion, and he has received research grants from Lundbeck, Sumitomo Dainippon Pharma and Sunovion. F.Cal., R.M., L.B., G.M.L., C.F., and F.D. have no conflict of interest to declare. 1M.A.R. and F.D. equally contributed to this work. https://doi.org/10.1124/pr.117.014977. 475 476 Caraci et al. 2. Inflammatory System . ............................................................493 3. Opioid System ......................................................................494 4. Cholinergic System .................................................................495 5. Dopaminergic System . ............................................................495 6. Neurotrophin Signaling . ............................................................496 VIII. Nonpharmacological Approaches in Treatment-resistant Depression ........................496 IX. Conclusions. ..............................................................................497 References . ..............................................................................497 Abstract——Major depressive disorder is one of the neurotrophin function, and epigenetics. Advances in most prevalent and life-threatening forms of mental drug discovery processes in TRD have also influenced illnesses and a major cause of morbidity worldwide. the classification of antidepressant drugs and novel Currently available antidepressants are effective for classifications are available, such as the neuroscience- most patients, although around 30% are considered based nomenclature that can incorporate such advances treatment resistant (TRD), a condition that is associated in drug development for TRD. This review aims to provide with a significant impairment of cognitive function and an up-to-date description of key mechanisms in TRD and poor quality of life. In this respect, the identification of the describe current therapeutic strategies for TRD before molecular mechanisms contributing to TRD represents an examining novel approaches that may ultimately address essential step for the design of novel and more efficacious important neurobiological mechanisms not targeted by drugs able to modify the clinical course of this disorder currently available antidepressants. All in all, we suggest and increase remission rates in clinical practice. New that drug targeting different neurobiological systems insights into the neurobiology of TRD have shed light should be able to restore normal function but must also on the role of a number of different mechanisms, including promote resilience to reduce the long-term vulnerability to the glutamatergic system, immune/inflammatory systems, recurrent depressive episodes. I. Introduction selection of the therapeutic approaches and may ultimately lead to the development of novel therapeutic strategies. In Major depressive disorder (MDD) is a chronic de- particular, we will discuss how etiological mechanisms and bilitating illness that represents a major economic and a better definition of the neurobiological dysfunction in medical burden for our society. It is characterized by MDD patients can provide key information to identify different and heterogeneous symptoms that lead to altered genes and pathways that are not a direct target of functional disability in affected individuals. the current antidepressants and may therefore represent Although a large number of antidepressant drugs have potential “limiting factor” of the effectiveness of pharmaco- been developed over the last 50–60 years, the therapeutic logical intervention. Moreover, following a description of response is often partial, and around 20%–30% of patients the current therapeutic strategies, we will discuss novel are considered treatment resistant or they do not respond approaches that address important neurobiological mech- adequately to two successive antidepressant treatments anisms and may ultimately offer new hopes for a more under a proper therapeutic regimen (McIntyre et al., 2014). thoroughly impact on TRD patients. Treatment-resistant depression (TRD) is associated with a significant impairment of cognitive function, higher risk for comorbidity, and an increased suicidality (Gaynes, 2016). II. The New Neuroscience-Based Nomenclature On these bases, there is a great deal of interest in and the Classification of Antidepressant Drugs: identifying the elements that may contribute to TRD to Implications for Drug Discovery and improve clinical outcomes. Clinical Practice The present review will provide an up-to-date description of key issues in TRD and how the comprehension of specific The classification of psychotropic medications repre- aspects related to MDD could be instrumental for a proper sents an essential tool for the clinician and it should ABBREVIATIONS: AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATC, anatomical-therapeutic-chemical; BDNF, brain-derived neurotrophic factor; CB1, cannabinoid 1; cLH, congenital learned helplessness; CMS, chronic mild stress; CRCT1, CREB- regulated transcription coactivator 1; ECT, electroconvulsive