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VOLUME 2 NUMBER 4 2006 DEPRESSION: Mind and Body Advances in the Understanding and Treatment of Depression and its Physical Symptoms

Editor-in-Chief Alan F Schatzberg, Stanford, CA, USA

The Role of Vagus Nerve Stimulation as a Therapy for Treatment-Resistant Depression Mustafa M Husain, Kenneth Trevino, Louis A Whitworth, and Shawn M McClintock

Neuropsychiatric Effects of IL-2: Mechanisms and Treatment Implications Stephen E Nicolson, Andrew H Miller, David Lawson, and Dominique L Musselman

The Bidirectional Relationship between Diabetes Mellitus and Depression Sanjay J Mathew and Susan Burd

www.depressionmindbody.com

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the ACCME through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal opportunity university. R7420_2_DEP2_4_COV_CME_03.qxd 20/7/06 17:23 Page 2

Depression: Mind and Body is supported by an unrestricted educational grant from Wyeth Pharmaceuticals

Editor-in-Chief Alan F Schatzberg Kenneth T Norris Jr, Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Editorial Advisory Board Dwight Evans Kurt Kroenke Professor and Chair, Department of Psychiatry, Professor of Medicine, Department of Medicine University of Pennsylvania, Philadelphia, PA, USA and Regenstrief Institute for Health Care, Indiana Maurizio Fava University School of Medicine, Indianapolis, IN, USA Psychiatrist and Director, Depression Clinical and Yves Lecrubier Research Program, Massachusetts General Hospital, Director of Research, Hôpital de la Salpêtrière, Boston, MA, USA Paris, France John Greden Norman Sartorius Professor and Chair, Department of Psychiatry, Psychiatry Department Director, University Hospital, University of Michigan Depression Center, Geneva, Switzerland Ann Arbor, MI, USA Donna Stewart Wayne Katon Professor and Chair, Women’s Health University Professor and Vice Chair, Department of Psychiatry Health Network and University of Toronto, and Behavioral Sciences, University of Washington, Toronto, ON, Canada Seattle, WA, USA

Editors Christos Ballas Po W Wang Assistant Clinical Professor, Department of Psychiatry, Senior Research Scientist, Bipolar Disorders Clinic, University of Pennsylvania Medical Center, Philadelphia, Department of Psychiatry and Behavioral Sciences, PA, USA Stanford University School of Medicine, Stanford, CA, USA

Editorial Policy Depression: Mind and Body is an independent journal published by Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editor-in-Chief, Editorial Advisory Board, and the Editors. Before publication, all material submitted to the journal is subjected to rigorous review by the Editor-in-Chief, Editorial Advisory Board, Editors, and/or independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and conflict of interest. Aims and Scope Depression: Mind and Body is designed to bring a critical analysis of the world literature on depression, written by clinicians, for clinicians, to an international, multidisciplinary audience. Our mission is to promote better understanding of the treatment of depression across the global healthcare system by providing an active forum for the discussion of clinical and healthcare issues. Leading Articles - These major review articles are chosen to reflect topical clinical and healthcare policy issues in depression. All contributions undergo a strict editorial review process. Clinical Reviews - The most important papers from the best of the international literature on depression are systematically selected by an internationally recognized panel of experts. The Editors then prepare concise and critical analyses of each paper, and, most importantly, place the findings into clinical context. Meeting Reports - Depression: Mind and Body also provides incisive reportage from the most important international congresses. Publisher’s Statement ©2006 Remedica Medical Education and Publishing. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission of the copyright owners. While every effort is made by the publishers and editorial board to see that no inaccurate or misleading data, opinions, or statements appear in this journal, they wish to make it clear that the material contained in the publication represents a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the board, publishers, and any supporting company accept no responsibility for the consequences of any such inaccurate or misleading data or statements. Neither do they endorse the content of the publication or the use of any drug or device in a way that lies outside its current licensed application in any territory. Depression: Mind and Body (ISSN 1479-5035) is published four times a year by Remedica Publishing Ltd and distributed by USA Mail Agent Pronto Mailers Association, 544 Lincoln Boulevard, Middlesex, NJ 08846. Subscription price $170 per year. Periodicals Postage Paid at Middlesex NJ. POSTMASTER: Please send address changes to Remedica Publishing Ltd, 544 Lincoln Boulevard, Middlesex NJ 08846-2439. Remedica Medical Education and Publishing Ltd., Commonwealth House, 1 New Oxford Street, London WC1A 1NU, UK. Telephone: +44 (0)20 7759 2999 Fax: +44 (0)20 7759 2951 Email: [email protected] Editorial Team: Emma Beagley, Scott Millar Editorial Director: Reghu Venkatesan Publishers: Ian Ackland-Snow, Simon Kirsch Design and Artwork: AS&K Skylight Creative Services ISSN 1479-5035 R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:39 Page 113

Dear Colleagues, Contents Welcome to the final issue of the second volume of Depression: Mind and Body. Leading Articles Although great advances have been made in therapies for The Role of Vagus Nerve Stimulation as a the treatment of depression, some patients fail to respond Therapy for Treatment-Resistant Depression to initial treatment courses, and many do not respond to Mustafa M Husain, Kenneth Trevino, multiple medication trials. These patients are described as Louis A Whitworth, and Shawn M McClintock 114 having treatment-resistant depression (TRD) and the prevalence of this disorder calls for new treatment techniques. In this Neuropsychiatric Effects of IL-2: issue, Dr Husain and colleagues (University of Texas Mechanisms and Treatment Implications Southwestern Medical Center at Dallas, Dallas, TX, USA) Stephen E Nicolson, Andrew H Miller, David Lawson, and Dominique L Musselman 120 discuss a novel neurostimulation technique, vagus nerve stimulation (VNS) therapy, and its role as an antidepressant The Bidirectional Relationship between therapy for patients with TRD. Studies have demonstrated Diabetes Mellitus and Depression the safety and efficacy of VNS therapy for patients suffering Sanjay J Mathew and Susan Burd 130 from TRD, and this article expands upon its mechanism of action and the results of recent trials. Our second article examines interleukin-2 (IL-2), a vital Clinical Reviews signaling molecule in immune and inflammatory responses as Epidemiology 134 well as in cell migration and differentiation. IL-2 has been used for the treatment of diseases such as cancer and AIDS; Clinical Practice 137 however, it exhibits strong adverse effects, including a high Comorbidities 140 incidence of depressive symptoms and memory disturbances. The mechanisms for these effects are not well documented Pathogenesis 142 or understood and Dr Nicolson and colleagues (Emory University School of Medicine, Atlanta, GA, USA) provide an insight into the neuropsychiatric effects of IL-2 and their Meeting Reports treatment implications. 14th Annual Meeting of the Association As is well-known, depression is frequently comorbid with a of European Psychiatrists (AEP) number of diseases. Drs Mathew and Burd (Mount Sinai Nice, France, 4–8 March, 2006 146 School of Medicine, New York, NY, USA) elaborate on the association between depression and diabetes, offering 159th Annual Meeting of the American Psychiatric Association (APA) pathophysiological hypotheses regarding this relationship and Toronto, ON, Canada, 20–25 May, 2006 148 reviewing treatment approaches for the depressed patient suffering from comorbid diabetes mellitus. As in all issues, the Clinical Reviews provide concise and critical analyses of the latest depression literature, placing recent developments into a clinical context. These are followed by reports of the most important presentations concerning depression from the Annual Meeting of the Association of European Psychiatrists (Nice, France) and an extended report of the highlights of the American Psychiatric Association Annual Meeting (Toronto, ON, Canada). We are pleased that the comments we have received about Depression: Mind and Body have been overwhelmingly positive and that the journal continues to be regarded as a useful resource by clinicians working in this fast-developing field. We welcome your comments and suggestions and look forward to your feedback and any thoughts to help us provide a relevant review of current topics. AF Schatzberg, MD Editor-in-Chief R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:39 Page 114

The Role of Vagus Nerve Stimulation as a Therapy for Treatment-Resistant Depression

Mustafa M Husain, Kenneth Trevino, Louis A Whitworth, and Shawn M McClintock University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Treatment-resistant depression (TRD) is diagnosed when a patient fails to respond to at least two adequate courses of treatment. This review describes a novel neurostimulation technique, vagus nerve stimulation (VNS) therapy, and its role as an antidepressant therapy for patients with TRD. VNS therapy involves the implantation of a pacemaker-like device that LEADING ARTICLE provides a brief intermittent electrical current to the left vagus nerve. The history of VNS therapy, including the anatomy of the vagus nerve and early research on VNS therapy in the treatment of seizures is briefly discussed, along with information on the prevalence and identification of TRD. Research on mechanisms of action, safety, and efficacy are covered in the context of the use of VNS therapy for TRD. Depression: Mind Body 2006;2(4):114–9.

Major depressive disorder (MDD) is a common psychiatric rate of any antidepressant treatment, with studies showing disorder [1], and is suggested to be more debilitating remission rates of 75% among patients with major depression, than other psychiatric or general health conditions [2]. and 95% among those with psychotic depression [8,9]. Research indicates that three to five adults per 1000 will Although ECT has an extremely high success rate, like experience MDD annually [3], and >15% of the population psychotropic medications it unfortunately also has a marked will suffer from depression at some point [1]. Antidepressant relapse rate. Studies have shown that 53–59% of patients medications have been successful in treating depression; treated with ECT relapse within 1 year and of these relapses, however, some patients fail to respond to initial treatment 78–94% occur within 6 months of treatment [10,11]. ECT courses, and many do not respond to multiple medication often produces a range of cognitive side effects with varying trials. A patient whose depression does not improve despite severity that typically include an acute confusional state, attempting several antidepressant treatments is considered and anterograde and retrograde amnesia [6,10–12]. Given to have treatment-resistant depression (TRD). The specific the limitations of ECT and the prevalence of depression, new definition of TRD varies, but the basic concept is depression antidepressant methods are needed. VNS therapy may provide that does not improve after an antidepressant treatment an additional treatment option for patients suffering from TRD. course of adequate dose and duration [4]. Additional treatment options for these patients include electroconvulsive What is TRD? therapy (ECT) and, more recently, the Vagus Nerve As described by Fava and Davidson, the goal of treating mood Stimulation (VNS) Therapy System™ (Cyberonics Inc., disorders is to restore the patient to a level of psychological Houston, TX, USA), an implantable device approved by the wellness and high functional ability [4]. Antidepressant US Food and Drug Administration (FDA) for the treatment medications are common and successful therapies for many of depression [5]. patients suffering from major depression. However, one study ECT was introduced in 1938 for the treatment of reported that 29–46% of depressed patients who received schizophrenia and is still used today for treating MDD, as treatment of adequate dose and duration failed to fully well as other severe psychiatric disorders (e.g. catatonia, respond to treatment, and 19–34% did not show any response psychosis) [6,7]. Patients are placed under general anesthesia [4]. Patients diagnosed with MDD who fail to respond to and administered muscle relaxants. A mild electrical current multiple treatment courses can be classified as having TRD. is then sent through a specific area of the brain to induce a To date, the exact number of treatment courses a patient seizure. ECT has been found to yield the highest remission must fail to be considered as having TRD has not been established; however, it is recommended that at least two Address for correspondence: Mustafa M Husain, University of Texas monotherapy trials with psychotropic medications from Southwestern Medical Center at Dallas, 5323 Harry Hines Bouelvard, different pharmacological classes be tried [13]. As described Dallas, TX 75235-8898, USA. Email: [email protected] by Thase and Rush, the severity of TRD can be rated on a

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five-stage scale of resistance determined by failure to Report, required by the FDA, approximately 32 065 of their respond to specific courses of treatment [14]. Before VNS therapy devices were implanted for the treatment of concluding that a patient is treatment resistant, the epilepsy between 1997 and 2004. adequacy of antidepressant treatment courses needs to be determined, and the patient’s original diagnosis should be Rationale for using VNS therapy for the verified to rule out another condition (e.g. medical illness, treatment of depression substance abuse) [13]. If antidepressant treatment courses Many clinical observations fueled the initial research into the fail, and the patient’s condition is severe and debilitating, use of VNS therapy to treat depression. Positron emission VNS therapy may be recommended. tomography (PET) imaging has indicated that VNS affects functioning of the limbic structures in a similar way as What is the vagus nerve? antidepressant medications [15,25]. Certain regions of the The vagus nerve is the tenth and longest cranial nerve, brain known to be related to depression have monosynaptic which connects to different parts of the central nervous and polysynaptic connections with the NTS of the vagus system. It lies between the carotid artery and the jugular nerve; thus, stimulation of the vagus nerve may therefore vein in the neck, and is a mixed nerve consisting of afferent affect those regions [16,26]. Moreover, the neurochemical and efferent fibers, with the majority of sensory fibers (80%) effects of VNS are similar to those of antidepressant being afferent. Afferent fibers bring information to the brain treatment. Studies indicate that VNS alters the concentration while efferent fibers send information away to extracranial of neurotransmitters implicated in mood disorders, including areas. The cell bodies for the efferent fibers, located in the serotonin, norepinephrine, γ-aminobutyric acid (GABA), nucleus ambiguus and the dorsal motor nucleus of the and glutamate [17,27,28]. During early research trials of vagus, primarily regulate parasympathetic autonomic VNS treatment for epilepsy, many patients reported an functions including heart rate, gastric secretions, and improvement in mood that, interestingly, was independent of intestinal motility [15,16]. Most of the afferent cells of the changes in the frequency or intensity of seizure activity vagus nerve are located in the nodose ganglion and project [15,17,29]. Psychiatric treatments with anticonvulsant information to the nucleus tractus solitarius (NTS) [16,17]. properties, such as psychotropic medications (i.e. The afferent fibers of the vagus nerve project to numerous carbamazepine, gabapentin, lamotrigine, and valproate) and cortical and subcortical regions of the brain; hence, ECT, have also shown antidepressant qualities [17,30–32]. stimulation of the vagus nerve may have widespread effects As VNS is an effective treatment for epilepsy, it seems likely on central nervous system function. that its effects on the brain may be similar to those produced by anticonvulsant drugs. History of VNS research and its therapeutic use for epilepsy VNS and treatment of depression: Research conducted by Zabara in the 1980s demonstrated pilot trial (protocol D-01) the therapeutic effect of VNS on seizures [18,19]. Zabara The pilot study for VNS in depression (D-01) was an open- was able to interrupt, and even terminate, seizures induced label trial designed to evaluate the safety and efficacy of in canines through stimulation of the vagus nerve [20]. VNS therapy in patients with TRD [33,34]. The VNS Therapy In 1988, Penry and Dean conducted the first clinical System was implanted in 60 participants at four centers. investigation of VNS for the treatment of patients with Enrolled participants were required to have a Diagnostic intractable partial seizures [21]. This study was followed by and Statistical Manual of Mental Disorders: 4th edition larger clinical trials that examined the efficacy and safety of (DSM-IV) diagnosis of MDD or bipolar I or II disorder [35], both acute and long-term use of VNS therapy among and to be currently experiencing a major depressive episode patients with refractory seizures [22–24]. These studies (MDE) for a length of ≥2 years, or have experienced four showed a significant reduction in the frequency and severity MDEs during their lifetime. Participants were also required to of seizures compared with baseline conditions. VNS therapy have demonstrated an inadequate response to two or more was approved in the European Union for the treatment of antidepressant medication treatments, as determined by the epilepsy in 1994 and the VNS Therapy System (formerly Antidepressant Treatment History Form [36]. One patient known as the NeuroCybernetic Prosthesis) was approved by showed improvement during the implant recovery period the US FDA in July 1997 for use as an adjunctive therapy in (during which the VNS therapy was not activated) and no reducing the frequency of seizures in adults and adolescents longer met enrollment criteria for the study. >12 years of age with medically refractory partial onset For the first 30 patients completing the acute phase of seizures. According to Cyberonics, Inc.’s Medical Device the pilot study, the stimulation parameters were [33]:

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• Pulse width of 500 µs, except for one patient HAM-D24 scores for the active VNS group (15% response who received a 250-µs pulse width. rate) and the sham-control group; the sham group actually • Frequency 20–30 Hz. produced a 10% effect [39]. • 30-s on-time and 5-min off-time (with a few At the end of the acute trial, all participants continued exceptions of shorter off-times). in a long-term open-label follow-up. The 205 participants • Output current range from 0.25–3.0 mA. who were evaluated during the long-term phase of D-02 (12 months) showed a decrease in depression severity. After

Response was defined as a ≥50% reduction in baseline 12 months of VNS treatment, participants’ HAM-D24 scores scores using the 28-item Hamilton Depression Rating Scale indicated a response rate of 29.8% (54 of 181 observed

(HAM-D28) [37], and remission was defined as a HAM-D28 participants) and a remission rate of 17.1% (31 of 181). In a score of ≤10. During the acute phase of the trial, participants comparison study the response rate for TRD patients not showed a 30.5% (18 of 59) response rate with a 15.3% receiving VNS and with treatment as usual was only 12.5% (9 of 59) remission rate. At time of exit from the acute phase during a 12-month period [40]. These data, which are of the pilot study, Clinical Global Impression (CGI) scale results similar to the results of the first pilot study, indicated that showed that 37.3% (22 of 59) of participants were considered VNS therapy was more beneficial after long-term treatment much improved, three participants were considered minimally relative to acute treatment. worse, and the remaining 34 participants were considered In 2001, the VNS Therapy System was approved for the either unchanged or minimally improved [34]. Interestingly, treatment of adults with treatment-resistant or treatment- for the first 30 participants implanted, an increase in intolerant, chronic, or recurrent depression, including both response rate from 40% (12 of 30) at exit from the acute unipolar and bipolar depression, in the European Union [15]. phase of the pilot study to 46% (13 of 28) after an The VNS Therapy System was approved by the FDA on the additional 9 months of VNS, and an increase in remission 15th of July 2005 for adjunctive long-term treatment of rate from 17% (three of 30) to 29% (eight to 28) during the chronic or recurrent depression for persons aged ≥18 years same time frame, was shown [38], suggesting that VNS who are experiencing TRD [41]. Since this approval, and at treatment is more effective in the long term. This study the date of this paper, >550 VNS Therapy devices have been justified additional clinical trials by demonstrating that VNS implanted and over 6800 devices have been prescribed was a safe and effective therapy for TRD. through Cyberonics Inc.’s Insurance Verification and Education Authorization form process. VNS therapy and depression: double-masked efficacy trial (protocol D-02) Mechanism of action The pivotal VNS therapy trial for the treatment of depression The exact mechanisms by which VNS therapy works are (D-02) was a double-masked, multicenter trial, which assessed unknown; however, its antidepressant effect is most likely the safety and efficacy of both an acute (12 weeks after related to the neuroanatomical pathways of the vagus implantation) and long-term (12 months after implantation) nerve. Afferents of the vagus nerve synapse on the NTS, phase. The 235 participants implanted with the VNS Therapy which then directly project to several areas in the brainstem, System were randomized to either the active VNS group or limbic, and cortical areas, as well as indirectly to the locus the sham-control group (current from the device remained coeruleus (LC) and parabrachial nucleus (PB) (Fig. 1). The PB off). After a 2-week implant recovery period, devices were and LC connect to the amygdala and the bed nucleus of the switched on for participants in the active group. During the stria terminalis, areas that have been implicated in mood following 2 weeks, stimulation parameters were adjusted to regulation [17]. determine maximal and comfortable tolerance to the Research has shown that stimulation of the vagus nerve stimulation settings. Patients then received 8 weeks of affects neurotransmitter activity. VNS enhances transmission stimulation at a fixed dose. The stimulation parameters of norepinephrine in the LC, and serotonin in the dorsal could be adjusted in response to intolerable side effects [39], raphe nucleus [17,27]. It may also increase GABA, or possibly and those in the sham-control group were treated in the decrease glutamate in the NTS [28]. These neurochemical same way as the active group (i.e. sham activation and effects of VNS correspond with the theorized antidepressant adjustments to the device were performed). mechanisms of psychotropic medication [17].

Participants’ HAM-D24 scores were used to define Neuroimaging has been used to further explain the response (a ≥50% reduction in scores compared with neuroanatomical effects of VNS. PET scans have indicated baseline) and remission (a score of ≤9). The results from the an increase in regional cerebral blood flow (rCBF) in the acute phase showed no significant difference between rostral medulla, thalamus, hypothalamus, insula, and

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Figure 1. Brain regions connected to or affected by the vagus nerve.

Cingulate gyrus

Thalamus Orbitofrontal cortex Hypothalamus Amygdala

Raphe nuclei Locus coeruleus

Vagus nerve Nucleus tractus solitarius

Reproduced with permission from Cyberonics, Inc.

postcentral gyrus, and a decrease in rCBF in the pulse generator sends brief intermittent electrical stimulation hippocampus, amygdala, and cingulate gyrus [25]. Single to the vagus nerve through the lead. photon emission-computed tomography (SPECT) has indicated The generator is implanted subcutaneously in the left a similar pattern of increased and decreased rCBF in many of chest wall, while the three helical contacts (cathode, anode, the same regions [42]. These studies demonstrate that and anchor) of the lead are wrapped around the left treatment with VNS produces significant changes in brain vagus nerve through a small incision in the neck (Fig. 3). areas involved with depression. The changes in the rCBF The electrode is then tunneled subcutaneously to the related to VNS have also been observed in depressed infraclavicular incision and connected to the pulse generator. patients being treated with selective serotonin reuptake During the implant surgery, the VNS Therapy System is inhibitors [43,44]. briefly activated to perform a lead test verifying that the device is operational and the lead is properly connected. The Description of the VNS Therapy System surgical procedure is typically performed by a neurosurgeon and surgical procedure for implant on either an inpatient or outpatient basis, and takes around The VNS Therapy System comprises an implantable VNS 1 h to complete [15,17]. The VNS Therapy System is Therapy Pulse Generator, (Cyberonics, Inc.), a lead, and a typically not activated for at least 14 days after initial programming wand [45]. The generator is a bipolar pulse implantation to ensure post-surgical recovery [45]. generator that is multi-programmable and similar to a cardiac The final component of the VNS Therapy System is the pacemaker in size and shape (Fig. 2). The pulse generator is computer-controlled programming wand, which is connected hermetically sealed in a titanium case and powered by a to a personal or hand-held computer that contains single battery with an estimated lifespan of 3–8 years, programming software for the pulse generator. To activate depending on the device stimulation parameters [45]. The and set device parameters, the wand is simply placed over

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Figure 2. The VNS Therapy System implant: bipolar pulse Figure 3. VNS electrode placement on the vagus nerve. generator and lead.

Reproduced with permission from Cyberonics, Inc.

observed in patients receiving VNS for treatment-resistant epilepsy [41]. Based on causal relationship, reported side effects of VNS can be divided into two primary groups: those related to the surgical implant procedure, and those related to the actual stimulation of the vagus nerve by the device. In the D-02 study, the most commonly reported side effects related to surgery were incision pain (36%), voice alteration (33%), incision site reaction (i.e. redness, itching, soreness; 29%), and pain around the device generator or leads (23%) Reproduced with permission from Cyberonics, Inc. [41]. Most side effects resolved within 30 days [41]. Additional surgery-related side effects that were less frequent included reactions around the device (i.e. swelling, the generator, which allows for noninvasive programming of tenderness), pharyngitis (inflammation of the throat), the VNS Therapy System. The VNS Therapy Pulse Model hypesthesia (impaired sense of touch), and dysphagia 102 and 102R Generators (the most recent models to date) (difficulty swallowing) [41]. can deliver an output current between 0.25–3.5 mA at Voice alteration and an increase in coughing were the a signal frequency between 1 and 30 Hz, with a pulse width most common side effects related to stimulation of the ranging from 130–1000 µs. For these models, the signal vagus nerve, with an occurrence of 55% and 24%, on-time ranges from 7–60 s, and the signal off-time ranges respectively. Dyspnea (difficulty breathing, shortness of from 0.2–180 min. The programming wand is also used breath), neck pain, dysphagia, laryngismus (throat, larynx to retrieve and record device settings (referred to as spasm), and paresthesia (tingling) were also reported as interrogating the device), as well as to perform diagnostic stimulation-related side effects, but were less frequent [41]. tests on the device and verify proper functioning of the lead Voice alteration is by far the most common side effect and is and generator [45]. The VNS Therapy System can be likely caused by spread of the current to the recurrent deactivated by placing a magnet over the area of the laryngeal nerve, which innervates the vocal cords [17]. VNS generator. The pulse generator is programmed to switch off side effects tend to resolve as tolerance to stimulation automatically if it is under a constant magnetic field, and develops; however, voice alteration can persist. To minimize resumes stimulation at the programmed settings once the side effects, VNS device stimulation parameters may be magnet is removed [46]. adjusted to allow for the development of tolerance [17].

Side effects of VNS Discussion The side effects of VNS reported in studies of patients with The prevalence of major depression and, in particular TRD, depression were similar in occurrence and frequency to those highlights the need for innovative and effective antidepressant

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treatments. Although VNS therapy was originally designed 10. Sackeim HA, Prudic J, Devanand DP et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral ECT at different stimulus intensities. Arch Gen for the treatment of seizures, observations in epilepsy studies Psychiatry 2000;57:425–34. suggested that VNS has antidepressant properties 11. Sackeim HA, Prudic J, Devanand DP et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of ECT. N Engl J Med 1993;328:839–46. [15,17,29]. The vagus nerve is anatomically connected to 12. Lisanby SH, Maddox JH, Prudic J et al. The effects of electroconvulsive therapy on brain structures related to depression [16,26], and research memory of autobiographical and public events. Arch Gen Psychiatry 2000;57:581–90. 13. Trivedi MH. Treatment-resistant depression. Ann Clin Psychiatry 2000;57:581–90. has shown that stimulation of this nerve affects the limbic 14. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58:S23–9. structures in a similar way to the mechanism of action of 15. Schlaepfer TE, Kosel M. Brain stimulation in depression. In: Griez EJL, editor. Mood antidepressants [15,25]. VNS also alters the concentration of Disorders: Clinical Management and Research Issues. Chichester: John Wiley & Sons, 2005:403–25. various neurotransmitters related to mood disorders [27,28]. 16. George MS, Sackeim HA, Rush AJ et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry 2000;47:287–95. Clinical studies of VNS for the treatment of depression 17. Sackeim HA. Vagus nerve stimulation. In: Lisanby SH, editor. Brain Stimulation in indicate that it is a safe and effective option. The adverse Psychiatric Treatment. Washington: American Psychiatric Publishing, 2004:99–143. 18. Zabara J. Time course of seizure control to brief, repetitive stimuli. Epilepsia 1985;26:518. effects that are frequently reported with ECT (i.e. confusional 19. Zabara J. Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr state, and anterograde and retrograde amnesia) have not Clin Neurophysiol 1985;61:S162. 20. Zabara J. Inhibition of experimental seizures in canines by repetitive vagal stimulation. been evident with VNS therapy and research suggests that Epilepsia 1992;33:1005–12. 21. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal VNS may actually help neurocognitive function in patients stimulation in humans: preliminary results. Epilepsia 1990;31:S40–3. whose TRD improves [30]. Data from the protocol D-01 and 22. Ben-Menachem E, Manon-Espaillat R, Ristanovic R et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. D-02 studies demonstrate that the VNS Therapy System is Epilepsia 1994;35:616–26. an effective treatment for TRD, with response rates of 23. Ramsay RE, Uthman BM, Augustinsson LE et al. Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects, and tolerability. Epilepsia 1994;35:627–36. 30.5% and 29.8%, respectively. 24. George R, Salinsky M, Kuzniecky R et al. Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. First Despite these results, further investigation of the International Vagus Nerve Stimulation Study Group. Epilepsia 1994;35:637–43. treatment modality is needed. At this time, the most 25. Henry TR, Bakay RA, Votaw JR et al. Brain blood flow alterations induced by therapeutic VNS in partial epilepsy: I. Acute effects at high and low levels of stimulation. effective output current for the device has not been Epilepsia 1998;39:983–90. established, and, since the output current can range from 26. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000;48:813–29. 27. Ben-Menachem E, Hamberger A, Hedner T et al. Effects of VNS on amino acids and other 0.25–3.5 mA, research to determine the setting with the metabolites in the CSF of patients with partial seizures. Epilepsy Res 1995;20:221–7. 28. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate highest efficacy and the fewest side effects is needed. transmission in nucleus tractus solitarius. Epilepsia 1999;40:1051–7. Although 30% of the patients in the D-02 study significantly 29. Harden CL, Pulver MC, Ravdin LD et al. A pilot study of mood in epilepsy patients treated with VNS. Epilepsy Behav 2000;1:93–9. improved; a considerable number did not. Additional studies 30. Sackeim HA, Keilp JG, Rush AJ et al. The effects of VNS on cognitive performance in patients with TRD. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:53–62. to determine those patients who are most likely to benefit 31. Post RM, Denicoff KD, Frye MA et al. A history of the use of anticonvulsants as mood from VNS therapy are therefore required, and long-term stabilizers in the last two decades of the 20th century. Neuropsychobiology 1998;38:152–66. 32. Sackeim HA. The anticonvulsant hypothesis of the mechanisms of action of ECT: studies of VNS in patients with TRD are also necessary. current status. J ECT 1999;15:5–26. While many questions remain to be answered, VNS therapy 33. Rush AJ, George MS, Sackeim HA et al. Vagus nerve stimulation (VNS) for treatment- resistant depressions: a multicenter study. Biol Psychiatry 2000;47:276–86. represents the latest treatment modality with demonstrated 34. Sackeim HA, Rush AJ, George MS et al. Vagus nerve stimulation (VNS) for treatment- resistant depression: efficacy, side effects, and predictors of outcome. safety and efficacy for patients suffering from TRD. Neuropsychopharmacology 2001;25:713–28. 35. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revision. Washington, DC: American Psychiatric Association, 2000. Disclosures 36. Sackeim HA, Prudic J, Devanand DP et al. The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive Dr Husain has received support from Cyberonics Inc., The Magstim therapy in major depression. J Clin Psychopharmacol 1990;10:96–104. Company Ltd, Neuronetics, Inc., and NIH/NIMH. Mr Trevino, Dr Whitworth, 37. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. 38. Marangell LB, Rush AJ, George MS et al. VNS for major depressive episodes: one year and Mr McClintock have no relevant financial interests to disclose. outcomes. Biol Psychiatry 2002;51:280–7. 39. Rush AJ, Marangell LB, Sackeim HA et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005;58:347–54. References 40. George MS, Rush AJ, Marangell LB et al. A one-year comparison of VNS with treatment 1. Kessler RC, Berglund P, Demler O et al. The epidemiology of MDD: results from the as usual for treatment-resistant depression. Biol Psychiatry 2005;58:364–73. National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095–105. 41. Cyberonics, Inc. Depression Physician’s Manual. VNS Therapy (TM) Pulse Model 2. World Health Organization; The World Health Report 2001. Mental Health: 102 Generator and VNS Therapy (TM) Pulse Duo Model 102R Generator. Houston: New Understanding, New Hope. Geneva: World Health Organization, 2001. Cyberonics, Inc., 2005. Available from URL: http://www.vnstherapy.com/manuals/ doc_download.asp?docid={6360242F-390A-4676-BDE0-7034395B834B}. 3. Murphy JM, Laird NM, Monson RR et al. Incidence of depression in the Stirling County Study: historical and comparative perspectives. Psychol Med 2000;30:505–14. 42. Zobel A, Joe A, Freymann N et al. Changes in regional cerebral blood flow by therapeutic VNS in depression: an exploratory approach. Psychiatry Res 2005;139:165–79. 4. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 43. Kennedy SH, Evans KR, Kruger S et al. Changes in regional brain glucose metabolism Psychiatr Clin North Am 1996;19:179–200. measured with PET after paroxetine treatment of major depression. Am J Psychiatry 5. Carpenter LL. Neurostimulation in resistant depression. J Psychopharmacol 2006;20:35–40. 2001;158:899–905. 6. Tharyan P, Adams CE. Electroconvulsive therapy for schizophrenia. Cochrane Database 44. Mayberg HS, Brannan SK, Tekell JL et al. Regional metabolic effects of fluoxetine in major of Systematic Reviews 2005;18(2):CD000076. depression. Biol Psychiatry 2000;48:830–43. 7. Greenberg RM, Kellner CH. Electroconvulsive therapy a selected review. Am J Geriatr 45. Cyberonics, Inc. Physician’s Manual. VNS Therapy (TM) Pulse Model 102 Generator and Psychiatry 2005;13:268–81. VNS Therapy (TM) Pulse Duo Model 102R Generator. Houston: Cyberonics, Inc., 2003. 8. Husain MM, Rush AJ, Fink M et al. Speed of response and remission in MDD with acute Available from URL: http://www.vnstherapy.com/manuals/doc_download.asp?docid= ECT: a Consortium for Research in ECT (CORE) report. J Clin Psychiatry 2004;65:485–91. {E5D2100B-A4C2-409B-B71C-E1CEA60FBD90}. 9. Petrides G, Fink M, Husain MM et al. ECT remission rates in psychotic versus nonpsychotic 46. George MS, Rush AJ, Sackeim HA et al. VNS: utility in neuropsychiatric disorders. depressed patients: a report from CORE. J ECT 2001;17:244–53. Int J Neuropsychopharmacol 2003;6:73–83.

DEPRESSION: MIND AND BODY Vol 2 No 4 2006 119 R7420_2_REM_DEP2_4_17.qxd 20/7/0617:39Page120 LEADING ARTICLE Suite 4000,Atlanta,GA30322,USA.Email:[email protected] Medicine, Woodruff Research MemorialBuilding,101Woodruff Circle, of PsychiatryandBehavioralSciences,EmoryUniversitySchool Address forcorrespondence: DominiqueLMusselman,Department necrosis factor- cytokines, suchasinterleukin-1 accumulating databasehas and thebrain.Indeed,duringpast20years,arapidly information abouttheinterfacebetweenimmunesystem development ofpsychiatricsymptomshasrevealed evenmore relationship betweenanactivatedimmunesystemandthe suffering from neuropsychiatric disorders. More recently, the documented inanumberofcross-sectional studiesofpatients Perturbations ofimmunesystemfunctionhavebeen receiving IL-2therapy. important treatmentimplicationsthatwouldallowforimprovedadherenceandthus,increasedsurvivalratesinpatients hypothalamic–pituitary–adrenal axis.Anunderstandingoftheneurobiologicaleffects ofIL-2administrationmayhave monoamine distributionandmetabolisminanimalhumanmodels,cancausedisturbancesthe are thoughtbemediatedbytheeffects ofIL-2onneurotransmitterandendocrinesystems.has beenshowntoeffect treated withIL-2canalsodeveloppsychosisand/ordelirium.TheseIL-2-inducedalterationsinbehaviorandcognition and cognitiveeffects ofIL-2treatmentrevealahighincidencedepressivesymptomsandmemory disturbances.Patients neuropsychiatric effects arefrequentlynotthoroughlydocumented.Thosefewstudiesthathavefocused onthebehavioral frequently causesadverseeffects, manyofwhichcanlimittreatment.Areviewtheliteraturesuggests thatIL-2-induced the immunesystem,suchascancerandacquireddeficiencysyndrome(AIDS)and,whileofteneffective, IL-2 inflammatory responsesaswellincellmigrationanddifferentiation. IL-2hasbeenusedinthetreatment ofdiseases Interleukin-2 (IL-2)hasamyriadoffunctionsinthehealthyindividual.Itisanimportantsignalingmoleculeimmuneand 1 Stephen ENicolson Mechanisms andTreatment Implications Neuropsychiatric Effects ofIL-2: Winship CancerInstitute,EmoryUniversitySchoolofMedicine,Atlanta,GA,USA. allowed clinicianstobetterunderstandthepathophysiologyof patients undergoing treatment withIL-2andIFN- interferon- Furthermore, patientsadministered involving extensivetissuedamageordestruction. reactions, aswellthosereceiving cancertreatments cells produce cytokinesand/orelicitaggressive inflammatory behavioral alterationsincludeindividualswhoseneoplastic of cancerpatientsatincreased riskforsuchcytokine-induced dysfunction, aswellpsychosis.Asubsetofthepopulation alterations includingdepression, fatigue,andcognitive 120 Department ofPsychiatryandBehavioralSciences, α (IFN- α (TNF- α ) are especially Depression: MindBody α ), caninduceahostofbehavioral 1 , AndrewHMiller demonstrated thatavarietyof (IL-1), IL-2,IL-6,andtumor cytokines suchasIL-2and vulnerable. Interestingly, D EPRESSION 2006; : M α 2 (4):120–9. 1 have N AND IND , DavidLawson 2 Division ofMedicalOncology, DepartmentofMedicine, B cell-mediated immunityandtheTh1response, specifically of IL-2comprisethesethostresponses designatedas ILs, suchasIL-6andIL-10,TNF- interfere withviralreproduction andtumorgrowth), other cascade ofothercytokinesincludingIFNs(cytokinesthat cells, aswellpromoting thesynthesisandrelease ofa suppressor Tcells,activatedBandnaturalkiller(NK) of IL-2thenstimulatesproliferation ofhelper, cytotoxic,and response tocontactwithanantigen.The subsequentrelease factor, isreleased byT-helper (Th)lymphocytesprimarilyin another. IL-2,theglycoprotein alsoknown asTcellgrowth because theyallowleukocytestocommunicatewithone a Interleukins, endothelial, hematopoetic,andneuronal cells[1–5]. cell movement,angiogenesis,anddifferentiation in regulate immuneandinflammatoryresponses, hematapoesis, Cytokines are soluble,low-molecular-weight proteins that Cytokines andIL-2 receiving IL-2treatment willbediscussed. strategies toreduce behavioralmorbiditiesinpatients potential mechanismsinvolved.Inaddition,intervention focus ontheneuropsychiatric effects ofIL-2andexplore the changes associatedwithspecificcytokines.Thisreview will discriminate betweentheneurocognitive andneurobehavioral behavioral symptomscausedbycytokines,andhavehelped ODY Vol 2No42006 2 , andDominiqueLMusselman specific classofcytokines,are sonamed α [6,7]. Theactions 1 R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:39 Page 121

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designed to fight intracellular pathogens including viruses Patients with unresectable Stage IV melanoma or renal cell and parasites. In the context of cancer, IL-2 administration is cancer were given IL-2 at doses of 720 000 units/kg every used to augment cell-mediated immune responses and NK 8 h to a maximum of 12–15 doses. This was repeated after cell activity directed toward tumor antigens. 1–2 weeks. Depending on response and tolerance, further courses of treatment may be given. Although a potentially IL-2 and the brain effective therapy, IL-2 is notorious for causing a host of The importance of IL-2 within the brain can be deduced neuropsychiatric and physical symptoms. Indeed, the from the widespread neuroanatomical localization of this adverse effects of IL-2 treatment impact every organ cytokine and its receptors in both humans and animals. system in the body, and, more often than not, are so Cytokines such as IL-2 appear to regulate normal nervous debilitating that treatment must be prematurely terminated system development and function [8]. In cell cultures, [20]. The spectrum of IL-2-induced adverse behavioral IL-2 promotes rat neuronal growth in terms of dendritic effects include marked disturbances in neurocognitive branching and survival [9,10]. As the highest concentration function (e.g. memory disturbances, confusion, and of IL-2 receptors is found in the hippocampus [11], it is delirium), mood (e.g. depression and anxiety), perhaps not surprising that IL-2 knockout mice exhibit neurovegetative function (e.g. anorexia, fatigue, and sleep malformed hippocampal cytoarchitecture [12]. A role for disturbance), and perception (e.g. psychosis) [20–24]. IL-2 in modulating neuronal function is also indicated by Physical symptoms and laboratory alterations include nausea, the greater density of IL-2 receptor mRNA within neurons, vomiting, dermatological toxicity, diarrhea, fever, headache, rather than in microglia [13]. liver enzyme elevations, alterations of electrolytes [20,21], In disease states, IL-2 and its receptors have been neutropenia, and thrombocytopenia [23]. Myocarditis has detected in periventricular white matter lesions, including also been reported [25]. At very high doses, IL-2 has been increased expression of IL-2 mRNA in damaged areas of observed to induce marked fluid retention, prerenal human brain compared with normal tissue [14]. Post azotemia, weight gain >5 kg, and serious neurological mortem analyses of the striatum of patients with Parkinson’s symptoms [24]. Of note, IL-2 has also been used to treat disease have revealed increased levels of cytokines, including human immunodeficiency virus (HIV) and other IL-2 [15], and have also shown IL-2 and its receptors in the immunological/hematological conditions. brain lesions of multiple sclerosis patients [16]. IL-2 and neurocognitive dysfunction Cytokine induction and sickness behavior As shown in Table 1, [19–22,26–49] most IL-2 studies of Recent data indicate that cytokines, including IL-2, can have cancer patients have not included specific or sensitive profound effects on behavior, including the induction of measures of neuropsychiatic symptoms in their reports of sickness behavior. The syndrome of sickness behavior shares adverse events; therefore, estimation of the incidence of many of its signs and symptoms with major depression, such behavioral side effects has been challenging. including anhedonia, cognitive dysfunction, anxiety/irritability, Nevertheless, a small number of studies using standard psychomotor slowing, anergia/fatigue, anorexia, sleep neuropsychological instruments have documented not only alterations, and an increased sensitivity to pain [17]. These the incidence, but also the spectrum, of neurocognitive behavioral changes are observed in humans and laboratory symptoms induced by IL-2 [27,33]. Capuron and colleagues animals suffering from infection and inflammation and can utilized a well-standardized series of computerized tests, the be reliably reproduced by the administration of cytokines in Cambridge Neuropsychological Test Automated Battery isolation or by administering agents (e.g. endotoxin or (CANTAB) [50], to examine a wide range of cognitive lipopolysaccharide) that induce cytokine production [18]. functions in patients administered IL-2 alone (n=17), IL-2 Extensive tissue damage and destruction, such as occurs plus IFN-α (n=7), or IFN-α alone administered at low-dose during surgery, radiation therapy, and chemotherapy, may also (n=7) or high-dose (n=16) [22]. Study subjects underwent activate cytokine production, leading to behavioral change. CANTAB testing before initiation of cytokine therapy, and again on day 5 of immunotherapy. Patients receiving IL-2 IL-2-induced neurocognitive and therapy exhibited significant impairment in tasks of spatial neurobehavioral symptoms working memory, planning, and problem solving. In Characterization of the specific effects of IL-2 upon behavior contrast, patients treated with IFN-α exhibited impaired occurred by chance with the US Food and Drug Administration reaction times and psychomotor slowing. It is of note that (FDA) approval in 1992 of high-dose, intravenous IL-2 sleep disturbances were not associated with any of the therapy for the treatment of malignant melanoma [19]. cognitive changes documented during IL-2 therapy. Another

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Table 1. Selected studies of IL-2 neurotoxicity. Study Study population IL-2 dosing schedule/ Discontinuation rate Psychometric Prevalence of neurocognitive concomitant therapeutic agents instruments used or neurobehavioral toxicity Thompson 22 patients Escalating weekly doses of rIL-2, 23% did not None reported Flu-like symptoms 59% et al. [26] with refractory given either IV by 2- or 24-h infusion, complete treatment malignancies or SC. Maximum IV dose was 30 MU Denicoff 44 metastatic IL-2 doses were either 30 000 All completed BDI with score ≥14 Neuropsychiatric effects et al. [27] cancer patients or 100 000 U/kg or 30 000 U/kg treatment, but 11% indicating moderate dose- and time-related administered with (n=31) did not complete level of depression appearing more often at or without (n=13) autologous follow-up higher doses (71% vs. 32%) lymphokine-activated killer cells Delusions 16% Moderate depression 20% Delirium 50% Thompson 23 progressive IL-2 was administered IV daily 26% did not None reported Confusion 13% et al. [28] cancer patients for 5 consecutive days every other complete treatment Restlessness 22% week for 4 weeks: patients received 0.3 or 3 MU/m2/day Sarna 19 patients with rIL-2 given 5 days/week by IV bolus Dose escalation None reported Fatigue 42% et al. [29] advanced malignancies at starting doses ranging from limited by toxicities Hyperasthesthia/ 0.05–2.56 MU/m2 in 100% of patients parathesia 26% Maximal tolerated dose was Confusion 5% 3.84 MU/m2 Pace 20 cancer patients IL-2 given in doses of 9 or Post-therapy testing MMSE MMSE slightly altered in 15% et al. [30] (13 melanoma, five 18 MU/m2/day. Patients were unsatisfactory due to EEG Overall slowing of background renal, two colon) tested before and after first dose technical reasons in Evoked cognitive EEG rhythm when compared 10% of patients potentials to baseline Absolute P300 was delayed in 17 (94%) patients and significantly delayed (>22 msec) in 10 (55%) patients, indicating a slowing of cognitive processing Smith 52 patients with renal Protocol of cisplatinum, IV IL-2 Unknown Physician-administered, Severe fatigue: 100% by end et al. [31] cell carcinoma and (18 IU/m2/day, 4–5 days/week, observer-rated checklist of week 4 (compared with metastatic melanoma 2 weeks/month) with SC INF-α of 52 symptoms on 30% at onset) a 3-point scale MDD: 76% by week 4 other than the rule-out organic etiology criteria (compared with 12% at onset) Joffe 55 advanced renal 8-week cycle of IL-2 (20 MU/m2 on 20% discontinued QOL questionnaire Malaise, nausea, and anorexia et al. [20] carcinoma patients days 3–5 in weeks 1, 4, and 5 MU/m2 RSCL 30–66% 3× weekly in weeks 2–3) with IFN-α QOL questionnaires before, and 5-FU. Patients responding to the during, and after treatment first cycle were eligible to continue were received from only with further cycles 11 patients. Significant deteriorations were identified within the entire group in loss of appetite, dry mouth, lack of energy, nervous feeling, lack of sexual interest, shivering, nausea, and tiredness Creagan 19 advanced malignant IL-2 at 3 MU/m2 SC daily × 5 42% did not None reported Severe lethargy 32% et al. [32] melanoma patients plus levamisole 50 mg/m2 by continue to second Severe musculoskeletal mouth 3×/day ×5 treatment cycle pain 5% Severe anorexia 11% Severe insomnia 5% Walker 17 advanced colorectal Randomized, parallel group study 100% discontinued MMSE Delirium 22% (vs. 0% et al. [33] cancer patients of rIL-2 with chemotherapy (5-FU therapy before the SCID in control group) and leucovorin) vs. chemotherapy 6 months in the IL-2 HADS Compared with patients who alone. rIL-2 dose: 18 MIU/m2/24 h group (compared TMT were given chemotherapy continuously over 5 days once every with 88% in the DSST alone, patients receiving rIL-2 4 weeks. Up to 6 months of treatment control group) reported statistically significant was given impairment on post-treatment testing including HADS, TMT, and DSST Atkins 270 metastatic IL-2 600 000 or 720 000 IU/kg every 70% discontinued NCI CTC (no specific Malaise 34% et al. [19] melanoma patients 8 h for up to 14 consecutive doses before the second criteria for confusion Confusion 30% over 5 days, as clinically tolerated. course, 99% before in pre-1998 version) Somnolence 17% A second identical treatment cycle the fifth course Coma 1% was scheduled after 6–9 days of rest, with courses repeated every 6–12 weeks in stable or responding patients Capuron 48 renal cell carcinoma Patients were treated either with SC 36% patients MADRS (severe Severe depression on day 5 et al. [34] or melanoma patients IL-2 alone (n=20), in combination who developed depression defined in 50% of patients treated with IFN-α (n=6); or with IFN-α alone. severe depression as score >15) with IL-2 and IFN-α; 25% Doses of IL-2 were 18 MIU/m2/day SC discontinued treatment Covi scale [35] receiving IL-2 alone; and ×5 days or 18 MIU/m2/day SC ×5 days 14% treated with IFN-α alone Anxiety scores did not change significantly during treatment

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Table 1. Continued. Study Study population IL-2 dosing schedule/ Discontinuation rate Psychometric Prevalence of neurocognitive concomitant therapeutic agents instruments used or neurobehavioral toxicity Dutcher 50 metastatic renal Two alternating outpatient regimens 98% discontinued QLQ-C30 IL-2/INF-α course: et al. [21] cell cancer patients consisting of 4 weeks of rIL-2 plus before study completion McCorkle and Young 50% fatigue/flu-like symptoms; IFN-α (course A) followed by 4 weeks symptom distress 64% CNS symptoms (mood, of 5-FU plus IFN-α (course B). Up to scale [36] agitation, anxiety, depression) four courses given. Dosage of rIL-2: 5-FU/IFN-α course: 5–20 MIU/m2/day ×3 days/week (control n=45) Fatigue 20%; CNS 0% Capuron 47 renal cell carcinoma Patients were assigned to high-dose >50% of treatment None reported HD: Malaise 21%; CNS level et al. [22] or melanoma patients IV 720 000 U/kg TID, low-dose IV courses for high-dose of consciousness 3%; 72 000 U/kg IV 3×day, or SC starting and low-dose interrupted CNS disorientation 10% at 250 000 U/kg/day due to toxicity, while LD: Malaise 10%; CNS level most patients in SC group of consciousness 3%; were able to receive full CNS disorientation 4% treatment courses SQ: Malaise 9%; CNS level of consciousness 0%; CNS disorientation 2% Woodson 40 melanoma patients Patients were randomized to receive 43% required NCI CTC (version 2.0) After the initiation of IL-2 et al. [38] a weekly vaccine paired with a regimen discontinuation or therapy, toxicities of greater of SC IL-2 (3 MIU/m2/day) dose modification severity began to occur in each administered daily for 6 weeks due to toxicity treatment group (not detailed) beginning either at week 1 or at week 4 of vaccine therapy Nicolini 26 female metastatic SC IL-2 + β-IFN after initial No interruptions of NCI CTC (version 2.0) Asthenia 70% et al. [39] breast cancer patients anti-estrogen treatment. therapy. Two patients (8%) Anorexia ≥14% IL-2 dose: 3 MIU/day for required dose reduction 3 days/week ×4 weeks due to creatininemia Donskov 104 metastatic renal IL-2 with or without HDC 30% discontinued NCI CTC (version 2.0) IL-2/HDC groups: lethargy et al. [40] cell carcinoma patients IL-2 dose: 18 MIU/day for 5 days/week before second 10–18%; confusion/memory ×3 weeks followed by 2 weeks rest. course, 76% before loss 6%; tremor 3%; headache Continuing for up to 4 cycles fourth course 5%; flu-like symptoms 10%; pain 0% IL-2-only groups: lethargy 10–20%; confusion/memory loss 7%; tremor 0%; headache 0%; flu-like symptoms 5–7%; pain 3% 5-FU: fluorouracil; BDI: Beck depression inventory; CANTAB: Cambridge Neuropsychological Test Automated Battery [41]; CNS: central nervous system; DSST: digit symbol substitution test of Wechsler Adult Intelligence Scale [42]; EEG: electroencephalogram; HADS: hospital anxiety and depression scale [43]; HDC: histamine dihydrochloride; IL: interleukin; IFN: interferon; IV: intravenous; MADRS: Montgomery and Asberg depression rating scale [44]; MDD: major depressive episode; MIU: million international units; MU: million units; MMSE: mini mental state examination [45]; NCI CTC: National Cancer Institute common toxicity criteria; QOL: quality of life; QLQ-C30: quality of life questionaire [46]; rIL-2: recombinant IL-2; RSCL: rotterdam symptom checklist [47]; SC: subcutaneous; SCID: structured clinical interview [48]; TMT: trail making test (parts A and B) [49]; TIL: tumor-infiltrating lymphocytes; U: units.

smaller study by Caraceni et al. utilized a battery of cognitive et al. [34], the clinician-administered Montgomery Asberg tests in patients (n=7) receiving a 5-day course of recombinant Depression Rating Scale (MADRS) [44] was used in a group of IL-2 [51]. Subjects showed a statistically significant decline in 17 patients receiving IL-2 for renal cell carcinoma. Within 3 cognitive performance on six of eight neuropsychological tests, days of initiating IL-2 therapy, significant increases in depressive including the mini mental state exam (MMSE) [45], Digit Span symptoms were apparent. By day 5 of treatment, 25% of (forward and backward), Corsi’s spatial test (forward and patients exhibited severe depressive symptoms (MADRS score backward recall), and Zazzo’s attention test (speed and >15), which increased to 33% after 4 weeks of IL-2 therapy. inaccuracy) [51]. Neurophysiological evaluation by means of P300 evoked potentials paralleled these results, revealing a IL-2 and psychosis slowing of cognitive processing. Performance recovered a week Although frequently seen during IL-2 therapy, the incidence of after IL-2 therapy ended. These results suggest that IL-2 psychotic symptoms, such as hallucinations and delusions, is interferes with multiple neural circuits, including those in the not well understood and may occur in up to 20% of IL-2 prefrontal and temporal cortices as well as subcortical brain treated patients [53,54]. Current standard clinical protocols areas [52]. dictate that when symptoms such as persistent crying, disorientation, delusions, or hallucinations develop during IL-2 IL-2 and alterations of mood treatment, IL-2 should be discontinued immediately for that Similar to the literature documenting IL-2-induced cycle [55], thereby limiting the number of doses received. neurocognitive dysfunction, a small number of other studies Unfortunately, no study has assessed the relative presence of have used psychometric rating scales to characterize neuropsychiatric symptoms as they relate to premature changes in mood induced by IL-2. In a study by Capuron termination of IL-2 therapy.

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Table 2. CNS pathways altered by IL-2, associated symptoms, and methods of detection. Alterations of CNS monoamine, Relevant CNS pathway/location Relevant symptom complex Assays to confirm “peripheral” cytokine, or neurohormone in humans (preclinical studies) in humans alterations in neurochemical pathway 5-HT production not altered Prefrontal cortex, amygdala, and Anorexia, altered sleep–wake cycle, ↓ plasma 5-HT, KYN, TRP, neopterin; in nucleus accumbens [77], hippocampus, caudate and anxiety, depression, impulsivity, SS allele of 5-HT promotor polymorphism or hippocampus [78] putamen, cerebellum ↓ learning and memory ↓ DA turnover basal ganglia and Nigrostriatal, mesolimbic, mesocortical Psychomotor slowing, impaired ↑ plasma prolactin levels nucleus accumbens [77,79,80] pathways, tuberoinfundibular and reaction time, hallucinations/delusions, ↓ plasma and urinary DA tuberohyophysial systems anhedonia ↑ CRF secretion in amygdala HPA axis; amygdala and hippocampus Anxiety, depression ↑ plasma ACTH, cortisol [27,82] and hypothalamus [81] DST nonsuppression ↑ IL-6, TNF-α release Spinal cord [83], HPA axis, Anorexia [84], impaired coordination, ↑ plasma IL-1, IL-4, IL-6, IFN-γ, TNF, hypothalamus sedation [85], psychomotor slowing CRP, NFκB, NFAT, AP-1 ↑ NE turnover in median eminence, Prefrontal cortex, hippocampus, Impaired spatial working memory, ↑ plasma and urinary catecholamines hippocampus [86],[87]; hypothalamus, thalamus, limbic planning, and problem solving ↓ NE release in hypothalamus [88] system, cerebellum ↓ ACh release in hippocampus [11,89] Prefrontal cortex, hippocampus, Confusion, sleep disturbances, ↑ serum anticholinesterase activity caudate-putamen, nucleus accumbens, delirium hypothalamus, thalamus ↑ Endogenous opioid release [88] Spinal cord [90], amygdala [91], (Increased/decreased) pain ↑ methionine-enkephalin, beta-endorphin nucleus accumbens [92], ventral perception, sedation, delirium plasma levels tegmental area [93] ↑ NDMA receptor functioning [94] Mesolimbic projections to cortex Psychosis, arousal, attention, Unknown motivation, psychomotor slowing ACh: acetylcholine; ACTH: adrenocorticotropic hormone; AP-1: activator protein-1; 5-HT: serotonin; CNS: central nervous system; CRF: corticotropin releasing factor; CRP: C-reactive protein; DA: dopamine; DST: dexamethasone suppression test; HPA: hypothalamic–pituitary–adrenal; IL: interleukin; KYN: kynurenine; NDMA: N- methyl-D-aspartate; NE: norepinephrine; NFκB: nuclear factor kappa B; NFAT: nuclear factor of activated T cells; TNF: tumor necrosis factor; TRP: tryptophan.

IL-2 and psychiatric disorders cytokine signals via afferent nerve fibers (e.g. the vagus nerve) Aside from examining the direct effects of IL-2 on behavior, [68–70]. Indeed, radioactively-labeled IL-2, administered a number of correlational studies have examined the intravenously, can cross the blood–brain barrier to the enter relationship between IL-2 plasma concentrations in the mouse brain, which provides evidence that IL-2 can psychiatric patients with disorders such as depression directly effect the central nervous system (CNS) [71,72]. [56–61] and schizophrenia [62–65]. Unfortunately, these Moreover, a single dose of systemic IL-2 has been shown to studies have yielded somewhat conflicting results. For increase permeability of the blood–brain barrier to cytokines example, as reviewed by DeLisi in 1996, patients with in animal models [73,74]. schizophrenia have been documented to have increased and Attention has been paid to cytokine interactions with decreased IL-2 plasma concentrations during psychotic neuroendocrine and neurotransmitter systems as possible episodes [66]. These contradictory findings are likely related mechanisms by which cytokines such as IL-2 influence to a small sample size (generally <50 patients) and multiple behavior, since both of these are well-known to be involved confounding factors that alter plasma concentrations of IL-2, in the pathophysiology of neuropsychiatric disease. Potential including adiposity, smoking, and ingestion of aspirin or points of interactions are seen at a cellular level, for nonsteroidal anti-inflammatory medications [25]. Moreover, example, in the rat brain, where 30% of CNS neurons show it has been suggested that cytokine alterations may only co-staining for IL-2, estrogen receptors, and glutamate characterize a subgroup of schizophrenia subjects, especially receptors [75]. Thus, IL-2 may in part induce changes in those with an increase in autoimmune diathesis [67]. behavior through effects on neurons where there exists a co-localization of immune, hormonal, and neurotransmitter The neurobiology of IL-2-induced systems [75]. behavioral change As seen in Table 2, a host of preclinical studies have A large body of research has been devoted to examining the documented perturbations by IL-2 of important neuro- neurobiological pathways by which IL-2 influences the brain transmitter (and neuropeptide) systems essential to the and behavior. Since cytokines, such as IL-2, are too large to regulation of mood and neurocognitive function, including freely pass through the blood–brain barrier, considerable serotonin (5-HT), dopamine, corticotrophin-releasing factor attention has focused on how cytokine signals that originate (CRF), norepinephrine (NE), acetylcholine (ACh), endogenous in the periphery reach the brain. Pathways by which opioids, and N-methyl-D-aspartate (NMDA) [76]. cytokines may influence the brain include passage through Although not well-studied in humans, repeated leaky regions in the blood–brain barrier, active transport administration of IL-2 to mice (0.55–17.6 × 103 IU per through specific transporter molecules, and transmission of mouse) increases the turnover of NE within the median

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eminence and hippocampus, alters 5-HT levels in the modulate NDMA receptors in ventral tegmental area neurons hippocampus and prefrontal cortex, and reduces dopamine in neonatal rats. Low doses of IL-2 (0.001–10 ng/mL) turnover in the caudate and substantia nigra [87]. The inhibited the effects of NDMA applied to these neurons, enhanced NE turnover observed in the median eminence while a higher dose (250 ng/mL) potentiated the effects and hippocampus of animals who have been administered [94]. The influence of IL-2 on these (and other) IL-2 peripherally [86], and the diminished ACh release in the neurotransmitter systems likely explains the wide ranging hippocampus [11,89], may contribute to their behavioral effects of IL-2 administration on behavior, including alterations (such as anhedonia, psychomotor retardation, difficulties with cognition, sleep and appetite alterations, and anorexia), although whether these behavioral alterations psychomotor slowing, mood symptoms, and psychosis. are in fact the result of disturbances in hippocampal NE or 5-HT function remains controversial [78]. IL-2 effects on HPA axis activity The effect of IL-2 on 5-HT neurotransmission in the brain In addition to their effects on neurotransmitter systems in is debatable. Some researchers have observed diminished the CNS, cytokines, including IL-2, have been shown to 5-HT levels in the hippocampus and prefrontal cortex after exert potent stimulatory effects on the hypothalamic– systemic IL-2 administration [87]; however, others have not pituitary–adrenal (HPA) axis, predominantly through activation [77,78]. Alterations of 5-HT concentrations in the brain by of corticotrophin-releasing hormone (CRH) [104,105]. As IL-2 (and other cytokines) can potentially occur through with other proinflammatory cytokines such as IL-1, IL-6, and reductions in serum L-tryptophan. Tryptophan, the primary TNF-α, IL-2 administration stimulates CRH release from the precursor of 5-HT, is reduced during diminished dietary amygdala and hypothalamus [27,81,106–111], an effect intake and/or induction of the enzyme indolamine that appears to be mediated in part by nitric oxide [81]. 2,3 dioxygenase (IDO), which breaks tryptophan down into Moreover, several preclinical and clinical studies have shown kynurenine and quinolinic acid. Quinolinic acid, in turn, that IL-2 administration, like IFN-α therapy, is also exhibits neurotoxic properties [95–97]. Indeed, IL-2 increases associated with HPA axis activation, as manifested by IDO activity in human peripheral blood mononuclear cells increased plasma concentrations of ACTH and cortisol. (PBMCs), and is associated with a subsequent reduction in However, in contrast to IFN-α therapy [112], chronic IL-2 plasma tryptophan [98]. Tryptophan depletion has long administration results in persistent elevations in cortisol been known to precipitate depressive symptoms in [113–116], which may be related to disruption of the vulnerable patients [99]. functioning of glucocorticoid receptors (and possibly related Animal and cell culture models reveal a more complex to interactions between glucocorticoid receptors and relationship between IL-2 and dopamine. In the rat striatum, inflammatory signaling pathways such as p38 mitogen- IL-2 administration has led to increased dopaminergic activated kinases and transduction and activation of transmission in a dose-dependent manner [100]. However, transcription 5 [STAT 5] signaling). Glucocorticoid receptors although low concentrations of IL-2 may potentiate dopamine mediate negative feedback on CRH and ultimately cortisol release in mesencephalic cell cultures, higher concentrations release [117–119]. Central administration of CRH has have been observed to inhibit its release [101]. In animal behavioral effects in animals that are similar to those seen in models, the effect of IL-2 on the dopamine system has been patients suffering from depression/sickness behavior, including linked to behavioral consequences. Peripheral administration diminished activity, lowered appetite, and disturbed sleep of IL-2 resulted in a two-fold increase in climbing behavior, a [120]. Furthermore, in humans, memory impairment, impaired marker of increased dopamine activity in mice. This behavior executive function, and psychosis, as well as reduced ceased when the mice were injected with both D1 and D2 hippocampal volume have all been associated with increased dopamine receptor antagonists [102]. The decrease in DA endogeneous cortisol secretion or glucocorticoid administration turnover in basal ganglia and nucleus accumbens observed in [121–131]. These results suggest that consideration should animal models may also occur within the human CNS, be given to glucocorticoid antagonism (e.g. RU38486 or resulting in anhedonia, marked psychomotor slowing, and glucocorticoid synthesis inhibitors) in addressing IL-2 effects perhaps even psychotic symptoms. on HPA axis activity and behavior. With regard to pain pathways in the rat hypothalamus, application of exogenous IL-2 increased release of the IL-2 effects on HPA axis function endogenous opioids, methionine-enkephalin and β-endorphin In contrast to other proinflammatory cytokines, which are [88]. It should be noted that in the peripheral nervous more likely to induce hypothyroidism [56,132], IL-2 system, IL-2 may decrease pain through its binding to opioid administered to HIV-infected patients over a course µ-receptors [90,103]. Lastly, IL-2 has also been shown to of 5 days has been shown to stimulate the pituitary–thyroid

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axis [133]. In these IL-2-treated patients, free thyroxine and trifluperidol) interfere with cytokine release [138,139]. levels were elevated to hyperthyroid levels. IL-2’s An in vitro study of the effects of neuroleptics on blood perturbation of thyroid function differs from other cytokines samples of non-psychotic patients has also shown an (typically IL-1, IL-6, and TNF-α) that induce euthyroid sick antagonism of IL-2 release by both typical and atypical syndrome (ESS), characterized by normal thyroid stimulating antipsychotics [140]. Although other psychoactive hormone (TSH) and thyroxine (T4) levels and reduced medications have been shown to interfere with IL-2 release triiodothyronine (T3) levels in the early stages, and by in vitro, i.e. bromocriptine [141], cannabinol [142], and normal TSH and reduced T3 and T4 in the later stages [134]. opioids [143], or to decrease cytokine-induced catabolism The mechanism by which ESS occurs is believed to involve of tryptophan, i.e. St John’s Wort [144], whether the both the direct effects of cytokines on thyroid gland function diminished IL-2 release exerts untoward effects upon as well as inhibition of the metabolic enzymes (5’-deiodination) cancer-related outcomes remains unknown. that convert peripheral T4 to T3 (the more biologically active Most data involving treatment of cytokine-induced form of thyroid hormone), especially in the liver [134]. depressive symptoms have involved patients receiving IFN-α. In a study of 55 melanoma patients receiving low-dose IL-2 One randomized, double-blind, placebo-controlled trial of combined with vaccination, 25% of patients developed patients undergoing treatment for malignant melanoma thyroid abnormalities [135]; unfortunately, the incidence of demonstrated efficacy for the selective serotonin reuptake thyroid perturbations and associated changes in mood were inhibitor paroxetine in the prophylactic treatment of IFN-α- not measured. As even subtle alterations in thyroid hormone induced depression [145]. An open-label study describes availability (both hyper- and hypothyroidism) are known to similar results using both paroxetine and citalopram [146]. be associated with mood disorders [136], the mechanism(s) Reports indicate other antidepressants may also be effective whereby IL-2 may alters thyroid function should remain a in the treatment of INF-α-induced depression, including subject of continuing investigation. bupropion [147], mirtazapine [148], milnacipram [149], and sertraline [150]. Antidepressants such as paroxetine have Neuropsychiatric adverse effects of IL-2: been shown to inhibit the release of proinflammatory treatment implications cytokines [151], which may account for their effectiveness in Given the neurocognitive and neurobehavioral symptoms INF-induced depression. No randomized, double-blind, that develop during IL-2 therapy, and the well-known placebo-controlled trials have yet been conducted to impairment of quality of life, treatment compliance, and evaluate amelioration of the cognitive, mood, and psychotic survival of cancer patients who suffer from neuropsychiatric symptoms induced by IL-2. Even though paroxetine syndromes, the current challenge for the medically ill patient pretreatment of malignant melanoma patients undergoing and healthcare provider alike is the treatment, and perhaps high-dose IFN-α reduced the incidence of IFN-α-induced even prevention, of IL-2-induced CNS dysfunction. Usually, depression [148], whether antidepressant pretreatment treatment of the neuropsychiatric side effects of cytokine represents an effective neuroprotective strategy for therapy has included dose reduction and/or termination of minimizing IL-2-induced depression and neurotoxicity immunotherapy, leading to compromised treatment [137]. remains unknown. Any treatment for cytokine-induced symptoms with Moreover, although both IL-2 and IFN-α patients may psychotropic medication is considered off-label use. respond to antidepressant treatment, it is possible that the Symptomatic treatments include temazepam or zolpidem mechanism of these psychotropic agents may have both for insomnia, haloperidol for agitation or combativeness, overlapping yet distinct features with either cytokine. For and lorazepam for anxiety [55]. However, these example, while increasing the availability of 5-HT (and other recommended treatments for IL-2-induced symptoms are neurotransmitters) may be relevant to the development and without evidence from randomized, clinical trials. treatment of depression in both conditions, as discussed Information regarding the management of neuropsychiatric previously, antidepressant effects on HPA axis reactivity and symptoms induced by IL-2 therapy has been gleaned solely glucocorticoid sensitivity may be relatively more important from small, open-label studies. In a small study of patients for patients undergoing IL-2 therapy (who may exhibit more who developed delirium during IL-2 treatment (n=7), their profound and persisting HPA axis activation, which, in turn, severe agitation or paranoia improved with low-dose may contribute to mood lability, cognitive dysfunction, and haloperidol (no more than 10 mg/day in five of the seven psychosis). In fact, data indicate that antidepressants can patients) administered over a 1–2-day period [53]. More reduce elevated CRH activity (and hypercortisolism), recent studies utilizing animal models have revealed that enhance glucocorticoid receptor function (and overcome neuroleptics (such as chlorpromazine, loxapine, flupentixol, glucocorticoid resistance), and decrease the production of

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Figure 1. Mechanisms of IL-2 effects on behavior.

IDO 5-HT

IL-2

Behavioral changes Proinflammatory Depression CRH cytokines Memory impairment Psychosis Glucocorticoid resistance

ACTH Cortisol Antidepressant therapy • Increases 5-HT availability negative feedback • Decreases CRH/cortisol hypersecretion • Reverses glucocorticoid resistance

5-HT: serotonin; ACTH: adrenocorticotropic hormone; CRH: cortisol-releasing hormone; IDO: indoleamine 2,3-dioxygenase; IL-2: interleukin-2.

proinflammatory cytokines [152,153]. A model conceptualizing received research support from DANA Foundation, GlaxoSmithKline, IL-2 behavioral effects and treatment implications is Janssen, NIH, Pharmacia & Upjohn, and Schering-Plough and is a proposed in Figure 1. member of the Speakers Bureau for Forest Pharmaceuticals Inc., GlaxoSmithKline, Organon Inc., and Pfizer. Dr Nicolson has no financial Conclusion interests to disclose. Further characterization of neurocognitive dysfunction (and its relationship with alterations of neuroimmune function References 1. Bennett NT, Schultz GS. Growth factors and wound healing: Part II. Role in normal and neurochemistry within the brain) will provide valuable and chronic wound healing. Am J Surg 1993;166:74–81. information regarding the mechanism of IL-2-induced 2. Bennett NT, Schultz GS. Growth factors and wound healing: biochemical properties neuropsychiatric symptoms. This information is especially of growth factors and their receptors. Am J Surg 1993;165:728–37. 3. Michalek SM, Moore RN, McGhee JR et al. The primary role of lymphoreticular cells in important as patients receiving immunotherapies such as the mediation of host responses to bacterial endotoxim. J Infect Dis 1980;141:55–63. IL-2 are burdened with multiple stressors, including the 4. Clark RA. Growth factors and wound repair. J Cell Biochem 1991;46:1–2. 5. Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human physiological effects of their particular cancer (including infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 1996;9:532–62. 6. Haynes BF, Fauci AS. Chapter 295. Introduction to the immune system. In: Kasper DL, pain, lack of mobility, and decreased functional status), the Braunwald E, Fauci AS et al. Harrison’s Principles of Internal Medicine. 16th ed. existential meaning of the diagnosis, grief, guilt, preparations Online Version: The McGraw-Hill Companies, Inc; 2005. 7. Hanisch UW, Quirion R. Interleukin-2 as a neuroregulatory cytokine. Brain Res Rev for death, financial challenges, and time constraints, among 1996;21:246–84. others. Research into the particular neuropsychiatric 8. Ye JH, Zalcman SS, Tao L. Kainate-activated currents in the ventral tegmental area of neonatal rats are modulated by interleukin-2. Brain Res 2005;1049:227–33. syndrome or syndromes caused by IL-2 administration can 9. Sarder M, Saito H, Abe K. Interleukin-2 promotes survival and neurite extension of only serve to provide fresh avenues for exploration of cultured neurons from fetal rat brain. Brain Res 1993;625:347–50. 10. Awatsuji H, Furukawa Y, Nakajima M et al. Interleukin-2 as a neurotrophic factor for treatment approaches that will allow physicians to help supporting the survival of neurons cultured from various regions of fetal rat brain. J Neurosci Res 1993:35:305–11. patients maximize their health. 11. Araujo BM, Lapchak PA, Collier B et al. Localization of interleukin-2 immunorreactivity and interleukin-2 receptors in the rat brain. Brain Res 1989;498:257–66. 12. Beck R Jr, King M, Ha G et al. IL-2 deficiency results in altered septal and hippocampal Acknowledgements cytoarchitecture: relation to development and neurotrophins. J Neuroimmunol 2005;160:146–53. This manuscript was supported by R01 MH071580. 13. Shimojo M, Imai Y, Nakajima K et al. Interleukin-2 enhances the viability of primary cultured rat neocortical neurons. Neurosci Lett 1993;51:170–3. 14. Kadhim H, Tabarki B, De Prez C et al. Interleukin-2 in the pathogenesis of perinatal white Disclosures matter damage. Neurology 2002;58:1125–8. Dr Lawson is a speaker/consultant for Chiron and Schering-Plough. 15. Nagatsu T, Mogi M, Ichinose H et al. Cytokines in Parkinson’s disease. J Neural Transm Suppl 2000;58:143–51. Dr Miller has received grants from Centocor, Inc., Forest Laboratories, 16. Hofman FM, von Hanwehr RI, Dinarello CA et al. Immunoregulatory molecules and Inc., GlaxoSmithKline, Janssen, and Schering-Plough. Dr Musselman has IL 2 receptors identified in multiple sclerosis brain. J Immunol 1986;136:3239–45.

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17. Kent S, Bluthe RM, Kelley KW et al. Sickness behavior as a new target for drug 52. Karp BI, Yang JC, Khorsand M et al. Multiple cerebral lesions complicating therapy with development. Trends Pharmacol Sci 1992;13:24–8. interleukin-2. Neurology 1996;47:417–24. 18. Yirmiya R, Weidenfeld J, Pollak Y et al. Cytokines, “depression due to a general medical 53. Denicoff KD, Rubinow DR, Papa MZ et al. The neuropsychiatric effects of treatment with condition,” and antidepressant drugs. Adv Exp Med Biol 1999;461:283–316. interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987;107:293–300. 19. Atkins MB, Lotze MT, Dutcher JP et al. High-dose recombinant interleukin-2 therapy 54. Smith MJ, Khayat D. Residual acute confusional and hallucinatory syndromes induced for patients with metastatic melanoma: analysis of 270 patients treated between 1985 by interleukin-2 /alpha-interferon treatment. Psychooncology 1992;1:115–8. and 1993. J Clin Oncol 1999;17:2105–16. 55. Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. 20. Joffe JK, Banks RE, Forbes MA et al. A phase II study of interferon-[alpha], interleukin-2, J Immunother 2001;24:287–93. and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence 56. Jozuka H, Jozuka E, Takeuchi S et al. Comparison of immunological and endocrinological of pretease activation. BrJ Urol 1996;77:638–48. markers associated with major depression. J Int Med Res 2003;31:36–41. α 21. Dutcher J, Logan T, Gordon M et al. Phase II trial of interleukin 2, interferon , 57. Nunes SOV, Reiche EMV, Morimoto HK et al. Immune and hormonal activity in adults and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. suffering from depression. Braz J Med Biol Res 2002;35:581–7. Clin Cancer Res 2000;6:3442–50. 58. Androsova LV, Kushner SG, Abramova LI et al. [Interleukin level in endogenous 22. Capuron L, Ravaud A, Dantzer R. Timing and specificity of the cognitive changes induced depression]. Zh Nevrol Psikhiatr Im SS Korsakova 2001;101:45–8. by interleukin-2 and interferon-alpha treatments in cancer patients. Psychom Med 2001;63:376–86. 59. Rothermundt M, Arolt V, Fenker J et al. Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 2001;251:90–7. 23. Flaherty LE, Atkins M, Sosman J et al. Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two 60. Kagaya A, Kugaya A, Takebayashi M et al. Plasma concentrations of interleukin-1beta, Phase II Cytokine Working Group trials. J Clin Oncol 2001;19:3194–202. interleukin-6, soluble interleukin-2 receptor and tumor necrosis factor alpha of depressed patients in Japan. Neuropsychobiology 2001;43:59–62. 24. Eton O, Rosenblum M, Legha S et al. Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma. Cancer 2002;95:127–34. 61. Maes M, Stevens WJ, Declerck LS et al. Significantly increased expression of T-cell activation markers (interleukin-2 and HLA-DR) in depression: further evidence for an 25. Haack M, Hinze-Selch D, Fenzel T et al. Plasma levels of cytokines and soluble cytokine inflammatory process during that illness. Prog Neuropsychopharmacol Biol Psychiatry receptors in psychiatric patients upon hospital admission: effects of confounding factors 1993;17:241–55. and diagnosis. J Psychiatric Res 1999:33:407–18. 62. Zhang XY, Zhou DF, Cao LY et al. Cortisol and cytokines in chronic and treatment-resistant 26. Thompson J, Lee D, Cox W et al. Recombinant interleukin 2 toxicity, pharmacokinetics, patients with schizophrenia: association with psychopathology and response to and immunomodulatory effects in a phase I trial. Cancer Res 1987; 47:4202–7. antipsychotics. Neuropsychopharmacology 2005;30:1532–8. 27. Denicoff KD, Ribinow DR, Papa MZ et al. The neuroendocrine effects of interleukin-2 63. Mahendran R, Chan YH. Interleukin-2 levels in chronic schizophrenia patients. treatment. J Clin Endocrinol Metab 1987;69:402–10. Ann Acad Med Singapore 2004;33:320–3. 28. Thompson J, Lee D, Lindgren C et al. Influence of dose and duration of infusion of 64. Baker I, Masserano J, Wyatt RJ. Serum cytokine concentrations in patients with interleukin-2 on toxicity and immunomodulation. J Clin Oncol 1988;6:669–78. schizophrenia. Schizophr Res 1996;20:199–203. 29. Sarna G, Figlin R, Pertcheck M et al. Systemic administration of recombinant methionyl 65. Ebrinc S, Top C, Oncul O et al. Serum interleukin 1 alpha and interleukin 2 levels in human interleukin-2 (Ala 125) to cancer patients: clinical results. J Biol Response Mod patients with schizophrenia. J Int Med Res 2002;30:314–7. 1989;8:16–24. 66. DeLisi L. Is there a viral or immune dysfunction etiology to schizophrenia? Re-evaluation 30. Pace A, Pietrangeli A, Bove L et al. Neurotoxicity of antitumoral IL-2 therapy: evoked a decade later. Schizophr Res 1996;22:1–4. cognitive potentials and brain mapping. Ital J Neurol Sci 1994;15:341–6. 67. Jones AL, Mowry BJ, Pender MP et al. Immune dysregulation and self-reactivity 31. Smith MJ, Vuillemin E, Benhammouda A et al. Psychological side effects induced by in schizophrenia: do some cases of schizophrenia have an autoimmune basis? interleukin-2/alpha-interferon treatment. Psychooncology 1994;3:289–98. Immunol Cell Biol 2005;83:9–17. 32. Creagan ET, Rowland KM Jr, Suman VJ et al. Phase II study of combined levamisole 68. Rivest S, Lacroix S, Vallieres L et al. How the blood talks to the brain parenchyma and the with recombinant interleukin-2 in patients with advanced malignant melanoma. paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious Am J Clin Oncol 1997;20:490–2. stimuli. Proc Soc Exp Biol Med 2000;223:22–38. 33. Walker LG, Walker MB, Heys SD et al. The psychological and psychiatric effects 69. Plotkin SR, Banks WA, Kastin AJ. Comparison of saturable transport and extracellular of rIL-2 therapy: a controlled clinical trial. Psychooncology 1997;6:290–301. pathways in the passage of interleukin-1 alpha across the blood-brain barrier. 34. Capuron L, Ravaud A, Dantzer R. Early depressive symptoms in cancer patients receiving J Neuroimmunology 1996;67:41–7. interleukin 2 and/or interferon alfa-2b therapy. J Clin Oncol 2000;18:2143–51. 70. Watkins LR, Maier SF, Goehler LE. Cytokine-to-brain communication: a review & analysis 35. Covi L, Lipman R, McNair D et al. Symptomatic volunteers in multicenter drug trials. of alternative mechanisms. Life Sci 1995;57:1011–26. Prog Neuropsychopharmacol 1979;3:521–33. 71. Waguespack P, Banks W, Kastin A. Interleukin-2 does not cross the blood-brain barrier 36. McCorkle R. The measurement of symptom distress. Semin Oncol Nurs 1987;3:248–56. by a saturable transport system. Brain Res Bull 1994;34:103–9. 37. Yang J, Sherry R, Steinberg S et al. Randomized study of high-dose and low-dose 72. Banks W, Niehoff M, Zalcman S. Permeability of the mouse blood-brain barrier to murine interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127–32. interleukin-2: predominance of a saturable efflux system. Brain Behav Immun 38. Woodson E, Chianese-Bullock K, Wiernasz C et al. Assessment of the toxicities of systemic 2004;18:434–42. low-dose interleukin-2 administered in conjunction with a melanoma peptide vaccine. 73. Ellison M, Povlishock J, Merchant R. Blood-brain barrier dysfunction in cats following J Immunother 2004;27:380–8. recombinant interleukin-2 infusion. Cancer Res 1987;47:5765–70. 39. Nicolini A, Carpi A. Beta-interferon and interleukin-2 prolong more than three times 74. Saija A, Princi P, Lanza M et al. Systemic cytokine administration can affect blood-brain the survival of 26 consecutive endocrine dependent breast cancer patients with distant barrier permeability in the rat. Life Sci 1995;56:775–84. metastases: an exploratory trial. Biomed Pharmacother 2005;59:253–63. 75. Zhu C, Liu Q, Wei Y et al. Coexistence of immune-neuro-endocrine substances in the rat 40. Donskov F, Middleton M, Fode K et al. Two randomised phase II trials of subcutaneous central neurons. J Tongji Med Univ 1999;19:81–5. interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell 76. Dunn AJ, Wang J, Ando T. Effects of cytokines on cerebral neurotransmission: comparison carcinoma. Br J Cancer 2005;93:757–62. with the effects of stress. Adv Exp Med Biol 1999;461:117–27. 41. Morris RG, Evenden JL, Sahakian BJ et al. Computer aided assessment of dementia: 77. Song C, Merali Z, Anisman H. Variations of nucleus accumbens dopamine and serotonin comparative studies of neuropsychological deficits in Alzheimer type dementia and following systemic interleukin-2, interleukin-2, or interleukin-2 treatment. Neuroscience Parkinson’s disease. In: Stahl S, Iversen SD, Goodman E (editors). Cognitive 1999;88:823–36. Neurochemistry. Oxford: Oxford Unversity Press. 1987. 78. Sudom K, Turrin NP, Hayley S et al. Influence of chronic interleukin-2 infusion and stressors 42. Wechsler D. Manual of the Wechsler Adult Intelligence Scale. Psychological Corporation, on sickness behaviors and neurochemical change in mice. Neuroimmunomodulation New York. 1955. 2004;11:341–50. 43. Zigmond A, Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand 79. Anisman H, Kokkinidis L, Merali A. Interleukin-2 decreases accumbal dopamine efflux 1983;67:361–70. and responding for rewarding lateral hypothalamic stimulation. Brain Res 1996;731:1–11. 44. Montgomery S, Asberg M. A new depression scale designed to be sensitive to change. 80. Pettito JM, McCarthy DB, Rinker CM et al. Modulation of behavioral and neurochemical Br J Psychiatry 1979;134:382–9. measures of forebrain clopmine function in mice by species-specific interleukin-2. 45. Folstein MF, Folstein SE, McHugh A. “Mini-Mental State”: a practical method for grading J Neuroimmunol 1997;73:183–90. the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. 81. Raber J, Koob GF, Bloom FE. Interleukin-2 (IL-2) induces corticotropin-releasing factor 46. Aaronson N, Ahmedzai S, Bergman B et al. The European Organization for Research and (CRF) release from the amygdala and involves a nitric oxide-mediated signaling: Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical comparison with the hypothalamic response. J Pharmacol Exp Ther 1995;272:815–24. trials in oncology. J Natl Cancer Inst 1993;85:365–76. 82. Hanisch UW, Neuhaus J, Rowe W et al. Neurotoxic consequences of central long-term 47. de Haes JC, van Knippenberg FC, Neijt J. Measuring psychological and physical distress administration of interleukin-2 in rats. Neuroscience 1997;79:799–818. in cancer patients: structure and application of the Rotterdam Symptom Checklist. 83. Kaplin A, Deshpande D, Scott E et al. IL-6 induces regionally selective spinal cord injury Br J Cancer 1990;62:1034–8. in patients with the neuroinflammatory disorder transverse myelitis. J Clin Invest 48. American Psychiatric Association. Structured clinical interview for DSM-III R. 2005;115:2731–41. American Psychiatric Press, Inc, Washington, DC. 1990. 84. Sakic B, Gauldie J, Denburg J et al. Behavioral effects of infection with IL-6 adenovector. 49. Army Individual Test Battery Manual. War Department, Washington, DC. 1944. Brain Behav Immun 2001;15:25–42. 50. Fray PJ, Robbins TW, Sahakian BJ. Neuropsychiatric applications of CANTAB. 85. Kapsimalis F, Richardson G, Opp M et al. Cytokines and normal sleep. Curr Opin Pulm Int J Geriatr Psychiatry 1996;11:329–36. Med 2005;11:481–4. 51. Caraceni A, Martini C, Belli F et al. Neuropsychological and neurophysiological assessment 86. Zalcman S, Green-Johnson J, Murray L et al. Cytokine-specific central monoamine of the central effects of interleukin-2 administration. Eur J Cancer 1993;29A:1266–9. alterations induced by interleukin (IL)-1, IL-2 and IL-6. Brain Res 1994;643:40–99.

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87. Lacosta S, Merali Z, Anisman H. Central monoamine activity following acute and repeated 121. Lupien SJ, Gillin CJ, Hauger RL. Working memory is more sensitive than declarative systemic interleukin-2 administration. Neuroimmunomodulation 2000;8:83–90. memory to the acute effects of corticosteroids: a dose-response study in humans. 88. Lapchak P, Araujo D. Interleukin-2 regulates monoamine and opioid peptide release Behav Neurosci 1999;113:420–30. from the hypothalamus. Neuroreport 1993;4:303–6. 122. Lupien SJ, Fiocco A, Wan N et al. Stress hormones and human memory function across 89. Seto D, Karr S, Quirion R. Evidence for direct and indirect mechanisms in the potent the lifespan. Psychoneuroendocrinology 2005;30:225–42. modulatory action of in terleukin-2 on the release of acetylcholine in rat hippocampal 123. Zobel AW, Schulze-Rauschenbach S, von Widdern OC et al. Improvement of working slices. Br J Pharmacol 1997;120:1151–7. but not declarative memory is correlated with HPA normalization during antidepressant 90. Song P, Lie-Cheng W, Wang G et al. Interleukin-2 regulates membrane potentials and treatment. J Psychiatr Res 2004;38:377–83. calcium channels via mu opioid receptors in rat dorsal root ganglion neurons. 124. Duffy LS, Greenberg DB, Younger J et al. Iatrogenic acute estrogen deficiency and Neuropharmacology 2002;43:1324–9. psychiatric syndromes in breast cancer patients. Psychosomatics 1999;40:304–8. 91. Graeff FG. Neuroanatomy and neurotransmitter regulation of defensive behaviors and 125. Wolkowitz OM, Reus VI, Canick J et al. Glucocorticoid medication, memory and steroid related emotions in mammals. Braz J MedBiolRes 1994;27:811–29. psychosis in medical illness. Ann NY Acad Sci 1997;823:81–96. 92. Sanchis-Segura C, Grisel JE, Olive MF et al. Role of the endogenous opioid system on the neuropsychopharmacological effects of ethanol: new insights about an old question. 126. Belanoff JK, Flores BH, Kalezhan M et al. Rapid reversal of psychotic depression using Alcohol Clin Exper Res 2005;29:1522–7. mifepristone. J Clin Psychopharmacol 2001;21:516–21. 93. Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. 127. Belanoff JK, Kalehzan M, Sund B et al. Cortisol activity and cognitive changes in psychotic Trends Pharmacol Sci 1992;13:177–84. major depression. Am J Psychiatry 2001;158:1612–6. 94. Ye J, Tao L, Zalcman S. Interleukin-2 modulates N-methyl-D-aspartate receptors of native 128. Posener JA, Schildkraut JJ, Williams GH et al. Acute and delayed effects of corticotropin- mesolimbic neurons. Brain Res 2001;894:241–8. releasing hormone on dopamine activity in man. Biol Psychiatry 1994;36:616–21. 95. Lestage J, Verrier D, Palin K et al. The enzyme indoleamine 2,3-dioxygenase is induced 129. Posener JA, Schatzberg AF, Williams GH et al. Hypothalamic-pituitary-adrenal axis effects in the mouse brain in response to peripheral administration of lipopolysaccharide and on plasma homovanillic acid in man. Biol Psychiatry 1999;45:222–8. superantigen. Brain Behav Immun 2002;16:596–601. 130. Sautter FJ, Bissette G, Wiley J et al. Corticotropin-releasing factor in posttraumatic stress 96. Liebau C, Merk H, Schmidt S et al. Interleukin-12 and interleukin-18 change ICAM-I disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy expression, and enhance natural killer cell mediated cytolysis of human osteosarcoma cells. control subjects. Biol Psychiatry 2003;54:1382–8. Cytokines Cell Mol Ther 2002;7:135–42. 131. Rothschild AJ, Benes F, Hebben N et al. Relationships between brain CT scan findings 97. Capuron L, Neurauter G, Musselman DL et al. Interferon-alpha-induced changes and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry in tryptophan metabolism: relationship to depression and paroxetine treatment. 1989;26:565–75. Biol Psychiatry 2003;54:906–14. 132. Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid 98. Maes M, Scharpe S, Meltzer HY et al. Increased neopterin and interferon-gamma secretion 2003;13:547–51. and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatr Res 1994;54:143–60. 133. Witzke O, Winterhagen T, Saller B et al. Transient stimulatory effects on pituitary-thyroid 99. Moore P, Landolt HP, Seifritz E et al. Clinical and physiological consequences of rapid axis in patients treated with interleukin-2. Thyroid 2001;11:665–70. tryptophan depletion. Neuropsychopharmacology 2000;23:601–22. 134. Papanicolaou DA. Euthyroid Sick Syndrome and the role of cytokines. Rev Endocr Metab 100. Lapchak P. A role for interleukin-2 in the regulation of striatal dopaminergic function. Disord 2000;1:43–8. Neuroreport 1992;3:165–8. 135. Chianese-Bullock K, Woodson E, Tao H et al. Autoimmune toxicities associated with 101. Alonso R, Chaudieu I, Diorio J et al. Interleukin-2 modulates evoked release of the administration of antitumor vaccines and low-dose interleukin-2. J Immunother [3H] dopamine in rat cultured mesencephalic cells. J Neurochem 1993;61:1284–90. 2005;28:412–9. 102. Zalcman S. Interleukin-2-induced increases in climbing behavior: inhibition by dopamine 136. Musselman DL, Nemeroff CB. Depression and endocrine disorders focus on the thyroid D-1 and D-2 receptor antagonists. Brain Res 2002;944:157–64. and adrenal system. Br J Psychiatry Suppl 1996:30:123–8. 103. Jiang C, Lu C. Interleukin-2 and its effects in the central nervous system. Biol Signals 137. Loftis J, Hauser P. The phenomenology and treatment of interferon-induced depression. Recept 1998;7:148–56. J Affect Disord 2004;82:175–90. 104. Besedovsky H, del Rey A, Sorkin E et al. Immunoregulatory feedback between 138. Kowalski J, Labuzek K, Herman Z. Flupentixol and trifluperidol reduce interleukin-1 beta interleukin-1 and glucocorticoid hormones. Science 1986;233:652–4. and interleukin-2 release by rat mixed glial and microglial cell cultures. Pol J Pharmacol 105. Rivier C. Influence of immune signals on the hypothalamic-pituitary axis of the rodent. 2004;56:563–70. Front Neuroendocrinol 1995;16:151–82. 139. Labuzek K, Kowalski J, Gabryel B et al. Chlorpromazine and loxapine reduce 106. Raab C, Weidmann E, Schmidt A et al. The effects of interleukin-2 treatment on interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell endothelin and the activation of the hypothalamic-pituitary-adrenal axis. Clincal cultures. Eur Neuropsychopharmacol 2005;15:23–30. Endocrinol (Oxf) 1999;50:37–44. 140. Szuster-Ciesielska A, Slotwinska M, Stachura A et al. Neuroleptics modulate cytokine 107. Butler LD, Mohler KM, Layman NK et al. Interleukin-2 induced systemic toxicity: and reactive oxygen species production in blood leukocytes of healthy volunteers. induction of mediators and immunopharmacologic intervention. Immunopharmacol Arch Immunol Ther Exp (Warsz) 2004;52:59–67. Immunotoxicol 1989;11:445–87. 141. Figueroa F, Carrion F, Martinez M et al. Bromocriptine induces immunological changes 108. Katahira M, Iwasaki Y, Aoki Y et al. Cytokine regulation of the rat proopiomelanocortin related to disease parameters in rheumatoid arthritis. Br J Rheumatol 1997;36:1022–3. gene expression in AtT-20 cells. Endocrinology 1998;129:2414–22. 142. Herring A, Kaminski N. Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP 109. Spina MP, Santi G, Poggiato M et al. [In vitro effects of IL-2 on human hypophyseal response element-binding protein, and interleukin-2 secretion by activated thymocytes. adenoma] Minerva Endocrinol 1994;19:163–8. J Pharmacol Exp Ther 1999;291:1156–63. 110. Hanisch UK, Rowe W, Sharma S et al. Hypothalamic-pituitary-adrenal activity during chronic central administration of interleukin-2. Endocrinology 1994;135:2465–72. 143. D’Ambrosio A, Noviello L, Negri L et al. Effect of novel non-peptidic delta opioid receptor antagonists on human T and B cell activation. Life Sci 2004;75:63–75. 111. Karanth S, McCann SM. Anterior pituitary hormone control by interleukin-2. Proc Natl Acad Sci USA1991;88:2961–5. 144. Winkler C, Wirleitner B, Schroecksnadel K et al. St. John’s wort (Hypericum perforatum) counteracts cytokine-induced tryptophan catabolism in vitro. Biol Chem 112. Capuron L, Raison CL, Musselman DL et al. Association of exaggerated HPA axis response 2004;385:1197–202. to the initial injection of interferon-alpha is associated with the development of depression during interferon-alpha therapy. Am J Psychiatry 2003;160:1342–5. 145. Musselman DL, Lawson DH, Gumnick JF et al. Paroxetine for the prevention of 113. Witzke O, Winterhagen T, Kribben A et al. Interleukin-2 given to asymptomatic the depression and neurotoxicity induced by high dose interferon-alpha therapy. HIV-infected individuals leads to an exaggerated response of the pituitary gland N Engl J Med 2001;344:961–6. to the action of CRH. Clin Endocrinol 2003;59:104–9. 146. Kraus MR, Schafer A, Al-Taie O et al. Prophylactic SSRI during interferon alpha re-therapy 114. Spinazze S, Viviani S, Bidoli P et al. Effect of prolonged subcutaneous administration in patients with chronic hepatitis C and a history of interferon-induced depression. of interleukin-2 on the circadian rhythms of cortisol and beta-endorphin in advanced J Viral Hepat 2005;12:96–100. small cell lung cancer patients. Tumori 1991;77:496–9. 147. Malek-Ahmadi P, Ghandour E. Bupropion for treatment of interferon-induced depression. 115. Chambrier C, Mercatello A, Tognet E et al. Hormonal and metabolic effects of chronic Ann Pharmacother 2004;38:1202–5. interleukin-2 infusion in cancer patients. J Biol Response Mod 1990;9:251–5. 148. Russo S, Boon JC, Korf J et al. Mirtazapine for the treatment of interferon-induced 116. Bindon C, Czerniecki M, Ruell P et al. Clearance rates and systemic effects of intravenously psychopathology. General Hospital Psychiatry 2003;25:497. administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer 149. Yoshida K, Higuchi H, Takahashi H et al. Favorable effect of milnacipran on depression 1983;47:123–33. induced by interferon-alpha. Journal of Neuropsychiatry & Clinical Neurosciences 117. Irusen E, Matthews JG, Takahashi A et al. p38 Mitogen-activated protein kinase-induced 2003;15:242–3. glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 2002;109:649–57. 150. Gleason OC, Yates WR. Five cases of interferon-alpha induced depression treated with antidepressant therapy. Psychosomatics 1999;40:510–2. 118. Goleva E, Kisich KO, Leung DY. A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance. J Immunol 2002;169:5934–40. 151. Albrecht JT, Canada TW. Cachexia and anorexia in malignancy. Hematol Oncol Clinof North Am 1996;10:791–800. 119. Wang X, Wu H, Miller AH. Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry 152. Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relavence to the 2004;9:65–75. pathophysiology and treatment. Biol Psychiatry 2001;49:391–404. 120. Owens MJ, Nemeroff CB. Physiology and pharmacology of corticotropin-releasing factor. 153. Raison CL, Miller AH. Depression in cancer: new developments regarding diagnosis Pharmacol Rev 1991;43:425–73. and treatment. Biol Psychiatry 2003;54:283–94.

DEPRESSION: MIND AND BODY Vol 2 No 4 2006 129 R7420_2_REM_DEP2_4_17.qxd 20/7/0617:39Page130 LEADING ARTICLE Box 1217,NewYork, NY10029,USA.Email:[email protected] Address forcorrespondence: SanjayJMathew, OneGustaveLevyPlace, quickly becominganachronistic. adolescents [4].Thus,the“adult”labelfortype2diabetesis 8–45% ofallnewcasesdiabetesinchildren and Quite alarmingly, type2diabetesisestimatedtoaccountfor virtual epidemicproportions amongadolescentsintheUS[4]. factors suchasobesityandbeingoverweighthavereached progressively duringthelast20years,andcommonrisk noted thattheageofonsetfortype2diabeteshasdropped reasons, includingsedentarylifestyleand diet.Itshouldbe 40–59 years(approximately 750000newcases)formultiple 600 000newcasesin2005)andamongindividualsaged prevalent inthe>60yearsagegroup (approximately In termsofnewcases,diabeteswasprojected tobemore aged >60years,theprevalence ofdiabeteswas>20%[3]. glucose regulation, pre-diabetes, anddiabetes;inpatients also showedaprofound age-associatedriskofabnormal that are suspected butnotdiagnosed[3].TheCDCsurvey diagnosed withthisdiseaseandanother6.2millioncases population. Thisincludes14.6millionpeoplewhohavebeen suffer from diabetes–approximately 7%oftheUS suggests thatasmany20.8millionpeopleintheUS the USCenterforDiseaseControl andPrevention (CDC) been referred toasapandemic[1,2].Arecent surveyfrom the worldwideincidenceisincreasing sorapidlythatithas and from cardiovascular disease,amputations,andblindness, Diabetes mellitusistheleadingcauseofpremature Epidemiology ofdiabetesandmajordepression discussed withinthecontextofbroadercardiovasculardiseaseriskfactors. although examplesdiscusstype1,or“juvenile-onset”diabetes.Finally, therelationshipbetweendepressionanddiabetes is depressed patientsuffering fromcomorbiddiabetesmellitus.Theprimaryfocusofthisarticleistype 2diabetesmellitus, offering severalpathophysiologicalhypothesesregardingthisrelationship,aswellreviewingtreatment approachesforthe article willdiscussthecomplexbidirectionalrelationshipbetweenthesetwochronicanddisablingmultifactorialillnesses, fatigue, lethargy, andneurovegetativesymptoms,diminishresponsetobothpsychologicalsomatictreatments.This inadequate managementofdiabetesinmooddisorderpatientsmayexacerbatepsychiatricsymptoms,contributetopersistent and diet,areducedqualityoflife,anincreaseinoverallhealthcareexpenditurepatientswithdiabetesmellitus.Int Major depressivedisorderandrelatedmooddisordersareassociatedwithpoormetaboliccontrol,adherencetomedication Department ofPsychiatry, MountSinaiSchoolofMedicine,NewYork, NY, USA Sanjay JMathewandSusanBurd Diabetes MellitusandDepression The Bidirectional Relationshipbetween 130 D EPRESSION : M death N AND IND B because ofitsearlyageonset. and ultimatelylethal(through suicide)courseofillness of depression [12],andthismaybeaprolonged, unremitting, with type1diabeteshavea2–3-foldgreater prevalence rate mood andpoorglycemiccontrol [11].Children/adolescents correlations havebeenobservedbetween deteriorating status, andthosewithphysicaldisabilities[10].Significant women, patientswithlowereducationalorsocioeconomic who are atgreatest riskfordevelopingdepression are typically diabetes thaninthegeneralpopulation[9].Diabeticpatients shown tobe3–4timesmore prevalent inpatients with bipolar disorder, andseasonalaffective disorder) hasbeen disorders, andMDD(anditsvariants,includingdysthymia, diabetes haveahigherrelative riskofdevelopingmood of type2diabetes[8]. between theonsetofdepressive symptomsandadiagnosis development oftype2diabetes,withamean8.7years diabetes [5–7].MDDhasbeenobservedtoprecede the much highersubsequentrelative riskofdevelopingtype2 patients withmajordepressive disorder (MDD)havea among AsiansandAsian-Americans[3]. and recently anincreased prevalence hasalsobeennoted and non-Hispanicwhites(8%)are notmuchlowerthanthis, Hispanic blacks(15%),Hispanic/Latino-Americans(14%), diabetes, >18%inrecent surveys[3].Ratesamongnon- the AmericanIndianpopulationhashighestrateof prevalence ofdiabeteshavelongbeenrealized. Inparticular, ODY At thesametime,patientswithbothtype1and2 Three separate epidemiological studieshaveshownthat Racial andethnicdifferences intheage-associated Vol 2No42006 Depression: MindBody 2006; 2 (4):130–3. urn, R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:39 Page 131

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Pathophysiology of comorbid diabetes Table 1. Monitoring diabetes in depressed patients. and depression What are the moderating and mediating factors that influence Glycosylated hemoglobin: measures the average level the development and persistence of type 2 diabetes in of glycemia over the preceding 2–3 months patients with mood disorders? Behavioral and lifestyle factors Frequency: 2×/year if treatment goals are met and patient (sedentary lifestyle, dietary factors, poor adherence to has stable glycemic control; 4×/year if glycemic control treatments), as well as associated cardiovascular problems, is unstable undoubtedly play a significant role in increasing an individuals’ Values: <7% for patients in general (<6% is normal, vulnerability to the development and maintenance of without significant hypoglycemia) this disorder. Additional laboratory tests: fasting serum glucose, Since MDD generally precedes the onset of diabetes, LDL, HDL, triglycerides careful attention paid to depressed, non-diabetic individuals HDL: high-density lipoprotein; LDL: low-density lipoprotein. could provide information regarding the development of this condition (Table 1). The study of asymptomatic persons who eventually go on to develop diabetes has yielded important limitation of these surveys, although intriguing and clues regarding its pathogenesis. Biological factors that potentially informative about causal pathways to illness, predate the clinical onset of type 2 diabetes include [1,13]: is the retrospective nature of the self-reported abuse. Some interesting work has investigated the role of • Insulin resistance in muscle, fat, and liver cells. childhood abuse and stressful life experiences as markers of • Abnormal beta-cell functioning in the pancreas. vulnerability to depression. One prominent study examined • Excess accumulation of intracellular triglycerides the relationship between a functional polymorphism of the in muscle and liver. serotonin transporter and the risk of developing major depression in relation to stressful life events [19]. In this A unifying hypothesis underlying these factors is large, prospective, longitudinal study of a representative abnormal mitochondrial function. In a landmark study, rates birth cohort from New Zealand, subjects were genotyped of mitochondrial adenosine triphosphate (ATP) synthesis in for a functional serotonin transporter polymorphism and skeletal muscle were found to be decreased by 30% in a assessed for magnitude of self-reported stressful life group of lean, insulin-resistant children whose parents had events, including maltreatment. In the “resilient” genotype type 2 diabetes, compared with controls with normal insulin (l/l genotype), no matter how severely they experienced sensitivity who were matched for physical activity [14]. An mistreatment, the relative risk of developing depression inherited defect in mitochondrial oxidative phosphorylation was significantly decreased compared with the group with was hypothesized to result in lipid accumulation and the vulnerable genotype (s/s genotype). This study contribute to insulin resistance in muscle [14]. Interestingly, demonstrated that a gene–environment interaction may recent work using magnetic resonance spectroscopy in explain an individuals’ vulnerability to developing depression patients with mood disorders has also implicated impaired in the wake of stressful life events. Genetic variability in mitochondrial oxidative phosphorylation [15]. serotonin function may be relevant to the expression of One clinically salient moderating variable for the diabetes in depressed patients; serotonin (5-HT) transporter development of diabetes is the impact of childhood polymorphisms modulate human blood glucose control [20], traumatic experiences. While several decades of research and metabolic syndrome is associated with reduced brain have now documented the fact that childhood trauma responsiveness to serotonin [21]. (including neglect and sexual and physical abuse) poses a significant risk for the development of major depression Brain mechanisms in diabetes [16], more recent epidemiological surveys suggest that early Historically, diabetes has been viewed as a pancreatic or adverse experiences may also be a risk factor for adult-onset endocrine disorder, not a brain disorder. One reason for this diabetes [17,18]. For example, individuals reporting maternal view was that a peptide the size of insulin would be too emotional or physical abuse during childhood had higher rates large to cross the blood–brain barrier, and thus glucose of self-reported diabetes in adulthood (Midlife Development regulation in the brain would be insulin independent. in the US survey, n=3032) [17]. A separate, larger study However, more recent research has found that the brain is showed an association between childhood neglect specifically, not insulin insensitive; in fact, brain insulin activity is and not abuse per se, and increased risk of diabetes necessary for normal glucose homeostasis. Furthermore, (National Comorbidity Survey, n=5877) [18]. A fundamental discrete brain pathology has been found in humans with

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diabetes and in animal models, while brain mechanisms and depression were randomized to two groups. One group underlying insulin resistance have been documented [1]. received treatment as usual and the other was randomized There are intimate brain–peripheral organ pathways to Pathways case management, which provided educational that serve to maintain homeostatic regulation of energy and adherence support [27]. The somewhat surprising expenditure [22]. Specific hypothalamic neurons respond finding was that the Pathways collaborative care model to adiposity-related signals via hormones such as leptin. improved depressive symptoms but did not result in These hormones are secreted in proportion to energy stores improved glycemic control [27]. and circulating nutrients, and adaptive changes in energy In choosing a drug to treat patients with diabetes expenditure and hepatic glucose production result in and depression from among the different classes of response to these inputs. As weight gain progresses, antidepressants, it is important to consider which drugs increased insulin resistance is observed along with increased cause weight gain and hypoglycemia. Certain monoamine demand for pancreatic insulin secretion, and a subsequent oxidase inhibitors, tricyclic antidepressants (TCAs), increased risk of type 2 diabetes [22]. mirtazapine, and atypical antipsychotics (most notably Hippocampal regions such as the dentate gyrus (critical clozapine and olanzapine) may not be optimal for treating to neurogenesis), deficits in gray matter density, and this patient population as they can result in hypoglycemia, hypothalamic nuclei have been implicated in diabetes [23]. greater insulin sensitivity, weight gain, and/or increased Excess secretions of neurotransmitters in conjunction with HbA1C [28]. long-chain polyunsaturated fatty acid deficiency, especially Beyond standard drugs for the treatment of depression omega-3 fatty acids, were found to damage neurons in the and diabetes, new agents soon to gain US Food and Drug hypothalamus as well as insulin receptors in the brain [24]. Association approval might offer promising new directions Finally, diabetes may result in changes in hippocampal for patients. Rimonabant (Sanofi-Aventis, Bridgewater, synaptic plasticity. These alterations in plasticity parallel NJ, USA) is the first in a class of selective CB-1 receptor (part findings in major depression and the speculated mechanism of the endocannibinoid system) blockers, and are found in of action of antidepressants, such as selective serotonin brain and adipose tissue. The endocannibinoid system has reuptake inhibitors (SSRIs), which may work by increasing been implicated in body mass regulation, insulin resistance, synaptic plasticity and neurogenesis [25]. and lipid metabolism, and it is hoped that varied applications of this drug, including treatment of the mood and anxiety Implications for treatment disorders associated with metabolic syndrome and/or Patients with comorbid depression and diabetes typically diabetes, might be possible. show an improvement after treatment with antidepressants, but primarily with respect to depressive symptoms. Diabetes in the context of cardiovascular However, glycemic control, as indexed by glycosylated risk status hemoglobin A1C (HbA1C), is uncertain with long-term While this review has focused on type 2 diabetes, this illness antidepressant treatment. should be examined in the context of a broader general A recent paper by Lustman et al. featured one of the medical, cardiovascular, and metabolic profile. It is now well largest investigations to date of SSRI treatment in patients established that major depression is a risk factor for coronary with depression and diabetes [26]. A sample of 152 patients artery disease and poor cardiovascular outcomes in patients who had received open-label sertraline for 16 weeks were with established heart disease [29]. The INTERHEART study subsequently randomized in a discontinuation arm to of modifiable risk factors for acute myocardial infarction (MI) sertraline or placebo for up to 1 year. The major finding was identified psychosocial factors as stronger predictors for that depression recurrence was diminished and survival was incident MI than classic risk factors such as diabetes, increased four-fold in the sertraline group compared with smoking, hypertension, and obesity [30]. Both behavioral the placebo group. Surprisingly, the short-term impact of (dietary factors, non-adherence to medications, poor social glycemic control was positive (i.e. after 4 weeks of open- support, lack of exercise) and biological mechanisms label treatment with sertraline, glycosylated HbA1C actually (increased platelet activation, increased catecholamine levels, decreased), although long-term data suggested no difference inflammatory processes, alterations in cardiac autonomic in standard diabetic measures (blood glucose levels, HbA1C) tone) may explain the associated risk between depression between the placebo and sertraline-treated groups. and cardiovascular disease [29]. SSRIs were found to be safe Katon et al. asked the question: does enhancing the and effective in the treatment of depressed patients with quality of depression care improve both depression and acute coronary syndromes by the SADHART (Sertraline diabetes [27]? A total of 329 patients with both diabetes Antidepressant Heart Attack Trial) [31], although larger

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Table 2. Characteristics of metabolic syndrome [29]. References 1. Taylor R. Causation of type 2 diabetes – the Gordian knot unravels. N Engl J Med 2004;350:639–41. The Third Report of the National Cholesterol Education 2. Steinbrook R. Facing the diabetes epidemic—mandatory reporting of glycosylated Program Expert Panel on Detection, Evaluation, and hemoglobin values in New York City. N Engl J Med 2006;354:545–8. 3. Center for Disease Control and Prevention. Data on file, 2005, http://www.cdc.gov Treatment of High Blood Cholesterol in Adults (ATP III, 4. Dietz WH. Overweight in childhood and adolescence. N Engl J Med 2004;350:855–7. NHLBI) defines metabolic syndrome as three or more 5. Eaton WW, Armenian H, Gallo J et al. Depression and risk for onset of type II diabetes. A prospective population-based study. Diabetes Care 1996;19:1097–102. of the following abnormalities: 6. Kawakami N, Takasuka N, Shimizu H et al. Depressive symptoms and occurrence of type 2 diabetes among Japanese men. Diabetes Care 1999;22:1071–6. 7. Everson-Rose SA, Meyer PM, Powell LH et al. Depressive symptoms, insulin resistance, • Waist circumference ≥102 cm (40 inches) in men and risk of diabetes in women at midlife. Diabetes Care 2004;27:2856–62. and ≥88 cm (35 inches) in women 8. Brown ES, Verghese FP, McEwewn BS. Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 2004;55:1–9. ≥ • Serum triglyceride level 150 mg/dL 9. Anderson RJ, Freedland KE, Clouse RE et al. The prevalence of comorbid depression • HDL cholesterol level <40 mg/dL in men in adults with diabetes: a meta-analysis. Diabetes Care 2001;24:1069–78. 10. Fisher L, Chesla CA, Mullan JT et al. Contributors to depression in Latino and and <50 mg/dL in women European-American patients with type 2 diabetes. Diabetes Care 2001;24:1751–7. • Blood pressure ≥130/85 mmHg 11. Lustman PJ, Anderson RJ, Freedland KE et al. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 2000;23:934–42. • Fasting glucose level ≥110 mg/dL 12. Grey M, Whittemore R, Tamborlane W. Depression in type 1 diabetes in children: natural history and correlates. J Psychosom Res 2002;53:907–11. 13. Polonsky KS. Retinol-binding protein 4, insulin resistance, and type 2 diabetes. N Engl J Med 2006;354:2596–8. prospective studies are necessary to evaluate the role of 14. Peterson KF, Dufour S, Befroy D et al. Impaired mitochondrial activity in the insulin- resistant offspring of patients with type 2 diabetes. N Engl J Med 2004;350:664–71. antidepressant pharmacotherapy on cardiovascular outcomes. 15. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from Metabolic syndrome, or syndrome X, is characterized by magnetic resonance spectroscopy research. Mol Psychiatry 2005;10:900–10. 16. Klein DN. Depression and childhood adversity and abuse. Depression: Mind Body abdominal obesity, atherogenic dyslipidemia, hypertension, 2006;2:89–93. insulin resistance, inflammation, and prothrombotic states 17. Goodwin RD, Weisberg SP. Childhood abuse and diabetes in the community. Diabetes Care 2002;25:801–2. (Table 2) [32]. An important link between metabolic 18. Goodwin RD, Stein MB. Association between childhood trauma and physical disorders syndrome and MDD is the accumulation of increased among adults in the United States. Psychol Med 2004;34:509–20. 19. Caspi A, Sugden K, Moffitt TE et al. Influence of life stress on depression: moderation intra-abdominal visceral fat [33,34], which, along with by a polymorphism in the 5-HTT gene. Science 2003;301:386–9. increased prothrombotic factors such as plasminogen 20. Yamakawa M, Fukushima A, Sakuma K et al. Serotonin transporter polymorphisms affect human blood glucose control. Biochem Biophys Res Commun 2005;334:1165–71. activator inhibitor-1 (PAI-1) and factor VIII activity [35], 21. Muldoon MF, Mackey RH, Korytkowski MT et al. The metabolic syndrome is associated with reduced central serotonergic responsivity in healthy community volunteers. may represent crucial factors contributing to the increased J Clin Endocrinol Metab 2006;91:718–21. cardiovascular mortality observed in MDD patients. 22. Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science 2005;307:375–9. 23. Musen G, Lyoo IK, Sparks CR et al. Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes 2006;55:326–33. Conclusion 24. Klein JP, Waxman SG. The brain in diabetes: molecular changes in neurons and their In patients with diabetes, the presence of comorbid implications for end-organ damage. Lancet Neurol 2003;2:548–54. 25. Perera TD, Lisanby SH. Neurogenesis and depression. J Psychiatr Pract 2000;6:322–33. depression is associated with an increased morbidity and 26. Lustman PJ, Clouse RE, Nix BD et al. Sertraline for prevention of depression recurrence mortality rates [36]. Diabetes is recognized as a disease with in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2006;63:521–9. discrete brain pathology, and brain mechanisms underlying 27. Katon WJ, Von Korff M, Lin EH et al. The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry insulin resistance have recently been identified. 2004;61:1042–9. Antidepressant medications that are weight-neutral 28. Schwartz TL, Nihalani N, Jindal S et al. Psychiatric medication-induced obesity. Obes Rev 2004;5:115–21. should be recommended as first-line agents for comorbid 29. Whooley MA. Depression and cardiovascular disease: healing the broken-hearted. depression and diabetes, although these medications might JAMA 2006;295:2874–81. 30. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated not improve glycemic control. Behavioral therapies that with myocardial infarction in 52 countries (the INTERHEART study): case-control study. promote weight reduction through regular exercise and Lancet 2004;364:937–52. 31. Glassman AH, O’Connor CM, Califf RM et al. Sertraline treatment of major depression dietary modification are critical to the long-term success of in patients with acute MI or unstable angina. JAMA 2002;288:701–9. all treatments in these patients. Finally, diabetes should be 32. Grundy SM, Brewer HB Jr, Cleeman JI et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Instititute/American Heart Association conference viewed within the context of the larger cardiovascular and on scientific issues related to definition. Circulation 2004;109:433–8. metabolic risk profile of the patient, and regular monitoring 33. Weber-Hamann B, Werner M, Hentschel F et al. Metabolic changes in elderly patients with major depression: evidence for increased accumulation of visceral fat at follow-up. is critical for patients with one or more risk factors. Psychoneuroendocrinology 2006;31:347–54. 34. Kalhl KG, Bester M, Greggersen W et al. Visceral fat deposition and insulin sensitivity in depressed women with and without comorbid personality disorder. Psychosom Med Disclosures 2005;67:407–12. 35. Eskandari F, Mistry S, Martinez PE et al. Younger, premenopausal women with major Dr Mathew is a member of the Speakers’ Bureau for AstraZeneca, depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism 2005;54:918–24. Cephalon Inc., and Pfizer. Dr Burd has no relevant financial relationships 36. Katon WJ, Rutter C, Simon G et al. The association of comorbid depression with mortality to disclose. in patients with type 2 diabetes. Diabetes Care 2005;28:2668–72.

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Clinical reviews were prepared by Christos Ballas, Paul Ballas, and Po Wang.

EPIDEMIOLOGY and interpersonal psychotherapy. Depression outcomes were collated during the short-term and continuation phases of the studies, which lasted up to 26 weeks. Social inequalities in response to antidepressant The 17-item Hamilton Rating Scale for Depression

treatment in older adults (HAM-D17) was used to assess for depression, response to

Cohen A, Houck PR, Szanto K et al. treatment (HAM-D17 ≤10), remission (HAM-D17 ≤6), and Arch Gen Psychiatry 2006;63:50–6. suicidality. The authors measured SES using levels of education and income. Several baseline clinical and This study examined the association between demographic characteristics were also analyzed, including socioeconomic status and response to depression concurrent medical burden measured using Cumulative treatment in patients aged ≥59 years. The authors used Illness Rating Scale–Geriatric. Three forms of regression pooled data from the open-label phase of two studies of analysis were used to evaluate the association between SES the efficacy of interpersonal psychotherapy with either and time to response or remission of depression. nortryptyline hydrochloride or paroxetine. Analysis of the The high- (n=50), middle- (n=158), and low- (n=40) data revealed that middle-income patients responded income subjects showed response rates of 78%, 77%, and better to antidepressant treatment than those on a low 80%, and medial response times of 7.4, 7.0, and 9.1 weeks, income. Suicide ideation was also less common in high- respectively. Remission was achieved in 44%, 47%, and and middle-income patients than in low-income patients. 48% of subjects, respectively. These data suggest that older adults on low incomes Hazard ratio (HR) comparisons revealed a significant receiving treatment for depression have a less favorable difference between probable treatment response in high- outcome than their higher-income counterparts. and middle-income subjects compared with low-income patients, following adjustment for demographic variables. Low socioeconomic status (SES) has repeatedly been shown Factoring in clinical characteristics in addition to SES and to be associated with elevated rates of morbidity and demographic variables revealed that middle-income subjects mortality throughout all stages of life for both physical and were more likely to respond to depression treatment than psychiatric disorders. Higher rates and increased persistence low-income participants (HR=1.8). When examined as a of depression have also been seen with low SES; however, single aggregate, high- and middle-income subjects were research into the effect of SES on treatment outcomes in significantly more likely to respond to treatment than low- depression has been inconclusive. The authors of this study income participants (HR=1.61). explored the effects of two aspects of SES – education and Suicide ideations were consistently higher in low-income income – on the efficacy of antidepressant treatment in subjects compared with those in the middle- or high- elderly patients with major depressive disorder. economic groups, even after adjustment for baseline clinical All 248 subjects had been participants in one of two open- characteristics. Specifically, the likelihoods of suicide label, National Institute of Mental Health-funded studies. ideations in middle- and high-income subjects were 0.48 Data were used from 145 of 169 subjects aged ≥59 years and 0.39 times, respectively, that of the reported suicidality who took part in the first study examining the efficacy of in low-income participants. Combining middle- and high- nortryptyline hydrochloride and interpersonal psychotherapy income groups reveals that this cohort is 0.46 times as likely in late-life depression. Data were also gathered from 103 of as low-income subjects to report suicide ideations. 116 total subjects aged >69 years who had participated in a Additional analysis revealed that suicide ideations and low second research project, exploring the efficacy of paroxetine SES were independent predictors of probable response to

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antidepressant treatment. The study also showed that per 100 000 person–years (0.24% or 3075 total suicides from number of years of education was not a significant predictor 1968–1999). Mean BMI was 21.8 kg/m2 and 1.9% of subjects of treatment response or suicidal ideations during treatment, were obese. Over the study period the prevalence of obesity and that number of years of education and income were not increased from 1% for men born in the 1950s to 2.8% for related to remission rates. men born between 1970 and 1981. Overall, higher BMI It could be concluded that low-income subjects were correlated with a lower suicide rate. For every BMI increase less likely to respond to depression treatment, but only of 5 kg/m2, the risk of suicide decreased by 13% (95% after accounting for certain demographic and clinical confidence interval 7–18%). This inverse correlation remained characteristics. Moreover, high- and middle-income subjects significant even when excluding men with baseline psychiatric had lower rates of suicidality than their lower-income illness. Furthermore, this correlation was similar for suicides counterparts. However, the study was limited by several that occurred within 5 years of study entry, 5–10 years, and factors. Subjects were pooled from open-label trials, which >10 years after baseline measurements. meant that there was no placebo arm to the data. The The strengths of this study include the large sample size, income category was based on census data and may not prospective follow-up design, and measurement of suicide have indicated subjects’ actual income. In addition, as all the deaths instead of suicide behaviors. Coupled with the study participants were aged ≥59 years, it is difficult to generalize by Carpenter et al. [1], these results indicate that the these results to younger populations. interactions between weight and suicide are different in men and women. These results do not mean that increased Address for reprints: A Cohen, Department of Social Medicine, Harvard Medical School, 641 Huntingdon Avenue, Boston, MA 02115, USA. weight is a protective factor against suicide for men, but Email: [email protected] rather that weight loss, depression, and suicide may have overlapping etiologies in men. The differential interaction in Association of body mass index with suicide women needs further study. mortality: a prospective cohort study of more 1. Carpenter K, Hasin D, Allison D et al. Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general than one million men population study. Am J Public Health 2000;90:251–7. Magnusson PK, Rasmussen F, Lawlor D et al. Address for reprints: F Rasmussen, Child and Adolescent Public Am J Epidemiol 2006;163:1–8. Health Epidemiology Group, Department of Public Health Sciences, Karolinska Institute, Norrbacka, SE-171 76 Stockholm, Sweden. Email: [email protected] Based on data from nearly 1.3 million men and 19 million person–years, higher body mass index was correlated with a lower suicide rate in men, which is the inverse Depressive symptoms and cognitive of previous findings in women. decline in late life Ganguli M, Du Y, Dodge H et al. Being overweight or obese carries significant medical risks, Arch Gen Psychiatry 2006;63:153–60. and may also have important associations with morbidity and mortality rates in psychiatric illnesses. However, previous Baseline depressive symptoms did not predict cognitive studies have found that results differ for men and women. decline in the older adult without dementia in this More than 40 000 individuals were interviewed in a US community sample, in contrast to the significant survey of major depression, suicidal ideation, suicide effects reported in at-risk groups (those with major attempt, and body mass index (BMI), and the results depression or dementia). revealed a positive association between BMI and depression and suicidal ideation in women, but an inverse association Cognitive impairment is a common feature of major in men [1]. depression, and major depression may predict the future Magnusson and colleagues examined data on BMI development of dementia in older adults. The authors aimed assessed at 18–19 years of age, psychiatric diagnoses, to determine whether depressive symptoms predicted parental socioeconomic data, and suicide death information cognitive impairment in a population-based community from 1 299 177 men conscripted to the Swedish military study. Cognitive function was prospectively examined every from 1968 to the end of 1999. Men with a severe, chronic 2 years for 12 years in 1265 older adults (aged ≥67 years) medical condition or documented handicap that excluded without baseline dementia. The study controlled for baseline them from the military were not captured in this dataset. depressive symptoms, as measured by the modified Center From the nearly 1.3 million men, almost 19 million for Epidemiological Studies – Depression Scale (mCES-D). person–years were covered. The overall suicide rate was 16.2 Depression was defined as a mCES-D score of ≥5.

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The mean sample age was 74.6 years and 60.8% were cognitive impairment and depression. The study authors also female. Subjects with depression at baseline had significantly note that there is a paucity of research on the effect of these lower cognitive functioning than individuals without two phenomena on the risk of future dementia. depression. Of 1265 subjects, 171 (13.5%) developed This article offers a summary of the 2003 National dementia during the 12-year follow-up. Eventual dementia Institute of Mental Health (NIMH) conference “Perspectives sufferers had lower mean baseline cognitive scores. on Depression, Mild Cognitive Impairment, and Cognitive However, depressive symptoms did not correlate with any Decline”, wherein discussion focused on the gaps that exist decline in cognitive scores, not even in the subjects who in our knowledge of depression and MCI, and what the best developed dementia. use of research funding would be to improve these deficits. Overall mortality rate during the 12-year follow-up was Participants included grantees from the National Institute on 50.4%, and baseline depression was a risk factor for early Aging, NIMH, and the National Institute of Neurological (between follow-up visits two and three), but not later, Disorders and Strokes in the US. mortality in the study (odds ratio 1.94). Researchers have some disagreement with regard to the Depressive symptoms have been reported to have a definition of depression in the elderly, as non-dysphoric or significant effect on cognitive function in an at-risk sample depression with intermittent symptoms may be prevalent in (i.e. in patients with major depression or dementia). the population but not well characterized by the DSM-IV However, this was not seen in a community sample of criteria for a major depressive episode. When the authors of subjects where depressive symptoms were less prevalent, this article refer to depression, they include these forms in and subjects did not have or were not at risk for dementia. their discussion. MCI has been subcategorized into amnestic and non- Address for reprints: M Ganguli, Western Psychiatric Institute and Clinic, 3811 O’Hara St, Pittsburgh, PA 15213-2593, USA. amnestic subtypes. Studies suggest that the amnestic Email: [email protected] subtype progresses to Alzheimer’s disease and non-amnestic MCI tends to develop into non-Alzheimer dementias. Perspectives on depression, mild cognitive However, there is no consensus regarding these subtypes of impairment, and cognitive decline MCI among clinicians. The study authors used the phrase Steffens DC, Otey E, Alexopoulos GS et al. “mild cognitive impairment” when discussing a subtype, Arch Gen Psychiatry 2006;63:130–8. and the term cognitive impairment for the more general state that is not considered to be normal aging. The “Perspectives on Depression, Mild Cognitive Despite the finding that many older depressed patients Impairment, and Cognitive Decline” conference was also have cognitive impairment, this association is not well arranged by the National Institute of Mental Health to defined. Several analyses have shown that the combination discuss depression and cognitive impairment. The aim of of cognitive impairment and depression is substantial in the the conference was to identify gaps in our understanding elderly population, with one study suggesting that 33–60% of these areas that significantly impact on public health, of older patients developed major depressive episodes at or and to offer suggestions as to how research investment after the onset of cognitive impairment [1]. can be allocated more efficiently. The recommendation Conference members identified several factors that of representatives from several government agencies influence the reported co-occurrence of MCI and depression was that greater collaboration between researchers across studies: investigating depression and those studying memory disorders is required. • The definition and measurement of cognitive impairment may influence reported rates. Evidence suggests that late-life depression and cognitive • Patient selection has a significant impact, as most studies impairment both increase the risk of developing dementia. of dementia and depression exclude subjects with serious However, these two phenomena are, for the most part, medical illness. investigated along two separate avenues of research. Mild • Cultural differences in the perception of depression and cognitive impairment (MCI) is a term that has been used to the expectation of normal aging may also have affected describe the state between normal cognition and dementia. the studies. Subjects are often excluded from studies of depression if they have cognitive impairment, and studies of MCI frequently The committee noted that divergent paths of research on omit patients with depression. Hence, there is little research biological markers of depression and cognitive deficits need published on the prevalence of the concomitance of to be reconciled. Cognitive research has focused significantly

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on temporal lobe structures, while depression research has depression relapse during pregnancy between women who concentrated on the basal ganglia and prefrontal cortex. maintained antidepressant treatment and those who Emerging evidence suggests that these regions of the brain discontinued medication. The study authors also observed are implicated in both disorders, and therefore integrating differences in time-to-relapse between groups. these research foci may be justified. The conference In total, 201 women were recruited through three concluded with acknowledgement by the attendees from different centers specializing in psychiatric conditions during the various organizations present that cognitive disorders pregnancy. All subjects were currently or had recently and depression have a serious impact on public health. received antidepressant medication, were at <16 weeks 1. Zubenko GS, Zubenko WN, McPherson S et al. A collaborative study of the emergence gestation, had a history of major depression prior to and clinical features of the major depressive syndrome of Alzheimer’s disease. Am J Psychiatry 2003;160:857–66. becoming pregnant, and were euthymic for >3 months prior to their last menstrual period. The study was Address for reprints: DC Steffens, Department of Psychiatry, Duke University School of Medicine, Campus Box 3903, Durham, prospective and naturalistic in design. Longitudinal data NC 27710, USA. were gathered from March 1999–April 2003. The study was not randomized, and treatment decisions were made independently of participation in the study. All participants CLINICAL PRACTICE were assessed utilizing the Structured Clinical Interview, Hamilton Rating Scale for Depression, and the Clinical Global Impressions Scale. Subjects were placed into four Relapse of major depression during pregnancy categories based on their medication status: medication in women who maintain or discontinue decreased below optimal dose; increased above optimal antidepressant treatment dose for ≥1 week; maintained on medication throughout Cohen LS, Altshuler LL, Harlow BL et al. study period; and discontinued for ≥1 week. JAMA 2006;295:499–507. Of the 201 subjects, 12 were lost to follow-up, eight chose to discontinue from the study, 13 miscarried, and five Historically, pregnancy has been regarded as offering electively terminated their pregnancies. The mean age of “protection” from depression. However, little research depression onset was 18.8 years, 20% of subjects had has been published on the relapse rates in women with depression of >20 years duration, 48% had depression of pre-existing depression and their use of medication <14 years duration, 40% had ≥5 prior episodes of during pregnancy. This prospective, naturalistic study depression, and 53% had comorbid psychiatric illness. assessed the risk of depression relapse in 201 pregnant Overall, 43% of the women in the study had a relapse of women who either continued or stopped their depression. Within the four subcategories the relapse rates antidepressant medication during pregnancy. The study were as follows: revealed that 43% of all study participants experienced a relapse. Of the 82 patients who continued their • 26% of women who continued their medication. medication, 26% experienced a relapse compared with • 68% of those who discontinued their medication. 68% of the 65 subjects who stopped their treatment. • 45% of subjects who increased their medication. This study suggests that pregnancy is not “protective” • 35% of those who decreased their medication. with regard to depression, as has been historically understood. Euthymic women receiving ongoing Of those women who decreased or discontinued antidepressant medication should be informed of the their medication, 61% (n=60) restarted treatment during risk of relapse if they discontinue their medication. the pregnancy. The study was limited as it did not have a randomized Research has suggested there is a high level of depression design – the study authors felt this would have been relapse in non-gravid patients who discontinue antidepressant unethical in a study of antidepressant use in pregnant medication; however, the risk in pregnant women has not women. As described above, the study participants been determined. A better understanding of the incidence of had extremely severe depression, and it is possible the relapse would be significant in discussing the risk–benefit relapse rate may have been lower in subjects with less assessment of continuing antidepressant medications (i.e. severe illness. exposing the fetus to the medication) versus discontinuing Address for reprints: LS Cohen, Perinatal and Reproductive Psychiatry, treatment (i.e. the risks of untreated depression) during Massachusetts General Hospital, WACC 812, 15 Parkman Street, pregnancy. This study explored the difference in the risk of Boston, MA 02114, USA. Email: [email protected]

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Long term outcomes from the IMPACT randomized Systematic detection and multidisciplinary care trial for depressed elderly patients in primary care of depression in older medical inpatients: Hunkeler E, Katon W, Tang L et al. a randomized trial BMJ 2006;332:259–63. Cole MG, McCusker J, Elie M et al. CMAJ 2006;174:38–44. Collaborative care (from a depression care manager, primary care physician, and psychiatrist) in the primary This randomized clinical trial examined the efficacy care setting improves compliance with antidepressant of a strategy of depression detection and treatment in treatment in older depressed adults, resulting in improved 1500 medical inpatients, aged ≥65 years, admitted to depression and better physical functioning and quality a general medical service. Patients (n=157) who had of life. The goal is to make collaborative treatment the major depression and consented to enter the study were standard of care. randomized to receive either standard care or the study intervention. The intervention involved consultation and The IMPACT (Improving Mood Promoting Access to treatment by a psychiatrist, and follow-up by a research Collaborative Care Treatment) program is an intervention nurse and the subjects’ primary care provider. Data were aimed at improving the psychiatric and functional outcomes gathered at 3 and 6 months on a variety of outcomes, of depressed (Diagnostic and Statistical Manual of Mental including depressive symptoms and medical outcomes. Disorders, 4th edition [DSM-IV] major depressive disorder, Amongst the 64 subjects who completed the study, no with or without dysthymic disorder) older adults, who difference was seen between the groups at the end of commonly seek psychiatric care from their primary care 6 months, suggesting that the system under examination physicians. Older (aged ≥60 years, 65% female, n=1801) was no more beneficial to patients than standard care ethnically diverse adults were randomly assigned to a for this population. collaborative care intervention (depression care manager, primary care physician, and psychiatrist) or standard care Major depressive disorder occurs in up to 30% of elderly (antidepressants, counseling by primary care physician, and inpatients, and has been associated with poorer outcomes. referral to specialty mental health care) for 1 year, and Treatment offers many benefits; however, up to 90% of assessed at the end of the treatment year (12 months), and these patients are not diagnosed with depression during again at 18 and 24 months. Initial response differences at their hospital stay. The study authors examined a strategy of 12 months favored collaborative care [1]. In the present systematic detection to determine its efficacy in reducing article, Hunkeler and colleagues report on the longer-term symptoms of depression and improving outcomes. follow-up at 18 and 24 months to determine whether the Patients screened were aged ≥65 years and had been differences in response were sustained. admitted to medical services via the emergency room of a Patients treated with collaborative care had higher rates primary acute care hospital in Montreal (QC, Canada). of antidepressant use at 12, 18, and 24 months compared Enrolled subjects scored ≤4 on the Short Portable Mental with those receiving standard care. Depressive symptoms Status Questionnaire and were further assessed using the were improved, and physical function and quality of life Diagnostic Interview Schedule. were better, for the collaborative care group compared with Patients were randomized to either the standard care or the standard care group at 12, 18, and 24 months, even intervention group. The intervention group received considering gender, age, ethnicity, severity of depression, treatment for 24 weeks including assessment and treatment and medical comorbidity. Use of counseling was higher by a psychiatrist and subsequent follow-up care by a in the collaborative care group at 12 months, but not at research nurse and the patient’s family physician. Treatment 18 or 24 months. involved supportive psychotherapy and antidepressant Other studies have demonstrated the positive impact of medication. Control subjects were informed they suffered collaborative care on depression outcomes. Public awareness from depression and were directed to talk to their physician of this study has resulted in IMPACT being advocated as a about treatment, but no additional systemic interventions model program for mental health care in the US. were made. All subsequent consultations for psychiatry were 1. Unutzer J, Katon W, Callahan CM et al. Collaborative care management of late-life honored, consistent with standard practice. Subjects were depression in the primary care setting. A randomized controlled trial. JAMA 2002;288:2836–45. evaluated at baseline, 3 months, and 6 months, and measures of physical illness, alcoholism, depression, activities Address for reprints: EM Hunkeler, Kaiser Permanente, Division of Research, 2000 Broadway, 2nd Floor, Oakland, CA 94612, USA. of daily living, health services utilization, suicide, and suicide Email: [email protected] attempts were collected.

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Out of 1500 patients who were initially screened, 225 (Women’s Health Initiative Memory Study) found a two- (15%) had major depression. Of these, 157 patients agreed to fold increase in the rate of dementia in women treated participate in the study; 79 were randomized to the standard with hormone replacement therapy (HRT) compared with care group and 78 to the intervention group. Thirty-six those who did not receive HRT. The study also showed (22.9%) of the study died prior to the 6-month follow up visit, that there was no improvement in mood of subjects 57 (36.3%) withdrew, and 64 (40.8%) completed the study. treated with HRT. It is conceivable that the effects of ERT Seventy-four (94.9%) patients in the intervention group and on mood may be age-dependent and different to those 21 (26.6%) in the standard care group received a consultation reported in the WHIMS. This current study is the first of its from a psychiatrist. At 6 months, there was no difference kind to explore the effects of estradiol on cognition, mood, between the standard care and experimental group on any of and quality of life (QoL) in a population of women aged the primary outcome measures of the study. ≥70 years. This study was unable to show the benefits of systematic The study was double-blind and placebo-controlled in detection and multidisciplinary care of elderly inpatients with design. Subjects randomly allocated to the treatment group depression. However, a high number of subjects withdrew or received estrogen for a total of 20 weeks, with a gradual died before the study could be completed. The same team escalation and de-escalation of dose in order to minimize side of attending physicians was managing both sets of patients, effects. Of the 278 women who were screened for the study, which also may have led to contamination of standard care 115 met entry criteria and were randomized into the study. by the experimental program. Subjects were assessed for cognitive function and mental state using the Cambridge Examination for Mental Address for reprints: MG Cole, Department of Psychiatry, St Mary’s Hospital Center, 3830 Lacombe Avenue, Montréal, QC H3T 1M5, Disorders of the Elderly. Additional cognitive tests Canada. Email: [email protected] administered included Block Design and the California Verbal Learning Test II. Symptoms of depression were A 20-week randomized controlled trial of estradiol measured utilizing the Beck Depression Inventory and replacement therapy for women aged 70 years and anxiety symptoms were assessed with the Beck Anxiety older: effect on mood, cognition and quality of life Inventory. The Short Form-36 Health Survey was used to Almeida OP, Lautenschlager NT, Vasikaran S et al. assess QoL and adverse events were quantified using the Neurobiol Aging 2006;27:141–9. Greene Climacteric Scale. Blood tests, including apoprotein E genotype determination, total plasma homocysteine, and Research into the effects of estrogen replacement measures of unconjugated 17 β-estradiol, were performed. therapy (ERT) on mood has led to contradictory The 115 women were randomized to either the estradiol results. Observational studies show it improves (n=58) or placebo group (n=57) for 20 weeks. Twenty-nine cognition, quality of life (QoL), and mood; however, subjects did not complete the study; of these, 22 discontinued the controlled Women’s Health Initiative trial did not the study protocol and seven were lost to follow-up. find improvements in any of these factors, and actually There were no significant differences in measures of reported an increase in the risk of dementia. Little data QoL, anxiety, or depression between groups. Women in have been published on the effects of ERT on women the estrogen treatment group had improved immediate at higher risk of cognitive decline (≥70 years old). memory of faces compared with control subjects, but This double-blinded, placebo-controlled study explored this effect disappeared after Bonferroni method adjustment these issues in 115 women who were randomized to for multiple comparisons. There was no significant receive either placebo or estradiol, and were assessed difference between groups in any of the other cognitive for changes in mood, cognition, and QoL. Results tests administered. showed no difference between groups in any outcome Total plasma concentration of estradiol did, as expected, measured. This study suggests that high levels of substantially increase in subjects in the treatment group. estrogen replacement do not significantly impact Women in the experimental group were four times as likely on any of the above three clinical variables. as those in the placebo group to leave the study due to side effects, the most common being breast tenderness and Estrogen replacement therapy (ERT) has been shown in vaginal itchiness. limited studies to improve cognitive scores, decrease the The results of this study suggest that estradiol risk of dementia, and improve mood. However, recent replacement is not effective in improving mood symptoms, investigations suggest that the findings of these early QoL, or cognitive function in older women. The authors studies may be misleading. Specifically, the WHIMS note that the study had 90% power to detect differences

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between the experimental and placebo groups. The clinical homozygotes of SERTPR (l/l genotype) had a greater significance of these findings may be limited as the majority response to fluoxetine than short variant carriers (s/l or s/s of women did not have low mood scores to begin with, and genotypes), with an odds ratio of 8.6. Other polymorphism there was therefore little room for improvement. response associations were not replicated by this study. This study extends the expanding literature on applying Address for reprints: OP Almeida, School of Psychiatry and Clinical Neurosciences, The University of Western Australia (M573), genetic research to phenotyping response differences in 35 Stirling Highway, Crawley, Perth, WA 6009, Australia. psychiatric patients. As response was determined relatively Email: [email protected] early (at 4 weeks, compared with typical clinical trials of 8 weeks) and overall response was low (36%), some Response to fluoxetine and serotonin 1A receptor eventual responders were likely missed; thus, these results are (C-1019G) polymorphism in Taiwan Chinese more aptly defined for early responders. This study is also major depressive disorder limited by the lack of a placebo comparison. Nevertheless, Hong C, Chen T, Yu YW et al. these results point to the need for a prospective trial Pharmacogenomics J 2006;6:27–33. predicting response from baseline genotyping, with the ultimate goal of individualizing treatment.

C allele homozygotes of the serotonin 1A receptor and Address for reprints: S-J Tsai, Department of Psychiatry, Taipei Veterans long variant homozygotes of the serotonin transporter General Hospital and National Yang-Ming University, No. 201, Shih-Pai have a greater response to fluoxetine. These results Road, Sec 2, Taipei 11217, Taiwan. Email: [email protected] advance the potential utility of genetics in phenotyping psychiatric illness, in particular treatment response. COMORBIDITIES Genetic research has moved toward identifying phenotypic differences between psychiatric patients, such as treatment responsiveness in depressed patients. Most of the work in Prevalence and correlates of restless legs this area has focused on the polymorphisms of the serotonin syndrome: results from the 2005 National system of receptors and transporters. Sleep Foundation poll Hong and colleagues studied polymorphisms in 224 Phillips B, Hening W, Britz P et al. Taiwanese unipolar depressed patients given fluoxetine for Chest 2006;129:76–80. 4 weeks. The following polymorphisms were investigated: Data from the National Sleep Foundation Sleep in • C–1019G polymorphism of the 5-hydroxytryptamine 1A America 2005 poll indicates a nearly 10% prevalence autoreceptor (HTR1A C–1019G). of restless legs syndrome among adults in the US. • Serotonin transporter gene-linked polymorphic region (SERTPR). Restless legs syndrome (RLS) has gained increasing • Variable-number tandem-repeat polymorphisms in intron 2 importance in public awareness since the recent approval of of the serotonin transporter gene (STin2). the first medication for its treatment by the US Food and • Serotonin 2A receptor (T102C) polymorphism. Drug Administration. The National Sleep Foundation • Tryptophan hydroxylase (A218C) polymorphism. conducts a yearly telephone interview of US adults to • G-protein beta3 subunit (C825T) polymorphism. evaluate the prevalence and comorbidities of sleep disorders. Phillips and colleagues report on the National Sleep These polymorphisms were chosen based on prior Foundation Sleep in America 2005 poll results for RLS. findings from other research groups who had found The entry question of the poll was, “In the past year, associations with selective serotonin reuptake inhibitor according to your own experiences or what others tell you, antidepressant response. how often did you have unpleasant feelings in your legs like Only 36.2% of patients met the response criteria of 50% creepy, crawly, or tingly feelings at night with an urge to move improvement in Hamilton Depression Rating Scale score. when you lie down to sleep?” A high rate of respondents The mean final dose of fluoxetine was 25.8 mg/day. endorsed this symptom at least a few nights per week. In terms of the HTR1A C–1019G polymorphism, those If respondents also endorsed these feelings as worse at homozygous for the C allele (C/C genotype) had a greater night than during the daytime, the diagnosis of RLS was response to fluoxetine than G allele carriers (G/C or G/G defined as likely (9.7% of the entire sample). Functional genotypes); the odds ratio was 4.4. Long variant problems (including daytime fatigue, missing work, and

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missing social events) were more common in individuals at adequately characterizes the relationship between risk of RLS. The likelihood of suffering from this syndrome depression and CA in the general population. The authors was higher in southern states and lower in northeastern studied this relationship overall and in specific subgroups states. Out of eight queried medical conditions, the rates of utilizing data from a case-controlled, population-based RLS were higher in six conditions (depression, anxiety study of out-of-hospital CA. disorder, hypertension, arthritis, diabetes, and Information was gathered from patients enrolled in the gastroesophageal reflux disease). This suggests that RLS is Group Health Cooperative of Puget Sound in western commonly comorbid or aggravated by many other Washington State (USA). Enrollees (n=2228) who had conditions, or possibly that the poll lacks diagnostic experienced an out-of-hospital CA between 1980 and 1994 specificity. However, other studies have found prevalence were identified. Out-of-hospital CA was defined as a sudden rates of approximately 10% for RLS, and patients with RLS pulseless condition with no known non-cardiac condition. often have a family history of the disorder. Overall, the Subjects were excluded if they had a prior non-cardiac available data suggest that RLS has a high prevalence. condition that was life threatening, including brain tumor, Dopamine agonists have demonstrated efficacy as a therapy liver disease, and end-stage renal disease. Randomly chosen for this disorder. enrollees (n=4164) acted as controls. An index date was randomly assigned based on the distribution of the date of Address for reprints: B Phillips, Fifth Floor, Kentucky Clinic, Division of CA in the experimental group. Clinical physician-diagnosed Pulmonary, Critical Care and Sleep Medicine, University of Kentucky College of Medicine, 800 Rose Street, Lexingon, KY 40536-0028, USA. depression was defined in this study as either the use of Email: [email protected] antidepressant medication at the index date or diagnosis of depression within a year of this index date by a physician. Clinical depression and risk of out-of-hospital Subjects were categorized as having no depression, cardiac arrest depression, or severe depression (either a referral to a mental Empana JP, Jouven X, Lemaitre RN et al. health clinic or hospitalization for depression). Information Arch Int Med 2006;166:195–200. on various cardiac diagnoses and measures of cardiac well- being was also collated. The authors of this case-controlled, population-based Of the entire study population, 3641 had a prior history study investigated the association between depression of heart disease, and 92.9% were Caucasian. Subjects with and sudden cardiac death. Data were gathered from depression were more likely to be hypertensive, diabetic, subjects enrolled in a health maintenance organization in have congestive heart failure, be current smokers, be the state of Washington (USA). Random enrollee control unemployed, or involved in a clerical occupation. patients (n=4164) were compared with 2228 enrollees Depression and severe depression were more common in aged 40–79 years who experienced out-of-hospital CA cases than in controls. The risk of CA in patients with cardiac arrest (CA) between 1980 and 1994. Depression depression was almost two-fold greater than in those was defined by the use of antidepressant medication without depression (odds ratio [OR]=1.88) and this OR or diagnosis by a physician 1 year prior to the CA, remained elevated after accounting for several cardiac while severe depression was classified as hospitalization variables, including previous diagnosis of heart disease. The or referral to a mental health clinic for depression. risk increase exhibited a graded manner, with a greater Subjects with depression had a higher odds ratio (OR) increase observed with severe depression (OR=1.77) than in of having a CA (OR=1.88), an effect that remained less severe illness (OR=1.30) when compared with controls. after accounting for confounding variables (OR=1.43). This graded increase in risk was still seen when the risk of The risk of CA was increased in both depressed CA was directly compared between patients with depression (OR=1.30) and severely depressed participants and those who suffered severe depression (OR=1.36). (OR=1.77). These data suggest that clinical depression This study offers evidence that clinical depression may be independently associated with CA. increases the risk of out-of-hospital CA, and that this risk increases with the severity of the depression. The study was Previously published research has shown an association limited by the fact that depression is often unrecognized in between depression and coronary heart disease-related primary care, and thus subjects with depression may have mortality. Research into the association between depression been misclassified as not being depressed. and sudden cardiac death has been limited by studies where few cardiac arrest (CA) events occurred and which Address for reprints: JP Empana, INSERM Avenir-U258, Hôpital Paul Brousse, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, involved select populations. Little has been published that France. Email: [email protected]

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Neuropsychological function and symptoms investigated subjects with higher mean TSH levels. Subjects in subjects with subclinical hypothyroidism were notified of their TSH levels and were allowed to seek and the effect of thyroxine treatment treatment outside the study. Additionally, anyone already Jorde R, Waterloo K, Storhaug H et al. receiving T4 supplementation was excluded. Therefore, this J Clin Endocrinol Metab 2006;91:145–53. study could have missed subjects who may have had cognitive or emotional symptoms and who sought In this study, subclinical hypothyroidism (defined by treatment. Placebo-controlled studies are necessary to thyroid-stimulating hormone [TSH] 3.5–10.0 mIU/L but address the potential utility of T4 supplementation and/or normal free T4 and T3) was not associated with cognitive T3 supplementation for subclinical hypothyroidism in or emotional deficits, and T4 supplementation did not patients with higher TSH levels (e.g. TSH ≥4.2), given that improve cognitive or emotional functioning. However, other studies have found associations between subclinical TSH levels of the study group overlapped with those of hypothyroidism and cognitive and depressive symptoms. the control group (reference range 0.20–4.2 mIU/L). Address for reprints: R Jorde, Institute of Clinical Medicine, University of Tromso, 9037 Tromso, Norway. Email: [email protected] Hypothyroidism is clearly associated with cognitive dysfunction and increased risk of depressive disorders. Studies have found that patients with subclinical hypothyroidism, PATHOGENESIS defined as elevated levels of thyroid-stimulating hormone (TSH) but normal levels of free T3 and T4, may also be associated with cognitive dysfunction and depressive Increased hippocampal plaques and tangles in symptoms. Jorde and colleagues examined whether treatment patients with Alzheimer disease with a lifetime of subclinical hypothyroidism with T4 supplementation would history of major depression improve cognitive function and depressive symptoms. Rapp MA, Schnaider-Beeri M, Grossman HT et al. Eighty-nine patients with subclinical hypothyroidism Arch Gen Psychiatry 2006;63:161–7. (TSH 3.5–10.0 mIU/L; reference range 0.20–4.20 mIU/L) were compared with 154 age- and gender-matched Plaque and tangle formation have been characterized euthyroid control subjects using a battery of 14 cognitive as the hallmark pathological changes that occur in tests, the Beck Depression Inventory (BDI), and the General Alzheimer’s disease (AD). Although there is evidence that Health Questionnaire (GHQ). Sixty-nine of the patients were major depression can impact these changes, no research randomly assigned and treated with T4 supplementation in a has been published on neuropathological interactions double-blind fashion for 1 year, and then reassessed using between the two disorders. The authors of this study the same series of neuropsychological tests. compared post mortem examinations of the brains of Mean TSH in the subclinical hypothyroidism group was 50 patients with AD and a history of major depression 5.57 mIU/L compared with 1.79 mIU/L in the control group. with those from 52 patients with AD only. The results While age was inversely related to cognitive performance, revealed that patients with both disorders had higher there were no significant cognitive differences between the levels of plaque and tangle formation than those with subclinical hypothyroidism and control groups. Paradoxically, AD alone. Those who had been diagnosed with AD subclinical hypothyroidism subjects had statistically better while suffering from co-occurring major depressive emotional functioning according to GHQ scores, and disorder had more pronounced neuropathological numerically, but not statistically, higher BDI scores. After changes in the hippocampus area. Utilizing an AD 1 year of intervention (dose titrated to target TSH of neuropathological rating scale, the authors discovered 0.5–1.5 mUI/L), subjects given T4 did not differ from those that those patients with both disorders had a more given placebo in any measured parameter (cognitive, rapid cognitive decline than those with AD alone. emotional, or physical symptoms). This study did not find subclinical hypothyroidism to be Plaque and tangle formation, especially in the hippocampus associated with significant cognitive deficits, and T4 and temporal lobes, are considered the hallmark change that supplementation did not result in any cognitive or emotional occurs in Alzheimer’s disease (AD). It has been noted that a changes beyond that of placebo. However, several lifetime history of major depressive disorder (MDD) increases limitations of this study may have masked potential findings. the risk of clinically diagnosed AD, and MDD has been The TSH range used in this study overlapped with the associated with memory deficits in the elderly by several laboratory reference range; previous studies have studies. Imaging analyses in the geriatric population have

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revealed a correlation between MDD and volume loss in the Eleven of the 44 subjects with a lifetime history of hippocampus. Additional research has also suggested a MDD were depressed at the time of baseline assessment. relationship between MDD and the pathological processes These 11 patients had higher mean CERAD ratings than AD that lead to AD; however, no study to date has explored a subjects with a history of MDD but not active depression at history of MDD as a factor in the progression of AD. The baseline assessment. Analysis revealed that the subjects who authors explored this issue with the hypothesis that plaques were depressed at baseline had a larger proportion of NFT and tangles would be more pronounced in patients with and NP in the hippocampus. Mean CERAD scores for both MDD and AD than in those with AD alone. NP and NFT in the hippocampus were higher in all subjects The cohort selected was part of a large study of AD, with with AD and MDD, whether the depression was active at the subjects screened from residents and new admissions to baseline or not. the Jewish Home Nursing Home (New York, NY, USA). This study showed that there is an association between Patients were screened using the Mini-Mental Status Exam depression history and differences in NFT and NP in the (MMSE) and the Clinical Dementia Rating Scale. After hippocampus of subjects with AD, as more NFT and NP patients were screened for dementia, the clinical diagnosis were found in the hippocampus of subjects with MDD than of AD was determined through specific research and in those without. Further analysis suggested that subjects Diagnostic and Statistical Manual of Mental Disorders Third who had both AD and MDD experienced a more rapid Edition (DSM-III) or DSM-IV criteria. The history and cognitive decline than those who did not have depression. presence of MDD was ascertained by examining medical The study was limited; without hippocampal volumetric size records, the Geriatric Depression Scale, and standardized data it is difficult to assess whether the changes observed questionnaires based on the Structured Clinical Interview for were a result of increased AD neuropathological density DSM-IV Axis I disorders. caused by impaired neurogenesis due to MDD or whether The researchers acquired post mortem data on the findings reflected an increase in NFT and NP. 102 subjects with AD. Of these, 44 patients also had a Furthermore, since the study was performed in very old lifetime history of MDD while 51 did not. The remaining subjects, the findings cannot be extrapolated to patients seven could not be classified. Eleven subjects had been with earlier onset AD. experiencing MDD at the time of baseline assessment. After Address for reprints: MA Rapp, Department of Psychiatry, Mount Sinai the death of a patient, an autopsy was performed that School of Medicine, 1 Gustave L Levy Place, Box 1230, New York, included neuropathological assessment of various parts of NY 10029, USA. Email: [email protected] the brain. The extent of the lesions was determined using

the Consortium to Establish a Registry for AD (CERAD) Alterations in 5-HT1B receptor function neuropathological battery. by p11 in depression-like states The mean age of death for the 95 patients in the final Svenningsson P, Chergui K, Rachleff I et al. study group was 81.36 years, and the mean MMSE score Science 2006;311:77–80. was 12.37 at the last assessment prior to death. The most

common causes of death were pneumonia, cardiovascular This study revealed that serotonin 1B receptor (5-HT1B) failure, and renal failure, with no differences seen between interacts with p11, a protein that translocates its binding patients with or without MDD. Post mortem analysis partner to the plasma membrane. p11 was shown

revealed that 83 subjects could be classified as having to increase cell membrane localization of the 5-HT1B definite AD, eight subjects had probable AD, and 10 were receptor. Over-expression of p11 in mice increased

classified as having possible AD. MDD was found to be 5-HT1B receptor function, and led to recapitulation equivalently distributed throughout these categories. The of some behaviors seen after antidepressant treatment. MMSE scores of subjects with AD and a lifetime history Both electroconvulsive therapy and antidepressant of MDD at baseline were slightly higher than those with treatment caused increases in p11 levels in rodent brains. AD alone. Lastly, p11 knockout mice exhibited a depression-like Post mortem analysis also showed that subjects with AD phenotype, and had a reduced response to

who had never experienced MDD had less neuritic plaques antidepressants and 5-HT1B receptor antagonists. (NP) and neurofibrillary tangles (NFT) than those with AD and a past history of MDD. The mean annual cognitive Medications that alter serotonin metabolism or reuptake are decline was greater in those with a history of MDD than in used in several psychiatric disorders. Fourteen different those without such a history (1.86 vs. 1.15 mean annualized serotonin receptors have been identified, of which a decline in MMSE score). number also have multiple splice variants. Serotonin 1B

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(5-HT1B) receptors function as both autoreceptors and Cognitive profile of subcortical ischaemic heteroreceptors on many neurons, and have been implicated vascular disease in the pathophysiology of numerous psychiatric disorders, Jokinen H, Kalska H, Mantyla R et al. including depression and anxiety. J Neurol Neurosurg Psychiatry 2006;77:28–33. The authors presented evidence from a yeast two-hybrid

screening assay that showed p11 interaction with 5-HT1B Subcortical ischemic vascular disease is a subtype of receptors, but not with other serotonin or dopamine receptors. vascular cognitive impairment and has specifically defined

p11 was shown to co-localize with 5-HT1B receptors, and the structural imaging findings (extensive cerebral white matter

p11 mRNA distribution in the brain resembled that of 5-HT1B lesions and lacunar infarcts in deep grey and white matter). receptor mRNA. p11 mRNA expression was found to be The results of this study indicate that this disease is increased in the cortex by long-term administration of associated with worse depressive symptoms, greater imipramine, traylcypromine (another tricyclic antidepressant), impairments in executive function, and more delayed and electroconvulsive therapy, but not haloperidol, diazepam, memory than is seen in other stroke patients. or risperidone. p11 mRNA was also down-regulated in the anterior cingulate cortex of patients with major depressive Vascular dementia is a major cause of cognitive impairment disorder. In accordance with the increased mRNA expression, and dementia, and has a large range of clinical presentations p11 protein levels increased in the cortex after administration based on the specific subtype. Subcortical ischemic vascular of imipramine and electroconvulsive therapy. disease (SIVD) is a subtype of vascular dementia, characterized

Many aspects of 5-HT1B receptor regulation and signaling by magnetic resonance imaging findings of extensive cerebral were characterized using cell culture experiments. COS-7 white matter lesions and lacunar infarcts in deep grey and

cells that were co-transfected with p11 and 5-HT1B receptors white matter. Clinical findings have not been clearly defined;

had higher 5-HT1B receptor expression levels on their however, involvement of frontal–subcortical circuits predicts

surfaces than COS-7 cells transfected with 5-HT1B receptors more severe executive, but less severe memory and spatial

alone. COS-7 cells co-transfected with both p11 and 5-HT1B dysfunction, in contrast to Alzheimer’s disease. receptors also had more forskolin-induced cyclic adenosine Jokinen and colleagues assessed the neuropsychological monophosphate formation blockade by serotonin than cells function (speed of mental processing, executive function,

expressing the 5-HT1B receptors only. short-term memory, immediate recall, delayed recall, verbal As the results suggested that p11 increases as a result of intellectual functions, and visuospatial functions) of: antidepressant treatment, the authors explored whether p11 also affected behaviors in the mouse model. Transgenic mice • Patients with SIVD (n=85; mean age 71.7 years, that over-expressed p11 behaved in a similar way to mice mean years of education 8.3). given antidepressants, while p11 knockout (KO) mice were • Younger, better educated, other stroke patients (n=238;

shown to have fewer 5-HT1B receptors. mean age 69.8 years, mean years of education 9.8). It is known that serotonin reduces glutamate release at • Younger, neurologically healthy controls (n=38; mean

the terminals of certain neurons via 5-HT1B receptors. The age 67.4 years, mean years of education 9.4). researchers monitored the amplitude of field excitatory post-synaptic potentials evoked by electrical stimulation of SIVD patients had more cortical and central atrophy, and glutamatergic fibers. Serotonin was able to mediate an effect in more medial temporal lobe atrophy than was seen in

the wild-type mice, but not the p11 KO mice. 5-HT1B receptors controls; SIVD patients also had greater medial temporal are also known to act as autoreceptors and to inhibit serotonin lobe atrophy and higher depression scores than other stroke release, and it was found that the p11 KO mice had increased patients. Rates of dementia did not differ between any of levels of serotonin metabolism and turnover. Experiments the three groups. that assessed exposure to antidepressants in p11 KO mice Overall, cognitive function in all domains was lower in the compared with controls suggested that p11 mediates SIVD patients than in the controls, even after taking into

behavioral responses to imipramine via 5-HT1B receptors, account age and education. SIVD patients had lower executive and that p11 KO mice have a depression-like phenotype. function and delayed memory recall compared with other This study offers significant evidence that p11 may play a stroke patients, after considering age and education. Correcting role in the molecular mechanisms that malfunction in depression. for depression scores did not affect the differences between the SIVD and other stroke patients; however, the delayed memory Address for reprints: P Greenguard, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, recall difference was accounted for by the difference in medial USA. Email: [email protected] temporal lobe atrophy between these groups.

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SIVD is a relatively homogeneous subtype of vascular The present study enrolled 13 older adults (mean age cognitive impairment with specifically defined structural 62.8 years) with unipolar depression who were receiving imaging findings. The results of this study indicate depressive antidepressants, and 13 age- and gender-matched controls. symptoms, impairments in executive function, and delayed Nobuhara and colleagues examined diffusion-weighted memory beyond that observed for the heterogeneous group of images in predetermined regions of interest: general stroke patients. These changes were observed as early as 3 months after the acute stroke. • Bilaterally in the frontal white matter at 8 mm above anterior commisure–posterior commissure (AC–PC) plane, Address for reprints: H Jokinen, Department of Neurology, Helsinki University Central Hospital, PO Box 302, FIN-00029 HUS, Helsinki, at the AC–PC plane, and at 8 mm below the AC–PC plane. Finland. Email: [email protected] • Bilaterally in temporal, parietal, and occipital white matter. • The genu and splenium of the corpus callosum. Frontal white matter anisotropy and symptom severity of late-life depression: a magnetic Fractional anisotropy (FA) is an index of water mobility or resonance diffusion tensor imaging study diffusion anisotropy and thus white matter integrity, such Nobuhara K, Okugawa G, Sugimoto T et al. that lower values suggest decreased white matter integrity. J Neurol Neurosurg Psychiatry 2006;77:120–2. FA values were lower in frontal and temporal regions in depressed subjects compared with healthy control subjects, Patients with depression in later life have decreased but not in the parietal, occipital, or corpus callosal white fractional anisotropy in frontal and temporal white matter regions of interest. Depression severity, measured matter tracts, compared with matched controls. This by Hamilton Depression Rating Scale scores, were inversely finding is consistent with reduced orbitofrontal white correlated with FA in the frontal cortical white matter matter tract integrity and increased pathology in 8 mm below the AC–PC plane, consistent with orbitofrontal late-life depression. cortex dysfunction (r=–0.58; p=0.04 uncorrected for multiple comparisons). Structural and functional imaging studies have implicated Despite the small sample size and exploratory nature of the prefrontal cortex and anterior paralimbic circuit in the this study, these results are consistent with current hypotheses pathophysiology of major depressive disorder. Magnetic of anterior paralimbic – including orbitofrontal – circuit resonance diffusion tensor imaging (DTI) measures the involvement in depression. Correlations with depression magnitude and directionality of tissue water movement, severity suggest state effects, but studies in euthymic which is greatest along axonal tracts and least across and patients are needed to assess the longitudinal effects of perpendicular to axonal tracts. Thus, DTI can provide an unipolar depression. index of the microstructural integrity of white matter tracts, Address for reprints: K Nobuhara, 10–15 Fumizono-cho, Moriguchi City, and has been used to evaluate white matter tract integrity in 570-8506, Japan. Email: [email protected] schizophrenia and depression.

DEPRESSION: MIND AND BODY Vol 2 No 4 2006 145 R7420_2_REM_DEP2_4_17.qxd 20/7/0617:40Page146 MEETING REPORT (NY StatePsychiatricInstitute,NewYork, NY, USA):focal not everyseizure improves depressive symptomatology. seizures are aprerequisite fortheantidepressant effect, but device posedaproblem. AswasfoundinECTtreatment, in thispatient.However, the limitedpowerofMST a casestudyofTRDanddescribedgoodresponse toMST three timesaweekfor10–12sessions.DrKoseldiscussed side-effects thanECT. Theapplicationissimilar, withtherapy non-invasive intervention,theprocedure mayhavefewer to generateseizures inthebrain;however, asthisisa (MST). Aswithelectroconvulsive therapy(ECT),MSTaims discussed thepotentialbenefitsofmagneticseizure therapy successful treatment are necessarytoimprove efficacy. the intervention,andDrBajboujstressed thatpredictors for of VNSappearstodependontheintensityandduration dyspnea, althoughthesedisappeared overtime.Theefficacy Side-effects includedhoarseness,cough,paresthesias, and observational studydidshowbetterresults inthelong-term. the treatment andcontrol conditions.However, an another trial,withnosignificantdifferences seenbetween relative lackofshort-termefficacy wasalsodemonstratedin remitting after1year, and afurther22%after2years.This remitted duringtheacutephase,withanother27% debated. Inanopenstudyof60patients,only15% depression (TRD).Theefficacy ofVNSiscurrently being stimulation (VNS)asatherapyfortreatment-resistant Univeritätsmedizin, Berlin,Germany)discussedvagusnerve of newtreatments fordepression. MalekBajbouj(Charité- Brain stimulationisapromising area forthedevelopment Brain stimulation focus ofthisreport. concentrated ontreatment issues,whichare theprimary 2700 participantsfrom 62countriespresent. Themeeting Psychiatrists (AEP)waswellattended,withapproximately The annualmeetingoftheAssociationEuropean De GelderseRoos,MentalHealthCare, Arnhem,andTrimbos Institute,Utrecht, TheNetherlands Jan Spijker Nice, France,4–8March,2006 of European Psychiatrists(AEP) 14th AnnualMeetingoftheAssociation 146 A newtechniquewasintroduced byRobertBerman Markus Kosel(UniversityHospital,Bonn,Germany) D EPRESSION : M N AND IND B biological treatment (mostlycombinedwithpsychotherapy). response and54%achievedremission whilereceiving a inpatients foundthatonly23%ofpatientsshowedno care. AnaturalisticGermanstudyof686depressed however, thissituationisbetterinspecializedmentalhealth undertreatment ofdepression, especiallyinprimarycare; medications, discussingthewell-knownunderdiagnosis and a similarlecture onnewdevelopmentsinantidepressant Möller (UniversityofMunich,Germany)delivered sleep disturbances,andminimalsideeffects. Hans-Jürgen promising newantidepressant thathasaddedefficacy in also referred toagomelatine(amelatonineagonist)asa treatment ofdepression withcomorbidanxiety. DrAckenheil differences betweenvariousantidepressant medicationsinthe Pittsburgh MedicalCenter, Pittsburgh, PA, USA)foundno analysis byMichaelThaseandcolleagues(Universityof antidepressant treatment fortherightpatient.Ameta- Munich, Germany)discussedhowtochoosetheright developments. Manfred Ackenheil(UniversityofMunich, Older techniqueswere alsoreviewed alongsidenew Pharmacological treatmentsfordepression these traitswasfound. role inmotivationanddrive;indeed,anincrease inbothof chosen asthesiteofelectrode implantationbecauseofits or otherpsychiatricsyndromes. Thenucleusaccumbenswas for thistherapy. There were noreported symptomsofmania switched off forseveralweeks,providing proof ofefficacy during thestudy-periodandrelapsed afterthedevicewas brain –asatherapyforTRD.Patients’depression improved an electrode isimplantedinthenucleusaccumbensof unwanted motoreffects. monkeys, itwaspossibletoinducefocalseizures without cognitive side-effects. Inanexperimentperformedon ECT, andtherefore improved efficacy anddecreased designed tohaveenhancedspatialtargeting compared with electrically administered seizure therapy(FEAST).FEASTis ODY Dr Koselalsodiscusseddeepbrainstimulation–where Vol 2No42006 R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:40 Page 147

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The success rate is remarkable for this population; however, >64 000 references. Dr Mackin then focused on cardiovascular in this study the mean duration of inpatient treatment was disease (CVD) and metabolic disease, and found (from 61 days, which is longer than usual. Dr Möller showed a 15 prospective studies) that an association between depression preference for the antidepressants with a dual action, and and CVD was present in the majority of patients. Depression indicated that venlafaxine and duloxetine are more efficacious predicts for CVD and some studies have even found a than other antidepressants. He also referred to a Cochrane dose–response relation with coronary calcifications, carotid meta-analysis from Cipriani et al., where the results pointed atheroscleroses, increased inflammatory processes, and to selective serotonin reuptake inhibitors (SSRIs) as the most reduced autonomic function. In a further 10 studies included efficacious treatment for depressed outpatients [1]. in the analysis, a strong association between depression and Siegfried Kasper (University of Vienna, Vienna, Austria) obesity was identified, especially in depressed adolescents. and Peter Falkai (University of Saarland, Saarbrücke, As a consequence of obesity, the risk for diabetes mellitus Germany) opened a discussion of SSRIs and suicidality. Data also increased, as was determined by another 11 studies. from studies of children and adolescents have found a small Mechanisms of this association are thought to involve the but significant increase in suicidality after starting hypothalamic–pituitary–adrenal axis, lifestyle, and the use antidepressant treatment (see also Baldessarini et al. [2]); of psychotropic drugs. Depression was also found to however, in adults there is limited evidence to support this independently increase the risk for metabolic disease. This association. There is more reason to expect the opposite, i.e. lecture made a very convincing argument that somatic that antidepressants prevent suicide. Recent meta-analyses illnesses in depressed patients should not be overlooked. have shed some light on this matter. Fergusson et al. found Enhancing treatment for depressive disorders is an an association between suicidal behavior and SSRI treatment enormously important goal, and this congress presented [3], in contrast with a review from Khan et al. [4]. Study some interesting new possibilities while enriching our findings showed that suicidality in depressed patients is at its knowledge of the existing ones. peak just before starting antidepressant treatment and not after this event; however, antidepressants are still potentially References dangerous drugs and can have lethal effects. 1. Cipriani A, Brambilla P, Furukawa T et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 2005;(4):CD004185. 2. Baldessarini RJ, Pompili M, Tondo L. Suicidal risk in antidepressant drug trial. Arch Gen Depression and physical illness Psychiatry 2006;63:246–8. 3. Fergusson D, Doucette S, Cranley Glass K et al. Association between suicide attempts Depression and physical illness frequently co-occur in patients, and selective serotonin reuptake inhibitors: a systematic review of randomised clinical and Paul Mackin (University of Newcastle, Newcastle, UK) trials. BMJ 2005;330:396–403. 4. Khan A, Khan S, Kolts R et al. Suicide rates in clinical trials of SSRIs, other antidepressants, performed a literature review on this subject, producing and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790–2.

DEPRESSION: MIND AND BODY Vol 2 No 4 2006 147 R7420_2_REM_DEP2_4_17.qxd 20/7/0617:40Page148 MEETING REPORT undergone >25trialsasaugmentationtherapyinmajor thyroid andrenal effects andalowtherapeuticindex.T3has but clinicalusehasbeenlimitedduetopotentialadverse a beneficialeffect oflithiumatplasmalevels0.4–0.6mmol/L, randomized clinicaltrials.There are >50studiessupporting of antidepressants havebeenvalidatedbynumerous Medicationstreating comorbidities (e.g.sertraline • Secondmedicationaddressing adverse effects ofthe • Targeting complementaryneurotransmitter mechanisms • Targeting similarneurotransmitter mechanisms • foundations ofpolypharmacyrationalinclude: after initialtreatment withanantidepressant. Thebasic 60–70% ofpatientshaveresidual depressive symptoms to address residual symptomsafterinitialtreatment. Upto nonadherence, rational polypharmacyisfrequently required drug–drug interactions,medicationerrors, andpatient is common.Despitetheincreased riskofadverseevents, medications totreat thesameoracomorbidcondition, better outcomes.”Polypharmacy, definedastwoormore entitled “Newaugmentationstrategiesindepression for MA, USA)chaired theindustry-sponsored symposium Jonathan Alpert(MassachusettsGeneralHospital,Boston, for betteroutcomes New augmentationstrategiesindepression patient care. to bestintegratethisknowledgecontinuallyimprove forum fordebateofthelatestscientificadvancesandhow leaders inthisprofession andproviding aninternational largest psychiatricconference intheworld,bringingtogether The AmericanPsychiatricAssociationannualmeetingisthe Department ofPsychiatryandBehavioralSciences,Stanford UniversitySchoolofMedicine,Stanford, CA,USA Po Wang andAlanSchatzberg Toronto, ON,Canada,May20–25,2006 Psychiatric Association(APA) 159th AnnualMeetingoftheAmerican 148 Lithium, liothyronine (T3),andbupropion augmentation plus zolpidem). primary medication(e.g.paroxetine plussildenafil) (e.g. citalopramplusbupropion). (e.g. fluoxetineplusbuspirone). D EPRESSION : M N AND IND B York, NY, USA)chaired theindustry-sponsored symposium Steven Roose(NewYork StatePsychiatric Institute,New and depression Interrupting thecycleofvasculardisease therapy approach toattainthegoalofremission. treatment ofdepression typicallyrequires acombined based cognitivetherapy)andinterpersonaltherapy. Overall, behavioral analysissystemofpsychotherapy, mindfulness- cognitive–behavioral therapy, well-beingtherapy, cognitive– cognitive therapyinvariousforms(cognitivetherapy, either interventionalone,basedonstudiesinvolving Combined psychotherapyandmedicationissuperiorto MDD, benefitingacuteresponse andmaintainingremission. with antidepressants forthetreatment ofpatients with were discussedatthemeetingandare showninTable 1. the lackofplacebocontrol group. Furthernovelstrategies A majorlimitationoftheaugmentationarmSTAR*D was in buspirone wasefficacious 20% ofpatients,while to anotherantidepressant causedremission inapproximately subjects remitted withcitalopramtreatment alone.Switching or augmentationstrategies.Onlyapproximately 30%of were thenrandomized toarangeofantidepressant switch treated withcitalopramforupto12weeks;nonremitters to initialantidepressant treatment. Patientswere first the mostsuitable“nextchoice”afterincompleteresponse care andpsychiatricsettings,withthegoalofidentifying outpatient treatment ofacutemajordepression inprimary results were reviewed atthismeeting.STAR*D investigated treatment strategiesintreatment-resistant patients,and Relieve Depression) trialwasconductedtocompare different still remain depressed afterthesevalidatedcombinations. other antidepressant medications.However, manypatients supported andcommonlyusedbyclinicianstoaugment depressive disorder (MDD).Bupropion isempirically ODY Psychotherapies are likewisevalidatedincombination The STAR*D (SequencedTreatment Alternativesto Vol 2No42006 augmentation withbupropion-SR or 30% oftheinitialnonremitters. R7420_2_REM_DEP2_4_17.qxd 20/7/06 17:40 Page 149

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Table 1. Novel antidepressant drug augmentation strategies.

Strategy Drug Notes New Olanzapine Double-blind studies in MDD antipsychotic Risperidone medications Ziprasidone New Lamotrigine Lamotrigine has better efficacy data in bipolar depression anticonvulsants Divalproex Divalproex may target agitation in MDD Selective Amphetamines Used for anergia, amotivation dopamine Bromocriptine No double-blind trials agonists Pramipexole Pramipexole (1.7 mg/day) has stronger efficacy data in bipolar depression Ropinirole Steroids Mifepristone Mifepristone may have efficacy in psychotic depression, but possibly more for the psychotic than depressive symptoms Estrogen and testoterone Estrogen and testosterone may be efficacious only in specific subsets of patients DHEA Hydrocortisone Other Modafinil Modafinil 100–200 mg/day

DHEA: dehydroepiandrosterone; MDD: major depressive disorder.

entitled “Interrupting the cycle of vascular disease and randomizing 369 patients with depression during the post- depression”. This session covered: MI period to treatment with either 50–200 mg sertraline or placebo for 24 weeks. Sertraline was efficacious in patients • Potential mechanisms underlying the interaction with a prior history of depression, but not in patients who between vascular disease and depression. developed their first depressive episode after the MI. • Comorbidity and treatment considerations of vascular disease and depression. Stroke and depression • The concept of vascular depression. Depression occurs in 10–27% of patients post-stroke. • The relationship between depression and diabetes mellitus. Depression predicts poorer rehabilitation, increased disability, and increased mortality following stroke, which may be related Cardiovascular disease and depression are among the top to biological (common cerebral deficits, e.g. executive or causes of medical mortality and morbidity. The presence of language functions) and psychosocial mechanisms. depression is a well-established predictor of myocardical Antidepressant treatment can benefit the outcome of infarction (MI), cerebrovascular events, reduced survival depression and stroke; however, in a meta-analysis of seven after MI, and development of diabetes. Hypothalamus– pharmacotherapy and two psychotherapy trials, clear pituitary–adrenocortical (HPA) axis hyperactivity might have efficacy was not demonstrated, although this may be due to a role in both depression and vascular disease, and the high threshold of complete depression remission hypercortisolemia can lead to insulin resistance and vascular required by the analysis. In some placebo-controlled trials, reactivity. An elevated immune response (increased levels of nortriptyline has shown an early and sustained response [1], C-reactive protein and interleukin-6 [IL-6]) may also be a while fluoxetine had a delayed response, in the treatment common feature in both depression and cardiovascular of post-stroke depression [2]. disease, and IL-6 could mediate insulin resistance. Finally, some antidepressants (e.g. paroxetine and nortriptyline) Diabetes and depression have been shown to decrease platelet “stickiness”, as well Diabetes and depression show a bidirectional relationship: as to affect central nervous system (CNS) targets, therefore depression is 3–4 times more common in individuals with influencing both depression and vascular disease. diabetes than in the general population, and depression often precedes the onset of diabetes. Although the Myocardial infarction and depression biological links between depression and diabetes are still The SADHART (Sertraline Antidepressant Heart Attack being explored, the psychological link is clearer (poorer Randomized Trial) investigated post-MI depression by treatment adherence, weight management by diet and

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exercise, and quality of life). Interestingly, controlled clinical from 19 published studies analyzing hippocampal volumes in trials of antidepressants or cognitive behavioral therapy for subjects with post-traumatic stress disorder (PTSD), trauma depressed patients with diabetes improved glycemic control [3]. without PTSD, and control subjects. Patients with PTSD had A recent placebo-controlled maintenance trial for individuals smaller bilateral hippocampal volumes compared with with diabetes whose depression responded to open-label control subjects. However, no differences were seen in sertraline found that a good initial open-treatment response volume between individuals with PTSD and those with and continued euthymic mood were associated with improved trauma without PTSD, suggesting that trauma itself may be levels of glycosylated hemoglobin for >1 year [4]. associated with regional brain changes.

Young Investigators’ Poster Session Advances in research: an Update for A broad range of topics were covered in the Young the Clinician Session Investigators’ Poster Session. A sampling of just a few of the David Kupfer (University of Pittsburgh Medical Center, posters is given below. Pittsburgh, PA, USA) chaired the Advances in Research: an Update for the Clinician Session. Cognitive and social functioning in recovery Floyd Bloom (Neurome, Inc., La Jolla, CA, USA) discussed from depression: results from a population-based, the fastest advancing areas of research in psychiatry and 3-year follow-up neuroscience: genomics, biological imaging, and computer- Airaksinen and colleagues (Karolinska Institutet, Stockholm, assisted data mining. The mouse genome and transgenic mice Sweden) examined 76 individuals with a Diagnostic and can provide a framework and research platform to help Statistical Manual of Mental Disorders-IV (DSM-IV) understand the human CNS. Mouse strains can be created diagnosis of MDD, identified from a population-based that experience high levels of anxiety and depression sample. Patients were administered social-functioning and (represented by a range of strain-specific performances on the episodic-memory scales at baseline and at 3-year follow-up. Forced Swim Test), develop earlier Alzheimer’s-like amyloid Social functioning was noted to improve when depressive plaques, or express or lack specific genes of interest (so called symptoms improved. Episodic-memory scores throughout “gene knock outs” e.g. mice deficient in glucocorticoid the study were lower than expected from normative data receptor expression in the forebrain). and irrespective of an improvement in depression. This Katherine Wisner (University of Pittsburgh, Pittsburgh, PA, suggests that cognitive dysfunction may persist for up to USA) reviewed use of selective serotonin reuptake inhibitor 3 years after an acute major depressive episode. (SSRI) antidepressants during pregnancy. Given the widespread use of antidepressants, many children are born Modafinil augmentation for fatigue associated after intrauterine exposure to SSRIs. Early studies found no with fibromyalgia increase in the risk of intrauterine fetal death or major physical Chlebowski and colleagues (State University of New York, malformations associated with first trimester exposure; Syracuse, NY, USA) examined 98 consecutive rheumatology however, a current focus of controversy is data suggesting patients with fibromyalgia who were given modafinil (mean that fetal paroxetine exposure may be associated with cardiac dose 162 mg/day). Fatigue improved by a mean of 28%, malformations. More recent studies have addressed later and modafinil was generally well tolerated. trimester exposure and adverse reproductive outcomes, including fetal growth changes and behavioral teratogenicity Prevalence of metabolic syndrome (finding no difference in cognitive function, verbal in VA bipolar patients comprehension, expressive language, mood, arousability, Cardenas and colleagues (University of California in Los activity, behavior problems, or temperament). Angeles, CA, USA) found that 49% of patients at the West Chambers et al. found that late exposure to fluoxetine was Los Angeles Veterans Affairs Hospital (CA, USA) presenting associated with a lower birth weight than early or no for treatment of bipolar disorders had metabolic syndrome. exposure [5]. However, this study did not control for an This is approximately twice the rate of metabolic syndrome improvement in depressive symptoms; therefore, mothers among the general population. remaining on antidepressants during late pregnancy may have had depression that required continued treatment. Hippocampal volume in post-traumatic stress Dr Wisner suggested that neonatal syndrome, a condition disorder: a meta-analysis characterized by difficulty in feeding and sleeping, Sood and colleagues (Maricopa Integrated Health System, irritability, prolonged crying, tremors, and seizures, may be Phoenix, AZ, USA) conducted a meta-analysis of the results related to either acute serotonin exposure (e.g. fluoxetine)

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or antidepressant withdrawal (e.g. paroxetine with decreases in plasma lipid concentrations; no patient on anticholinergic effects). For mild symptoms, behavioral ziprasidone discontinued treatment due to weight gain interventions (small and frequent feeds, increased physical or metabolic adverse effects. The anticipated superiority contact, and psycho-education for the mother) are advocated. of the second-generation antipsychotics over older Identifying the source of the symptoms (excessive serotonin antipsychotic medications was not demonstrated by this trial. exposure versus anticholinergic withdrawal) will guide Clozapine was reported as having superior efficacy after pharmacotherapy choices for more severe symptoms. inefficacy switches. Overall, switching to other treatments SSRI antidepressant exposure (after the 20th week of was common. gestation), but not tricyclic antidepressant exposure, has been suggested to increase the risk of persistent pulmonary Therapeutic neuromodulation: hypertension (PPH; or persistent fetal circulation). Out of 377 methods and mechanisms women whose infants had PPH, 14 had been exposed to This symposium consisted of four talks and a discussion that SSRIs after the 20th week of gestation, whereas in the focused on new techniques of brain stimulation in depression. comparison group of 836 matched women, six had been Mark Demitrack (Neuronetics, Inc., Malvern, PA, USA) exposed to SSRIs after the 20th week of gestation [6]. SSRI opened the symposium noting that most medication therapies exposure therefore increases the risk of PPH by as much as for depression have been developed in “easy-to-treat six-fold over the rare occurrence rate of PPH in the general depression”, i.e. patients without a prior history of poor population. Although the relative risk is great, the absolute treatment response. Few of the currently approved therapies risk is low; however, the mortality rate of PPH is high. have been studied in refractory patients. Given that STAR*D Jeffrey Lieberman (Columbia University, New York, NY, found only 30% of patients achieved remission after 12 USA) discussed the rationale and initial outcome measures weeks of citalopram therapy, and an additional 25–30% of CATIE (Clinical Antipsychotic Trials in Intervention remitted with an augmentation or switch strategy, new and Effectiveness). CATIE was designed to address differences more effective therapies are needed for the large percentage in efficacy among second generation antipsychotics of patients who do not achieve a full response. One approach (olanzapine, quetiapine, risperidone, ziprasidone) and has been to use electroconvulsive therapy, which, although perphenazine (representing first-generation antipsychotic very effective, has high relapse rates post-cessation. medications) in approximately 1500 patients with Additionally, follow-on maintenance drug therapy is less schizophrenia. In Phase I of the trial, patients were randomly effective in patients who did not previously respond to assigned to treatment. Patients who chose not to remain on medication than in patients with a history of prior good the first randomly assigned medication were given a second response. Along with the relatively low response rates to randomized drug, which included open clozapine treatment established therapies, treatment discontinuation due to (Phase II). The primary hypothesis was that new adverse events is also common. Thus, better-tolerated antipsychotic medications would be more effective than the treatments need to be developed. older antipsychotic, perphenazine. The primary outcome Philip Janicak (University of Illinois at Chicago, Chicago, IL, measure was “all-cause discontinuation”. A total of 74% of USA) reviewed data on vagus nerve stimulation (VNS). The patients switched from the first medication assigned. VNS Therapy System™, (Cyberonics, Inc., Houston, TX, USA) Olanzapine was statistically better than other medications in is currently the only implantable devise approved for the maintaining patients in the randomization. Perphenazine was treatment of major depression. Current US Food and Drug as effective, and unexpectedly, its extrapyramidal adverse Administration (FDA) approved indications are for treatment- effects were not more severe than, the second generation resistant and recurrent depression. The device, which is antipsychotics. In Phase II, inefficacious medication switches implanted in the side chest wall and has an electrode wrapped were randomized to open clozapine or an antipsychotic not around the vagus nerve, appears to stimulate a number of key used in Phase I. Clozapine was the most effective medication brain regions via afferents to the brain. in Phase II, while risperidone was best for patients who had The pivotal study compared active with sham VNS in a total switched for tolerability reasons. Olanzapine produced the of 220 patients. All subjects were chronically depressed (≥2 greatest increases in weight and plasma glucose and lipid years) or had ≥4 lifetime episodes of depression. The average levels, while quetiapine’s adverse effects included elevated duration of the current depressive episode was 4 years. A third plasma glucose and lipids. Risperidone caused elevated had received electroconvulsive therapy in the current episode, plasma glucose and prolactin concentrations, but weight did and 50% in current or past episodes. Patients had also not increase appreciably and plasma lipid levels decreased. received 2–6 adequate trials of antidepressant treatment in the Ziprasidone use was associated with weight loss and present episode.

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Treatment involved 2 weeks of stimulus adjustment twitching (21%), but these were all manageable. followed by 5 weeks of active versus sham treatment. Discontinuation rates due to side effects were 4–5% and All other medications were unchanged. Response was 3–4% in the active and sham conditions, respectively. defined as a ≥50% reduction in the Hamilton Rating Scale Alan Schatzberg (Stanford University School of Medicine, for Depression (HAM-D). A response rate of 15% was seen Stanford, CA, USA) served as the discussant, and emphasized in the active group compared with 10% in the sham the need to develop more effective and better-tolerated condition (p=0.25). treatments for depression since adverse events from current Sham patients were then crossed over to active treatment therapies are still highly problematic. Dr Schatzberg also while treated patients continued to receive active therapy. By presented recent data on alleles for the 5-HT2a receptor and 1 year, 30% of patients had responded to VNS treatment. promoter variants for the 5-HT transporter, which may predict A refractory group was subsequently followed for 1 year at for discontinuation of paroxetine treatment due to side the same sites and under standard treatment conditions. effects. These genes are currently under a patent application A significantly lower response rate of 13% was seen in this (on which Dr Schatzberg is a named inventor). comparison group. This comparison was part of the basis for Recent STAR*D data point to low response rates (15%) at the approval of VNS treatment. Phase III (using nortriptyline or mirtazapine monotherapy, or Side effects included voice alteration in approximately augmentation with T3 or lithium) of the clinical trials in 70% of patients and surgical complications occurred in <2% patients who did not respond to Phases I and II. Thus, of cases. To date, approximately 1100 patients in the US have response rates in the r-TMS and VNS trials do not seem been implanted with the VNS treatment device for refractory as low when considered in the light of the recent or recurrent depression. STAR*D results. Background expected response rate must Elliott Richelson (Mayo Clinic, Jacksonville, FL, USA) always be considered when assessing these refractory discussed recent studies of the biological basis of VNS for trials. The significant MADRS findings in the depression treatment. A number of possible mechanisms r-TMS study used categorical rather than continuous measure, were reviewed, including depolarization of key areas in the suggesting efficacy in a specific type of patient. Greater brain and promotion of neurogenesis. Of particular attention needs to be directed towards developing predictors importance is that electrical stimulation may help reverse of response for the various fields of antidepressant treatment. abnormalities in circuits involving the anterior cingulate, Overall, data from the r-TMS multicenter trial suggest the prefrontal cortex, and amygdala. treatment showed efficacy. John Reardon (Hartford Hospital, Hartford, CT, USA) Lastly, these new devices require further study to discussed rapid transmagnetic stimulation (r-TMS). There have maximize stimulus parameters, in particular VNS and the been multiple small studies suggesting that 3–4 weeks of frequency of therapy (3 times/week rather than 5 times/week therapy are more effective than 1–2 weeks, and have as for r-TMS). highlighted the left prefrontal cortex as a useful site of application. He then presented the first results from a Disclosures multicenter study of 300 unipolar, nonpsychotic patients with Dr Schatzberg is co-founder of Corcept Therapeutics and a Consultant a history of nonresponse to medication. Patients were aged for Forest Laboratories, Eli Lilly, and Neuronetics, Inc. Dr Wang has 18–70 years, and had received treatment 5 days/week for financial affliations with Abbott Laboratories, AstraZeneca, Bristol-Myers 6 weeks. Primary efficacy was improvement at 4 weeks and Squibb, Elan Pharmceuticals, Eli Lilly, GlaxoSmithKline, Janssen change in the Montgomery-Asberg Depression Rating Scale Pharmaceutica, Pfizer, Sanofi Aventis, Shire Laboratories, and Wyeth. (MADRS) was used to measure the primary outcome. An average point decrease of 5.2 was seen in the active group References compared with 3.4 in the sham condition (p=0.057). 1. Robinson RG, Schultz SK, Castillo C et al. Nortriptyline versus fluoxetine in the treatment Using a categorical definition of decrease in MADRS total of depression and in short-term recovery after stroke. Am J Psychiatry 2000;157:351–9. 2. Fruehwald S, Gatterbauer E, Rehak P et al. Early fluoxetine treatment of post-stroke score of ≥50%, a response rate of 18% was seen in the active depression – a three-month double-blind placebo-controlled study with an open-label group compared with 11% in the sham treatment group long-term follow up. J Neurol 2003;250:347–51. 3. Lustman PJ, Anderson RJ, Freedland KE et al. Depression and poor glycemic control: (statistically significant). Categorical and continuous outcomes a meta-analytic review of the literature. Diabetes Care 2000;23:934–42. observed on the HAM-D were significantly better in the active 4. Lustman PJ, Clouse RE, Nix BD et al. Sertraline for prevention of depression recurrence treatment group than in sham-treated patients. Crossing over in diabetes mellitus. Arch Gen Psychiatry 2006;63:521–9. 5. Chambers CD, Johnson KA, Dick LM et al. Birth outcomes in pregnant women taking from sham to active treatment in the next phase of the study fluoxetine. N Engl J Med 1996;335:1010–5. resulted in an overall 42% response rate. Side effects included 6. Chambers CD, Hernandez-Diaz S, Van Marter LJ et al Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. headache (57%), application site pain (35%), and muscle N Engl J Med 2006;354:579–87.

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