volume 2 number 4 2006 depression: mind and bodyattempting several antidepressant treatments is...

VOLUME 2 NUMBER 4 2006

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

DEPRESSION: Mind and BodyAdvances in the Understanding and Treatment of Depression and its Physical Symptoms

The Role of Vagus Nerve Stimulation as aTherapy for Treatment-Resistant DepressionMustafa M Husain, Kenneth Trevino, Louis A Whitworth, and Shawn M McClintock

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

The Bidirectional Relationship between Diabetes Mellitus and DepressionSanjay J Mathew and Susan Burd

www.depressionmindbody.com

This activity has been planned and implemented in accordance with theEssential Areas and Policies of the ACCME through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The Universityof Kentucky College of Medicine is accredited by the ACCME to providecontinuing medical education for physicians. The University of Kentucky is anequal opportunity university.

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

Editor-in-ChiefAlan F SchatzbergKenneth T Norris Jr, Professor and Chairman,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

EditorsChristos BallasAssistant Clinical Professor, Department of Psychiatry,University of Pennsylvania Medical Center, Philadelphia,PA, USA

Po W Wang Senior Research Scientist, Bipolar Disorders Clinic, Department of Psychiatry and Behavioral Sciences,Stanford University School of Medicine, Stanford, CA, USA

Editorial Advisory BoardDwight EvansProfessor and Chair, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Maurizio FavaPsychiatrist and Director, Depression Clinical and Research Program, Massachusetts General Hospital,Boston, MA, USA

John GredenProfessor and Chair, Department of Psychiatry, University of Michigan Depression Center, Ann Arbor, MI, USA

Wayne KatonProfessor and Vice Chair, Department of Psychiatry and Behavioral Sciences, University of Washington,Seattle, WA, USA

Kurt KroenkeProfessor of Medicine, Department of Medicine and Regenstrief Institute for Health Care, IndianaUniversity School of Medicine, Indianapolis, IN, USA

Yves Lecrubier Director of Research, Hôpital de la Salpêtrière,Paris, France

Norman SartoriusPsychiatry Department Director, University Hospital, Geneva, Switzerland

Donna StewartProfessor and Chair, Women’s Health University Health Network and University of Toronto, Toronto, ON, Canada

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, multidisciplinaryaudience. 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 clinicaland 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 ormisleading 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 theindependent evaluations and opinions of the authors and contributors. As a consequence, the board, publishers, and any supporting company accept no responsibility for theconsequences 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 thatlies 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 anddistributed by USA Mail Agent Pronto Mailers Association, 544 Lincoln Boulevard, Middlesex, NJ 08846. Subscription price $170 per year. Periodicals Postage Paid atMiddlesex NJ. POSTMASTER: Please send address changes to Remedica Publishing Ltd, 544 Lincoln Boulevard, Middlesex NJ 08846-2439.

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Contents

Leading ArticlesThe Role of Vagus Nerve Stimulation as aTherapy for Treatment-Resistant DepressionMustafa M Husain, Kenneth Trevino, Louis A Whitworth, and Shawn M McClintock 114

Neuropsychiatric Effects of IL-2: Mechanisms and Treatment ImplicationsStephen E Nicolson, Andrew H Miller, David Lawson, and Dominique L Musselman 120

The Bidirectional Relationship between Diabetes Mellitus and DepressionSanjay J Mathew and Susan Burd 130

Clinical ReviewsEpidemiology 134

Clinical Practice 137

Comorbidities 140

Pathogenesis 142

Meeting Reports14th Annual Meeting of the Association of European Psychiatrists (AEP) Nice, France, 4–8 March, 2006 146

159th Annual Meeting of the American Psychiatric Association (APA)Toronto, ON, Canada, 20–25 May, 2006 148

Dear Colleagues,

Welcome to the final issue of the second volume of Depression:Mind and Body.

Although great advances have been made in therapies forthe treatment of depression, some patients fail to respond to initial treatment courses, and many do not respond tomultiple medication trials. These patients are described ashaving treatment-resistant depression (TRD) and the prevalenceof this disorder calls for new treatment techniques. In thisissue, Dr Husain and colleagues (University of TexasSouthwestern Medical Center at Dallas, Dallas, TX, USA)discuss a novel neurostimulation technique, vagus nervestimulation (VNS) therapy, and its role as an antidepressanttherapy for patients with TRD. Studies have demonstratedthe safety and efficacy of VNS therapy for patients sufferingfrom TRD, and this article expands upon its mechanism ofaction and the results of recent trials.

Our second article examines interleukin-2 (IL-2), a vitalsignaling molecule in immune and inflammatory responses aswell as in cell migration and differentiation. IL-2 has beenused for the treatment of diseases such as cancer and AIDS;however, it exhibits strong adverse effects, including a highincidence of depressive symptoms and memory disturbances.The mechanisms for these effects are not well documentedor understood and Dr Nicolson and colleagues (EmoryUniversity School of Medicine, Atlanta, GA, USA) provide aninsight into the neuropsychiatric effects of IL-2 and theirtreatment implications.

As is well-known, depression is frequently comorbid with anumber of diseases. Drs Mathew and Burd (Mount SinaiSchool of Medicine, New York, NY, USA) elaborate on theassociation between depression and diabetes, offeringpathophysiological hypotheses regarding this relationship andreviewing treatment approaches for the depressed patientsuffering from comorbid diabetes mellitus.

As in all issues, the Clinical Reviews provide concise and criticalanalyses of the latest depression literature, placing recentdevelopments into a clinical context. These are followed byreports of the most important presentations concerningdepression from the Annual Meeting of the Association ofEuropean Psychiatrists (Nice, France) and an extended reportof the highlights of the American Psychiatric AssociationAnnual Meeting (Toronto, ON, Canada).

We are pleased that the comments we have received aboutDepression: Mind and Body have been overwhelminglypositive and that the journal continues to be regarded as auseful resource by clinicians working in this fast-developingfield. We welcome your comments and suggestions and lookforward to your feedback and any thoughts to help usprovide a relevant review of current topics.

AF Schatzberg, MD Editor-in-Chief

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Major depressive disorder (MDD) is a common psychiatricdisorder [1], and is suggested to be more debilitating than other psychiatric or general health conditions [2].Research indicates that three to five adults per 1000 willexperience MDD annually [3], and >15% of the populationwill suffer from depression at some point [1]. Antidepressantmedications have been successful in treating depression;however, some patients fail to respond to initial treatmentcourses, and many do not respond to multiple medicationtrials. A patient whose depression does not improve despiteattempting several antidepressant treatments is consideredto have treatment-resistant depression (TRD). The specificdefinition of TRD varies, but the basic concept is depressionthat does not improve after an antidepressant treatmentcourse of adequate dose and duration [4]. Additionaltreatment options for these patients include electroconvulsivetherapy (ECT) and, more recently, the Vagus NerveStimulation (VNS) Therapy System™ (Cyberonics Inc.,Houston, TX, USA), an implantable device approved by theUS Food and Drug Administration (FDA) for the treatmentof depression [5].

ECT was introduced in 1938 for the treatment ofschizophrenia and is still used today for treating MDD, aswell as other severe psychiatric disorders (e.g. catatonia,psychosis) [6,7]. Patients are placed under general anesthesiaand administered muscle relaxants. A mild electrical currentis then sent through a specific area of the brain to induce aseizure. ECT has been found to yield the highest remission

rate of any antidepressant treatment, with studies showingremission rates of 75% among patients with major depression,and 95% among those with psychotic depression [8,9].Although ECT has an extremely high success rate, likepsychotropic medications it unfortunately also has a markedrelapse rate. Studies have shown that 53–59% of patientstreated with ECT relapse within 1 year and of these relapses,78–94% occur within 6 months of treatment [10,11]. ECToften produces a range of cognitive side effects with varyingseverity that typically include an acute confusional state, and anterograde and retrograde amnesia [6,10–12]. Giventhe limitations of ECT and the prevalence of depression, newantidepressant methods are needed. VNS therapy may providean additional treatment option for patients suffering from TRD.

What is TRD?As described by Fava and Davidson, the goal of treating mooddisorders is to restore the patient to a level of psychologicalwellness and high functional ability [4]. Antidepressantmedications are common and successful therapies for manypatients suffering from major depression. However, one studyreported that 29–46% of depressed patients who receivedtreatment of adequate dose and duration failed to fullyrespond to treatment, and 19–34% did not show any response[4]. Patients diagnosed with MDD who fail to respond tomultiple treatment courses can be classified as having TRD.

To date, the exact number of treatment courses a patientmust fail to be considered as having TRD has not beenestablished; however, it is recommended that at least twomonotherapy trials with psychotropic medications fromdifferent pharmacological classes be tried [13]. As describedby Thase and Rush, the severity of TRD can be rated on a

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

Mustafa M Husain, Kenneth Trevino, Louis A Whitworth, and Shawn M McClintockUniversity 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 oftreatment. This review describes a novel neurostimulation technique, vagus nerve stimulation (VNS) therapy, and its role asan antidepressant therapy for patients with TRD. VNS therapy involves the implantation of a pacemaker-like device thatprovides a brief intermittent electrical current to the left vagus nerve. The history of VNS therapy, including the anatomy ofthe vagus nerve and early research on VNS therapy in the treatment of seizures is briefly discussed, along with informationon the prevalence and identification of TRD. Research on mechanisms of action, safety, and efficacy are covered in thecontext of the use of VNS therapy for TRD. Depression: Mind Body 2006;2(4):114–9.

DEPRESSION: MIND AND BODY Vol 2 No 4 2006114

Address for correspondence: Mustafa M Husain, University of Texas

Southwestern Medical Center at Dallas, 5323 Harry Hines Bouelvard,

Dallas, TX 75235-8898, USA. Email: [email protected]

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THE ROLE OF VNS AS A THERAPY FOR TREATMENT-RESISTANT DEPRESSION

DEPRESSION: MIND AND BODY Vol 2 No 4 2006 115

five-stage scale of resistance determined by failure torespond to specific courses of treatment [14]. Beforeconcluding that a patient is treatment resistant, theadequacy of antidepressant treatment courses needs to bedetermined, and the patient’s original diagnosis should beverified to rule out another condition (e.g. medical illness,substance abuse) [13]. If antidepressant treatment coursesfail, and the patient’s condition is severe and debilitating,VNS therapy may be recommended.

What is the vagus nerve?The vagus nerve is the tenth and longest cranial nerve,which connects to different parts of the central nervoussystem. It lies between the carotid artery and the jugularvein in the neck, and is a mixed nerve consisting of afferentand efferent fibers, with the majority of sensory fibers (80%)being afferent. Afferent fibers bring information to the brainwhile efferent fibers send information away to extracranialareas. The cell bodies for the efferent fibers, located in thenucleus ambiguus and the dorsal motor nucleus of thevagus, primarily regulate parasympathetic autonomicfunctions including heart rate, gastric secretions, andintestinal motility [15,16]. Most of the afferent cells of thevagus nerve are located in the nodose ganglion and projectinformation to the nucleus tractus solitarius (NTS) [16,17].The afferent fibers of the vagus nerve project to numerouscortical and subcortical regions of the brain; hence,stimulation of the vagus nerve may have widespread effectson central nervous system function.

History of VNS research and its therapeutic use for epilepsyResearch conducted by Zabara in the 1980s demonstratedthe therapeutic effect of VNS on seizures [18,19]. Zabarawas able to interrupt, and even terminate, seizures inducedin canines through stimulation of the vagus nerve [20]. In 1988, Penry and Dean conducted the first clinicalinvestigation of VNS for the treatment of patients withintractable partial seizures [21]. This study was followed bylarger clinical trials that examined the efficacy and safety ofboth acute and long-term use of VNS therapy amongpatients with refractory seizures [22–24]. These studiesshowed a significant reduction in the frequency and severityof seizures compared with baseline conditions. VNS therapywas approved in the European Union for the treatment ofepilepsy in 1994 and the VNS Therapy System (formerlyknown as the NeuroCybernetic Prosthesis) was approved bythe US FDA in July 1997 for use as an adjunctive therapy inreducing the frequency of seizures in adults and adolescents>12 years of age with medically refractory partial onsetseizures. According to Cyberonics, Inc.’s Medical Device

Report, required by the FDA, approximately 32 065 of theirVNS therapy devices were implanted for the treatment ofepilepsy between 1997 and 2004.

Rationale for using VNS therapy for thetreatment of depressionMany clinical observations fueled the initial research into theuse of VNS therapy to treat depression. Positron emissiontomography (PET) imaging has indicated that VNS affectsfunctioning of the limbic structures in a similar way asantidepressant medications [15,25]. Certain regions of thebrain known to be related to depression have monosynapticand polysynaptic connections with the NTS of the vagusnerve; thus, stimulation of the vagus nerve may thereforeaffect those regions [16,26]. Moreover, the neurochemicaleffects of VNS are similar to those of antidepressanttreatment. Studies indicate that VNS alters the concentrationof neurotransmitters implicated in mood disorders, includingserotonin, norepinephrine, γ-aminobutyric acid (GABA), and glutamate [17,27,28]. During early research trials ofVNS treatment for epilepsy, many patients reported animprovement in mood that, interestingly, was independent ofchanges in the frequency or intensity of seizure activity[15,17,29]. Psychiatric treatments with anticonvulsantproperties, such as psychotropic medications (i.e.carbamazepine, gabapentin, lamotrigine, and valproate) andECT, have also shown antidepressant qualities [17,30–32].As VNS is an effective treatment for epilepsy, it seems likelythat its effects on the brain may be similar to those producedby anticonvulsant drugs.

VNS and treatment of depression: pilot trial (protocol D-01)The pilot study for VNS in depression (D-01) was an open-label trial designed to evaluate the safety and efficacy ofVNS therapy in patients with TRD [33,34]. The VNS TherapySystem was implanted in 60 participants at four centers.Enrolled participants were required to have a Diagnostic and Statistical Manual of Mental Disorders: 4th edition(DSM-IV) diagnosis of MDD or bipolar I or II disorder [35],and to be currently experiencing a major depressive episode(MDE) for a length of ≥2 years, or have experienced fourMDEs during their lifetime. Participants were also required tohave demonstrated an inadequate response to two or moreantidepressant medication treatments, as determined by theAntidepressant Treatment History Form [36]. One patientshowed improvement during the implant recovery period(during which the VNS therapy was not activated) and nolonger met enrollment criteria for the study.

For the first 30 patients completing the acute phase ofthe pilot study, the stimulation parameters were [33]:

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MM HUSAIN, K TREVINO, LA WHITWORTH, AND SM MCCLINTOCK


• Pulse width of 500 µs, except for one patient who received a 250-µs pulse width.

• Frequency 20–30 Hz.• 30-s on-time and 5-min off-time (with a few

exceptions of shorter off-times).• Output current range from 0.25–3.0 mA.

Response was defined as a ≥50% reduction in baselinescores using the 28-item Hamilton Depression Rating Scale(HAM-D28) [37], and remission was defined as a HAM-D28

score of ≤10. During the acute phase of the trial, participantsshowed a 30.5% (18 of 59) response rate with a 15.3% (9 of 59) remission rate. At time of exit from the acute phaseof the pilot study, Clinical Global Impression (CGI) scale resultsshowed that 37.3% (22 of 59) of participants were consideredmuch improved, three participants were considered minimallyworse, and the remaining 34 participants were consideredeither unchanged or minimally improved [34]. Interestingly,for the first 30 participants implanted, an increase inresponse rate from 40% (12 of 30) at exit from the acutephase of the pilot study to 46% (13 of 28) after anadditional 9 months of VNS, and an increase in remissionrate from 17% (three of 30) to 29% (eight to 28) during thesame time frame, was shown [38], suggesting that VNStreatment is more effective in the long term. This studyjustified additional clinical trials by demonstrating that VNSwas a safe and effective therapy for TRD.

VNS therapy and depression: double-maskedefficacy trial (protocol D-02)The pivotal VNS therapy trial for the treatment of depression(D-02) was a double-masked, multicenter trial, which assessedthe safety and efficacy of both an acute (12 weeks afterimplantation) and long-term (12 months after implantation)phase. The 235 participants implanted with the VNS TherapySystem were randomized to either the active VNS group orthe sham-control group (current from the device remainedoff). After a 2-week implant recovery period, devices wereswitched on for participants in the active group. During thefollowing 2 weeks, stimulation parameters were adjusted todetermine maximal and comfortable tolerance to thestimulation settings. Patients then received 8 weeks ofstimulation at a fixed dose. The stimulation parameterscould be adjusted in response to intolerable side effects [39],and those in the sham-control group were treated in thesame way as the active group (i.e. sham activation andadjustments to the device were performed).

Participants’ HAM-D24 scores were used to defineresponse (a ≥50% reduction in scores compared withbaseline) and remission (a score of ≤9). The results from theacute phase showed no significant difference between

HAM-D24 scores for the active VNS group (15% responserate) and the sham-control group; the sham group actuallyproduced a 10% effect [39].

At the end of the acute trial, all participants continued in a long-term open-label follow-up. The 205 participantswho were evaluated during the long-term phase of D-02(12 months) showed a decrease in depression severity. After12 months of VNS treatment, participants’ HAM-D24 scoresindicated a response rate of 29.8% (54 of 181 observedparticipants) and a remission rate of 17.1% (31 of 181). In acomparison study the response rate for TRD patients notreceiving VNS and with treatment as usual was only 12.5%during a 12-month period [40]. These data, which aresimilar to the results of the first pilot study, indicated thatVNS therapy was more beneficial after long-term treatmentrelative to acute treatment.

In 2001, the VNS Therapy System was approved for thetreatment of adults with treatment-resistant or treatment-intolerant, chronic, or recurrent depression, including bothunipolar and bipolar depression, in the European Union [15].The VNS Therapy System was approved by the FDA on the15th of July 2005 for adjunctive long-term treatment ofchronic or recurrent depression for persons aged ≥18 yearswho are experiencing TRD [41]. Since this approval, and atthe date of this paper, >550 VNS Therapy devices have beenimplanted and over 6800 devices have been prescribedthrough Cyberonics Inc.’s Insurance Verification and EducationAuthorization form process.

Mechanism of actionThe exact mechanisms by which VNS therapy works areunknown; however, its antidepressant effect is most likelyrelated to the neuroanatomical pathways of the vagusnerve. Afferents of the vagus nerve synapse on the NTS,which then directly project to several areas in the brainstem,limbic, and cortical areas, as well as indirectly to the locuscoeruleus (LC) and parabrachial nucleus (PB) (Fig. 1). The PBand LC connect to the amygdala and the bed nucleus of thestria terminalis, areas that have been implicated in moodregulation [17].

Research has shown that stimulation of the vagus nerveaffects neurotransmitter activity. VNS enhances transmissionof norepinephrine in the LC, and serotonin in the dorsalraphe nucleus [17,27]. It may also increase GABA, or possiblydecrease glutamate in the NTS [28]. These neurochemicaleffects of VNS correspond with the theorized antidepressantmechanisms of psychotropic medication [17].

Neuroimaging has been used to further explain theneuroanatomical effects of VNS. PET scans have indicatedan increase in regional cerebral blood flow (rCBF) in therostral medulla, thalamus, hypothalamus, insula, and

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postcentral gyrus, and a decrease in rCBF in thehippocampus, amygdala, and cingulate gyrus [25]. Singlephoton emission-computed tomography (SPECT) has indicateda similar pattern of increased and decreased rCBF in many ofthe same regions [42]. These studies demonstrate thattreatment with VNS produces significant changes in brainareas involved with depression. The changes in the rCBFrelated to VNS have also been observed in depressedpatients being treated with selective serotonin reuptakeinhibitors [43,44].

Description of the VNS Therapy System and surgical procedure for implantThe VNS Therapy System comprises an implantable VNSTherapy Pulse Generator, (Cyberonics, Inc.), a lead, and aprogramming wand [45]. The generator is a bipolar pulsegenerator that is multi-programmable and similar to a cardiacpacemaker in size and shape (Fig. 2). The pulse generator ishermetically sealed in a titanium case and powered by asingle battery with an estimated lifespan of 3–8 years,depending on the device stimulation parameters [45]. The

pulse generator sends brief intermittent electrical stimulationto the vagus nerve through the lead.

The generator is implanted subcutaneously in the leftchest wall, while the three helical contacts (cathode, anode,and anchor) of the lead are wrapped around the left vagus nerve through a small incision in the neck (Fig. 3). The electrode is then tunneled subcutaneously to theinfraclavicular incision and connected to the pulse generator.

During the implant surgery, the VNS Therapy System isbriefly activated to perform a lead test verifying that thedevice is operational and the lead is properly connected. Thesurgical procedure is typically performed by a neurosurgeonon either an inpatient or outpatient basis, and takes around1 h to complete [15,17]. The VNS Therapy System istypically not activated for at least 14 days after initialimplantation to ensure post-surgical recovery [45].

The final component of the VNS Therapy System is thecomputer-controlled programming wand, which is connectedto a personal or hand-held computer that containsprogramming software for the pulse generator. To activateand set device parameters, the wand is simply placed over

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

Reproduced with permission from Cyberonics, Inc.

Nucleus tractus solitariusVagus nerve

Thalamus

Cingulategyrus

Orbitofrontal cortex

Raphe nuclei

Locus coeruleus

AmygdalaHypothalamus

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MM HUSAIN, K TREVINO, LA WHITWORTH, AND SM MCCLINTOCK


the generator, which allows for noninvasive programming ofthe VNS Therapy System. The VNS Therapy Pulse Model102 and 102R Generators (the most recent models to date)can deliver an output current between 0.25–3.5 mA at a signal frequency between 1 and 30 Hz, with a pulse widthranging from 130–1000 µs. For these models, the signal on-time ranges from 7–60 s, and the signal off-time rangesfrom 0.2–180 min. The programming wand is also used to retrieve and record device settings (referred to asinterrogating the device), as well as to perform diagnostictests on the device and verify proper functioning of the leadand generator [45]. The VNS Therapy System can bedeactivated by placing a magnet over the area of thegenerator. The pulse generator is programmed to switch offautomatically if it is under a constant magnetic field, andresumes stimulation at the programmed settings once themagnet is removed [46].

Side effects of VNSThe side effects of VNS reported in studies of patients withdepression were similar in occurrence and frequency to those

observed in patients receiving VNS for treatment-resistantepilepsy [41]. Based on causal relationship, reported sideeffects of VNS can be divided into two primary groups: thoserelated to the surgical implant procedure, and those relatedto the actual stimulation of the vagus nerve by the device. Inthe D-02 study, the most commonly reported side effectsrelated 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%)[41]. Most side effects resolved within 30 days [41].Additional surgery-related side effects that were less frequentincluded reactions around the device (i.e. swelling,tenderness), pharyngitis (inflammation of the throat),hypesthesia (impaired sense of touch), and dysphagia(difficulty swallowing) [41].

Voice alteration and an increase in coughing were themost common side effects related to stimulation of thevagus nerve, with an occurrence of 55% and 24%,respectively. Dyspnea (difficulty breathing, shortness ofbreath), neck pain, dysphagia, laryngismus (throat, larynxspasm), and paresthesia (tingling) were also reported asstimulation-related side effects, but were less frequent [41].Voice alteration is by far the most common side effect and islikely caused by spread of the current to the recurrentlaryngeal nerve, which innervates the vocal cords [17]. VNSside effects tend to resolve as tolerance to stimulationdevelops; however, voice alteration can persist. To minimizeside effects, VNS device stimulation parameters may beadjusted to allow for the development of tolerance [17].

DiscussionThe prevalence of major depression and, in particular TRD,highlights the need for innovative and effective antidepressant

Figure 2. The VNS Therapy System implant: bipolar pulsegenerator and lead.


Figure 3. VNS electrode placement on the vagus nerve.


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treatments. Although VNS therapy was originally designedfor the treatment of seizures, observations in epilepsy studiessuggested that VNS has antidepressant properties[15,17,29]. The vagus nerve is anatomically connected tobrain structures related to depression [16,26], and researchhas shown that stimulation of this nerve affects the limbicstructures in a similar way to the mechanism of action ofantidepressants [15,25]. VNS also alters the concentration ofvarious neurotransmitters related to mood disorders [27,28].

Clinical studies of VNS for the treatment of depressionindicate that it is a safe and effective option. The adverseeffects that are frequently reported with ECT (i.e. confusionalstate, and anterograde and retrograde amnesia) have notbeen evident with VNS therapy and research suggests thatVNS may actually help neurocognitive function in patientswhose TRD improves [30]. Data from the protocol D-01 andD-02 studies demonstrate that the VNS Therapy System isan effective treatment for TRD, with response rates of30.5% and 29.8%, respectively.

Despite these results, further investigation of thetreatment modality is needed. At this time, the mosteffective output current for the device has not beenestablished, and, since the output current can range from0.25–3.5 mA, research to determine the setting with thehighest efficacy and the fewest side effects is needed.Although 30% of the patients in the D-02 study significantlyimproved; a considerable number did not. Additional studiesto determine those patients who are most likely to benefitfrom VNS therapy are therefore required, and long-termstudies of VNS in patients with TRD are also necessary.While many questions remain to be answered, VNS therapyrepresents the latest treatment modality with demonstratedsafety and efficacy for patients suffering from TRD.

Disclosures Dr Husain has received support from Cyberonics Inc., The Magstim

Company Ltd, Neuronetics, Inc., and NIH/NIMH. Mr Trevino, Dr Whitworth,

and Mr McClintock have no relevant financial interests to disclose.

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17. Sackeim HA. Vagus nerve stimulation. In: Lisanby SH, editor. Brain Stimulation inPsychiatric Treatment. Washington: American Psychiatric Publishing, 2004:99–143.

18. Zabara J. Time course of seizure control to brief, repetitive stimuli. Epilepsia 1985;26:518.19. Zabara J. Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr

Clin Neurophysiol 1985;61:S162.20. Zabara J. Inhibition of experimental seizures in canines by repetitive vagal stimulation.

Epilepsia 1992;33:1005–12.21. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal

stimulation in humans: preliminary results. Epilepsia 1990;31:S40–3.22. 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. Epilepsia 1994;35:616–26.

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.

24. George R, Salinsky M, Kuzniecky R et al. Vagus nerve stimulation for treatment of partialseizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. FirstInternational Vagus Nerve Stimulation Study Group. Epilepsia 1994;35:637–43.

25. Henry TR, Bakay RA, Votaw JR et al. Brain blood flow alterations induced by therapeuticVNS in partial epilepsy: I. Acute effects at high and low levels of stimulation. Epilepsia 1998;39:983–90.

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

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

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patients with TRD. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:53–62.31. Post RM, Denicoff KD, Frye MA et al. A history of the use of anticonvulsants as mood

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:

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resistant depressions: a multicenter study. Biol Psychiatry 2000;47:276–86.34. Sackeim HA, Rush AJ, George MS et al. Vagus nerve stimulation (VNS) for treatment-

resistant depression: efficacy, side effects, and predictors of outcome.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.

36. Sackeim HA, Prudic J, Devanand DP et al. The impact of medication resistance andcontinuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J Clin Psychopharmacol 1990;10:96–104.

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

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;58:347–54.40. George MS, Rush AJ, Marangell LB et al. A one-year comparison of VNS with treatment

as usual for treatment-resistant depression. Biol Psychiatry 2005;58:364–73.41. Cyberonics, Inc. Depression Physician’s Manual. VNS Therapy (TM) Pulse Model

102 Generator and VNS Therapy (TM) Pulse Duo Model 102R Generator. Houston:Cyberonics, Inc., 2005. Available from URL: http://www.vnstherapy.com/manuals/doc_download.asp?docid={6360242F-390A-4676-BDE0-7034395B834B}.

42. Zobel A, Joe A, Freymann N et al. Changes in regional cerebral blood flow by therapeuticVNS in depression: an exploratory approach. Psychiatry Res 2005;139:165–79.

43. Kennedy SH, Evans KR, Kruger S et al. Changes in regional brain glucose metabolismmeasured with PET after paroxetine treatment of major depression. Am J Psychiatry2001;158:899–905.

44. Mayberg HS, Brannan SK, Tekell JL et al. Regional metabolic effects of fluoxetine in majordepression. Biol Psychiatry 2000;48:830–43.

45. Cyberonics, Inc. Physician’s Manual. VNS Therapy (TM) Pulse Model 102 Generator andVNS Therapy (TM) Pulse Duo Model 102R Generator. Houston: Cyberonics, Inc., 2003.Available from URL: http://www.vnstherapy.com/manuals/doc_download.asp?docid={E5D2100B-A4C2-409B-B71C-E1CEA60FBD90}.

46. George MS, Rush AJ, Sackeim HA et al. VNS: utility in neuropsychiatric disorders. Int J Neuropsychopharmacol 2003;6:73–83.

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Perturbations of immune system function have beendocumented in a number of cross-sectional studies of patientssuffering from neuropsychiatric disorders. More recently, therelationship between an activated immune system and thedevelopment of psychiatric symptoms has revealed even moreinformation about the interface between the immune systemand the brain. Indeed, during the past 20 years, a rapidlyaccumulating database has demonstrated that a variety ofcytokines, such as interleukin-1 (IL-1), IL-2, IL-6, and tumornecrosis factor-α (TNF-α), can induce a host of behavioralalterations including depression, fatigue, and cognitivedysfunction, as well as psychosis. A subset of the populationof cancer patients at increased risk for such cytokine-inducedbehavioral alterations include individuals whose neoplasticcells produce cytokines and/or elicit aggressive inflammatoryreactions, as well as those receiving cancer treatmentsinvolving extensive tissue damage or destruction.Furthermore, patients administered cytokines such as IL-2 andinterferon-α (IFN-α) are especially vulnerable. Interestingly,patients undergoing treatment with IL-2 and IFN-α haveallowed clinicians to better understand the pathophysiology of

behavioral symptoms caused by cytokines, and have helpeddiscriminate between the neurocognitive and neurobehavioralchanges associated with specific cytokines. This review willfocus on the neuropsychiatric effects of IL-2 and explore thepotential mechanisms involved. In addition, interventionstrategies to reduce behavioral morbidities in patientsreceiving IL-2 treatment will be discussed.

Cytokines and IL-2Cytokines are soluble, low-molecular-weight proteins thatregulate immune and inflammatory responses, hematapoesis,cell movement, angiogenesis, and cell differentiation inendothelial, hematopoetic, and neuronal cells [1–5].Interleukins, a specific class of cytokines, are so namedbecause they allow leukocytes to communicate with oneanother. IL-2, the glycoprotein also known as T cell growthfactor, is released by T-helper (Th) lymphocytes primarily inresponse to contact with an antigen. The subsequent releaseof IL-2 then stimulates proliferation of helper, cytotoxic, andsuppressor T cells, activated B cells, and natural killer (NK)cells, as well as promoting the synthesis and release of acascade of other cytokines including IFNs (cytokines thatinterfere with viral reproduction and tumor growth), otherILs, such as IL-6 and IL-10, and TNF-α [6,7]. The actions of IL-2 comprise the set of host responses designated as cell-mediated immunity and the Th1 response, specifically

Neuropsychiatric Effects of IL-2:Mechanisms and Treatment Implications

Stephen E Nicolson1, Andrew H Miller1, David Lawson2, and Dominique L Musselman1

1Department of Psychiatry and Behavioral Sciences, 2Division of Medical Oncology, Department of Medicine,Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.

Interleukin-2 (IL-2) has a myriad of functions in the healthy individual. It is an important signaling molecule in immune andinflammatory responses as well as in cell migration and differentiation. IL-2 has been used in the treatment of diseases ofthe immune system, such as cancer and acquired immune deficiency syndrome (AIDS) and, while often effective, IL-2frequently causes adverse effects, many of which can limit treatment. A review of the literature suggests that IL-2-inducedneuropsychiatric effects are frequently not thoroughly documented. Those few studies that have focused on the behavioraland cognitive effects of IL-2 treatment reveal a high incidence of depressive symptoms and memory disturbances. Patientstreated with IL-2 can also develop psychosis and/or delirium. These IL-2-induced alterations in behavior and cognition are thought be mediated by the effects of IL-2 on neurotransmitter and endocrine systems. IL-2 has been shown to effectmonoamine distribution and metabolism in animal and human models, and can cause disturbances in thehypothalamic–pituitary–adrenal axis. An understanding of the neurobiological effects of IL-2 administration may haveimportant treatment implications that would allow for improved adherence and thus, increased survival rates in patientsreceiving IL-2 therapy. Depression: Mind Body 2006;2(4):120–9.

Address for correspondence: Dominique L Musselman, Department

of Psychiatry and Behavioral Sciences, Emory University School of

Medicine, Woodruff Research Memorial Building, 101 Woodruff Circle,

Suite 4000, Atlanta, GA 30322, USA. Email: [email protected]

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designed to fight intracellular pathogens including virusesand parasites. In the context of cancer, IL-2 administration isused to augment cell-mediated immune responses and NKcell activity directed toward tumor antigens.

IL-2 and the brainThe importance of IL-2 within the brain can be deducedfrom the widespread neuroanatomical localization of thiscytokine and its receptors in both humans and animals.Cytokines such as IL-2 appear to regulate normal nervoussystem development and function [8]. In cell cultures, IL-2 promotes rat neuronal growth in terms of dendriticbranching and survival [9,10]. As the highest concentrationof IL-2 receptors is found in the hippocampus [11], it isperhaps not surprising that IL-2 knockout mice exhibitmalformed hippocampal cytoarchitecture [12]. A role for IL-2 in modulating neuronal function is also indicated by the greater density of IL-2 receptor mRNA within neurons,rather than in microglia [13].

In disease states, IL-2 and its receptors have beendetected in periventricular white matter lesions, includingincreased expression of IL-2 mRNA in damaged areas ofhuman brain compared with normal tissue [14]. Postmortem analyses of the striatum of patients with Parkinson’sdisease have revealed increased levels of cytokines, includingIL-2 [15], and have also shown IL-2 and its receptors in thebrain lesions of multiple sclerosis patients [16].

Cytokine induction and sickness behaviorRecent data indicate that cytokines, including IL-2, can haveprofound effects on behavior, including the induction ofsickness behavior. The syndrome of sickness behavior sharesmany of its signs and symptoms with major depression,including anhedonia, cognitive dysfunction, anxiety/irritability,psychomotor slowing, anergia/fatigue, anorexia, sleepalterations, and an increased sensitivity to pain [17]. Thesebehavioral changes are observed in humans and laboratoryanimals suffering from infection and inflammation and canbe reliably reproduced by the administration of cytokines inisolation or by administering agents (e.g. endotoxin orlipopolysaccharide) that induce cytokine production [18].Extensive tissue damage and destruction, such as occursduring surgery, radiation therapy, and chemotherapy, may alsoactivate cytokine production, leading to behavioral change.

IL-2-induced neurocognitive andneurobehavioral symptomsCharacterization of the specific effects of IL-2 upon behavioroccurred by chance with the US Food and Drug Administration(FDA) approval in 1992 of high-dose, intravenous IL-2therapy for the treatment of malignant melanoma [19].

Patients with unresectable Stage IV melanoma or renal cellcancer were given IL-2 at doses of 720 000 units/kg every 8 h to a maximum of 12–15 doses. This was repeated after1–2 weeks. Depending on response and tolerance, furthercourses of treatment may be given. Although a potentiallyeffective therapy, IL-2 is notorious for causing a host ofneuropsychiatric and physical symptoms. Indeed, theadverse effects of IL-2 treatment impact every organsystem in the body, and, more often than not, are sodebilitating that treatment must be prematurely terminated[20]. The spectrum of IL-2-induced adverse behavioraleffects include marked disturbances in neurocognitivefunction (e.g. memory disturbances, confusion, anddelirium), mood (e.g. depression and anxiety),neurovegetative function (e.g. anorexia, fatigue, and sleepdisturbance), and perception (e.g. psychosis) [20–24].Physical symptoms and laboratory alterations include nausea,vomiting, dermatological toxicity, diarrhea, fever, headache,liver enzyme elevations, alterations of electrolytes [20,21],neutropenia, and thrombocytopenia [23]. Myocarditis hasalso been reported [25]. At very high doses, IL-2 has beenobserved to induce marked fluid retention, prerenalazotemia, weight gain >5 kg, and serious neurologicalsymptoms [24]. Of note, IL-2 has also been used to treathuman immunodeficiency virus (HIV) and otherimmunological/hematological conditions.

IL-2 and neurocognitive dysfunctionAs shown in Table 1, [19–22,26–49] most IL-2 studies ofcancer patients have not included specific or sensitivemeasures of neuropsychiatic symptoms in their reports ofadverse events; therefore, estimation of the incidence ofsuch behavioral side effects has been challenging.Nevertheless, a small number of studies using standardneuropsychological instruments have documented not onlythe incidence, but also the spectrum, of neurocognitivesymptoms induced by IL-2 [27,33]. Capuron and colleaguesutilized a well-standardized series of computerized tests, theCambridge Neuropsychological Test Automated Battery(CANTAB) [50], to examine a wide range of cognitivefunctions in patients administered IL-2 alone (n=17), IL-2plus IFN-α (n=7), or IFN-α alone administered at low-dose(n=7) or high-dose (n=16) [22]. Study subjects underwentCANTAB testing before initiation of cytokine therapy, andagain on day 5 of immunotherapy. Patients receiving IL-2therapy exhibited significant impairment in tasks of spatialworking memory, planning, and problem solving. Incontrast, patients treated with IFN-α exhibited impairedreaction times and psychomotor slowing. It is of note thatsleep disturbances were not associated with any of thecognitive 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 neurocognitiveconcomitant 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 effectset 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 ator 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 endet 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 onlywith 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 whoalone. 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 weeksin 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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smaller study by Caraceni et al. utilized a battery of cognitivetests in patients (n=7) receiving a 5-day course of recombinantIL-2 [51]. Subjects showed a statistically significant decline incognitive performance on six of eight neuropsychological tests,including the mini mental state exam (MMSE) [45], Digit Span(forward and backward), Corsi’s spatial test (forward andbackward recall), and Zazzo’s attention test (speed andinaccuracy) [51]. Neurophysiological evaluation by means ofP300 evoked potentials paralleled these results, revealing aslowing of cognitive processing. Performance recovered a weekafter IL-2 therapy ended. These results suggest that IL-2interferes with multiple neural circuits, including those in theprefrontal and temporal cortices as well as subcortical brainareas [52].

IL-2 and alterations of moodSimilar to the literature documenting IL-2-inducedneurocognitive dysfunction, a small number of other studieshave used psychometric rating scales to characterize changes in mood induced by IL-2. In a study by Capuron

et al. [34], the clinician-administered Montgomery AsbergDepression Rating Scale (MADRS) [44] was used in a group of17 patients receiving IL-2 for renal cell carcinoma. Within 3days of initiating IL-2 therapy, significant increases in depressivesymptoms were apparent. By day 5 of treatment, 25% ofpatients exhibited severe depressive symptoms (MADRS score>15), which increased to 33% after 4 weeks of IL-2 therapy.

IL-2 and psychosisAlthough frequently seen during IL-2 therapy, the incidence ofpsychotic symptoms, such as hallucinations and delusions, isnot well understood and may occur in up to 20% of IL-2treated patients [53,54]. Current standard clinical protocolsdictate that when symptoms such as persistent crying,disorientation, delusions, or hallucinations develop during IL-2treatment, IL-2 should be discontinued immediately for thatcycle [55], thereby limiting the number of doses received.Unfortunately, no study has assessed the relative presence ofneuropsychiatric symptoms as they relate to prematuretermination of IL-2 therapy.

Table 1. Continued.

Study Study population IL-2 dosing schedule/ Discontinuation rate Psychometric Prevalence of neurocognitiveconcomitant 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: digitsymbol substitution test of Wechsler Adult Intelligence Scale [42]; EEG: electroencephalogram; HADS: hospital anxiety and depression scale [43]; HDC: histaminedihydrochloride; 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: structuredclinical interview [48]; TMT: trail making test (parts A and B) [49]; TIL: tumor-infiltrating lymphocytes; U: units.

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IL-2 and psychiatric disordersAside from examining the direct effects of IL-2 on behavior,a number of correlational studies have examined therelationship between IL-2 plasma concentrations inpsychiatric patients with disorders such as depression[56–61] and schizophrenia [62–65]. Unfortunately, thesestudies have yielded somewhat conflicting results. Forexample, as reviewed by DeLisi in 1996, patients withschizophrenia have been documented to have increased anddecreased IL-2 plasma concentrations during psychoticepisodes [66]. These contradictory findings are likely relatedto a small sample size (generally <50 patients) and multipleconfounding factors that alter plasma concentrations of IL-2,including adiposity, smoking, and ingestion of aspirin ornonsteroidal anti-inflammatory medications [25]. Moreover,it has been suggested that cytokine alterations may onlycharacterize a subgroup of schizophrenia subjects, especiallythose with an increase in autoimmune diathesis [67].

The neurobiology of IL-2-induced behavioral changeA large body of research has been devoted to examining theneurobiological pathways by which IL-2 influences the brainand behavior. Since cytokines, such as IL-2, are too large tofreely pass through the blood–brain barrier, considerableattention has focused on how cytokine signals that originatein the periphery reach the brain. Pathways by whichcytokines may influence the brain include passage throughleaky regions in the blood–brain barrier, active transportthrough specific transporter molecules, and transmission of

cytokine signals via afferent nerve fibers (e.g. the vagus nerve)[68–70]. Indeed, radioactively-labeled IL-2, administeredintravenously, can cross the blood–brain barrier to the enterthe mouse brain, which provides evidence that IL-2 candirectly effect the central nervous system (CNS) [71,72].Moreover, a single dose of systemic IL-2 has been shown toincrease permeability of the blood–brain barrier to cytokinesin animal models [73,74].

Attention has been paid to cytokine interactions withneuroendocrine and neurotransmitter systems as possiblemechanisms by which cytokines such as IL-2 influencebehavior, since both of these are well-known to be involvedin the pathophysiology of neuropsychiatric disease. Potentialpoints of interactions are seen at a cellular level, forexample, in the rat brain, where 30% of CNS neurons showco-staining for IL-2, estrogen receptors, and glutamatereceptors [75]. Thus, IL-2 may in part induce changes inbehavior through effects on neurons where there exists aco-localization of immune, hormonal, and neurotransmittersystems [75].

As seen in Table 2, a host of preclinical studies havedocumented perturbations by IL-2 of important neuro-transmitter (and neuropeptide) systems essential to theregulation of mood and neurocognitive function, includingserotonin (5-HT), dopamine, corticotrophin-releasing factor(CRF), norepinephrine (NE), acetylcholine (ACh), endogenousopioids, and N-methyl-D-aspartate (NMDA) [76].

Although not well-studied in humans, repeatedadministration of IL-2 to mice (0.55–17.6 × 103 IU permouse) increases the turnover of NE within the median

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 polymorphismor hippocampus [78] putamen, cerebellum ↓ learning and memory

↓ DA turnover basal ganglia and Nigrostriatal, mesolimbic, mesocortical Psychomotor slowing, impaired ↑ plasma prolactin levelsnucleus 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 catecholamineshippocampus [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 activitycaudate-putamen, nucleus accumbens, deliriumhypothalamus, 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 levelstegmental area [93]

↑ NDMA receptor functioning [94] Mesolimbic projections to cortex Psychosis, arousal, attention, Unknownmotivation, 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.

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eminence and hippocampus, alters 5-HT levels in thehippocampus and prefrontal cortex, and reduces dopamineturnover in the caudate and substantia nigra [87]. Theenhanced NE turnover observed in the median eminenceand hippocampus of animals who have been administeredIL-2 peripherally [86], and the diminished ACh release in thehippocampus [11,89], may contribute to their behavioralalterations (such as anhedonia, psychomotor retardation,and anorexia), although whether these behavioral alterationsare in fact the result of disturbances in hippocampal NE or 5-HT function remains controversial [78].

The effect of IL-2 on 5-HT neurotransmission in the brainis debatable. Some researchers have observed diminished 5-HT levels in the hippocampus and prefrontal cortex aftersystemic IL-2 administration [87]; however, others have not[77,78]. Alterations of 5-HT concentrations in the brain byIL-2 (and other cytokines) can potentially occur throughreductions in serum L-tryptophan. Tryptophan, the primaryprecursor of 5-HT, is reduced during diminished dietaryintake and/or induction of the enzyme indolamine 2,3 dioxygenase (IDO), which breaks tryptophan down intokynurenine and quinolinic acid. Quinolinic acid, in turn,exhibits neurotoxic properties [95–97]. Indeed, IL-2 increasesIDO activity in human peripheral blood mononuclear cells(PBMCs), and is associated with a subsequent reduction inplasma tryptophan [98]. Tryptophan depletion has longbeen known to precipitate depressive symptoms invulnerable patients [99].

Animal and cell culture models reveal a more complexrelationship between IL-2 and dopamine. In the rat striatum,IL-2 administration has led to increased dopaminergictransmission in a dose-dependent manner [100]. However,although low concentrations of IL-2 may potentiate dopaminerelease in mesencephalic cell cultures, higher concentrationshave been observed to inhibit its release [101]. In animalmodels, the effect of IL-2 on the dopamine system has beenlinked to behavioral consequences. Peripheral administrationof IL-2 resulted in a two-fold increase in climbing behavior, amarker of increased dopamine activity in mice. This behaviorceased when the mice were injected with both D1 and D2dopamine receptor antagonists [102]. The decrease in DAturnover in basal ganglia and nucleus accumbens observed inanimal models may also occur within the human CNS,resulting in anhedonia, marked psychomotor slowing, andperhaps even psychotic symptoms.

With regard to pain pathways in the rat hypothalamus,application of exogenous IL-2 increased release of theendogenous opioids, methionine-enkephalin and β-endorphin[88]. It should be noted that in the peripheral nervoussystem, IL-2 may decrease pain through its binding to opioidµ-receptors [90,103]. Lastly, IL-2 has also been shown to

modulate NDMA receptors in ventral tegmental area neuronsin neonatal rats. Low doses of IL-2 (0.001–10 ng/mL)inhibited the effects of NDMA applied to these neurons,while a higher dose (250 ng/mL) potentiated the effects[94]. The influence of IL-2 on these (and other)neurotransmitter systems likely explains the wide rangingeffects of IL-2 administration on behavior, includingdifficulties with cognition, sleep and appetite alterations,psychomotor slowing, mood symptoms, and psychosis.

IL-2 effects on HPA axis activityIn addition to their effects on neurotransmitter systems inthe CNS, cytokines, including IL-2, have been shown toexert potent stimulatory effects on the hypothalamic–pituitary–adrenal (HPA) axis, predominantly through activationof corticotrophin-releasing hormone (CRH) [104,105]. Aswith other proinflammatory cytokines such as IL-1, IL-6, andTNF-α, IL-2 administration stimulates CRH release from theamygdala and hypothalamus [27,81,106–111], an effectthat appears to be mediated in part by nitric oxide [81].Moreover, several preclinical and clinical studies have shownthat IL-2 administration, like IFN-α therapy, is alsoassociated with HPA axis activation, as manifested byincreased plasma concentrations of ACTH and cortisol.However, in contrast to IFN-α therapy [112], chronic IL-2administration results in persistent elevations in cortisol[113–116], which may be related to disruption of thefunctioning of glucocorticoid receptors (and possibly relatedto interactions between glucocorticoid receptors andinflammatory signaling pathways such as p38 mitogen-activated kinases and transduction and activation oftranscription 5 [STAT 5] signaling). Glucocorticoid receptorsmediate negative feedback on CRH and ultimately cortisolrelease [117–119]. Central administration of CRH hasbehavioral effects in animals that are similar to those seen inpatients suffering from depression/sickness behavior, includingdiminished activity, lowered appetite, and disturbed sleep[120]. Furthermore, in humans, memory impairment, impairedexecutive function, and psychosis, as well as reducedhippocampal volume have all been associated with increasedendogeneous cortisol secretion or glucocorticoid administration[121–131]. These results suggest that consideration shouldbe given to glucocorticoid antagonism (e.g. RU38486 orglucocorticoid synthesis inhibitors) in addressing IL-2 effectson HPA axis activity and behavior.

IL-2 effects on HPA axis functionIn contrast to other proinflammatory cytokines, which aremore likely to induce hypothyroidism [56,132], IL-2administered to HIV-infected patients over a course of 5 days has been shown to stimulate the pituitary–thyroid

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axis [133]. In these IL-2-treated patients, free thyroxinelevels were elevated to hyperthyroid levels. IL-2’sperturbation of thyroid function differs from other cytokines(typically IL-1, IL-6, and TNF-α) that induce euthyroid sicksyndrome (ESS), characterized by normal thyroid stimulatinghormone (TSH) and thyroxine (T4) levels and reducedtriiodothyronine (T3) levels in the early stages, and bynormal TSH and reduced T3 and T4 in the later stages [134].The mechanism by which ESS occurs is believed to involveboth the direct effects of cytokines on thyroid gland functionas well as inhibition of the metabolic enzymes (5’-deiodination)that convert peripheral T4 to T3 (the more biologically activeform of thyroid hormone), especially in the liver [134]. In a study of 55 melanoma patients receiving low-dose IL-2combined with vaccination, 25% of patients developedthyroid abnormalities [135]; unfortunately, the incidence ofthyroid perturbations and associated changes in mood werenot measured. As even subtle alterations in thyroid hormoneavailability (both hyper- and hypothyroidism) are known tobe associated with mood disorders [136], the mechanism(s)whereby IL-2 may alters thyroid function should remain asubject of continuing investigation.

Neuropsychiatric adverse effects of IL-2:treatment implicationsGiven the neurocognitive and neurobehavioral symptomsthat develop during IL-2 therapy, and the well-knownimpairment of quality of life, treatment compliance, andsurvival of cancer patients who suffer from neuropsychiatricsyndromes, the current challenge for the medically ill patientand healthcare provider alike is the treatment, and perhapseven prevention, of IL-2-induced CNS dysfunction. Usually,treatment of the neuropsychiatric side effects of cytokinetherapy has included dose reduction and/or termination ofimmunotherapy, leading to compromised treatment [137].Any treatment for cytokine-induced symptoms withpsychotropic medication is considered off-label use.Symptomatic treatments include temazepam or zolpidem for insomnia, haloperidol for agitation or combativeness,and lorazepam for anxiety [55]. However, theserecommended treatments for IL-2-induced symptoms arewithout evidence from randomized, clinical trials.Information regarding the management of neuropsychiatricsymptoms induced by IL-2 therapy has been gleaned solelyfrom small, open-label studies. In a small study of patientswho developed delirium during IL-2 treatment (n=7), theirsevere agitation or paranoia improved with low-dosehaloperidol (no more than 10 mg/day in five of the sevenpatients) administered over a 1–2-day period [53]. Morerecent studies utilizing animal models have revealed thatneuroleptics (such as chlorpromazine, loxapine, flupentixol,

and trifluperidol) interfere with cytokine release [138,139].An in vitro study of the effects of neuroleptics on bloodsamples of non-psychotic patients has also shown anantagonism of IL-2 release by both typical and atypicalantipsychotics [140]. Although other psychoactivemedications have been shown to interfere with IL-2 releasein vitro, i.e. bromocriptine [141], cannabinol [142], andopioids [143], or to decrease cytokine-induced catabolism of tryptophan, i.e. St John’s Wort [144], whether thediminished IL-2 release exerts untoward effects upon cancer-related outcomes remains unknown.

Most data involving treatment of cytokine-induceddepressive symptoms have involved patients receiving IFN-α.One randomized, double-blind, placebo-controlled trial ofpatients undergoing treatment for malignant melanomademonstrated efficacy for the selective serotonin reuptakeinhibitor paroxetine in the prophylactic treatment of IFN-α-induced depression [145]. An open-label study describessimilar results using both paroxetine and citalopram [146].Reports indicate other antidepressants may also be effectivein the treatment of INF-α-induced depression, includingbupropion [147], mirtazapine [148], milnacipram [149], andsertraline [150]. Antidepressants such as paroxetine havebeen shown to inhibit the release of proinflammatorycytokines [151], which may account for their effectiveness inINF-induced depression. No randomized, double-blind,placebo-controlled trials have yet been conducted toevaluate amelioration of the cognitive, mood, and psychoticsymptoms induced by IL-2. Even though paroxetinepretreatment of malignant melanoma patients undergoinghigh-dose IFN-α reduced the incidence of IFN-α-induceddepression [148], whether antidepressant pretreatmentrepresents an effective neuroprotective strategy forminimizing IL-2-induced depression and neurotoxicityremains unknown.

Moreover, although both IL-2 and IFN-α patients mayrespond to antidepressant treatment, it is possible that themechanism of these psychotropic agents may have bothoverlapping yet distinct features with either cytokine. Forexample, while increasing the availability of 5-HT (and otherneurotransmitters) may be relevant to the development andtreatment of depression in both conditions, as discussedpreviously, antidepressant effects on HPA axis reactivity andglucocorticoid sensitivity may be relatively more importantfor patients undergoing IL-2 therapy (who may exhibit moreprofound and persisting HPA axis activation, which, in turn,may contribute to mood lability, cognitive dysfunction, andpsychosis). In fact, data indicate that antidepressants canreduce elevated CRH activity (and hypercortisolism),enhance glucocorticoid receptor function (and overcomeglucocorticoid resistance), and decrease the production of

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proinflammatory cytokines [152,153]. A model conceptualizingIL-2 behavioral effects and treatment implications isproposed in Figure 1.

ConclusionFurther characterization of neurocognitive dysfunction (andits relationship with alterations of neuroimmune functionand neurochemistry within the brain) will provide valuableinformation regarding the mechanism of IL-2-inducedneuropsychiatric symptoms. This information is especiallyimportant as patients receiving immunotherapies such as IL-2 are burdened with multiple stressors, including thephysiological effects of their particular cancer (includingpain, lack of mobility, and decreased functional status), theexistential meaning of the diagnosis, grief, guilt, preparationsfor death, financial challenges, and time constraints, amongothers. Research into the particular neuropsychiatricsyndrome or syndromes caused by IL-2 administration canonly serve to provide fresh avenues for exploration oftreatment approaches that will allow physicians to helppatients maximize their health.

AcknowledgementsThis manuscript was supported by R01 MH071580.

DisclosuresDr Lawson is a speaker/consultant for Chiron and Schering-Plough.

Dr Miller has received grants from Centocor, Inc., Forest Laboratories,

Inc., GlaxoSmithKline, Janssen, and Schering-Plough. Dr Musselman has

received research support from DANA Foundation, GlaxoSmithKline,

Janssen, NIH, Pharmacia & Upjohn, and Schering-Plough and is a

member of the Speakers Bureau for Forest Pharmaceuticals Inc.,

GlaxoSmithKline, Organon Inc., and Pfizer. Dr Nicolson has no financial

interests to disclose.

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

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

IL-2

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Behavioral changesDepression

Memory impairmentPsychosis

CRH

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ACTHCortisol

5-HT

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• Decreases CRH/cortisol hypersecretion• Reverses glucocorticoid resistance

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Epidemiology of diabetes and major depressionDiabetes mellitus is the leading cause of premature deathfrom cardiovascular disease, amputations, and blindness, andthe worldwide incidence is increasing so rapidly that it hasbeen referred to as a pandemic [1,2]. A recent survey fromthe US Center for Disease Control and Prevention (CDC)suggests that as many as 20.8 million people in the USsuffer from diabetes – approximately 7% of the USpopulation. This includes 14.6 million people who have beendiagnosed with this disease and another 6.2 million casesthat are suspected but not diagnosed [3]. The CDC surveyalso showed a profound age-associated risk of abnormalglucose regulation, pre-diabetes, and diabetes; in patientsaged >60 years, the prevalence of diabetes was >20% [3].In terms of new cases, diabetes was projected to be moreprevalent in the >60 years age group (approximately 600 000 new cases in 2005) and among individuals aged40–59 years (approximately 750 000 new cases) for multiplereasons, including sedentary lifestyle and diet. It should benoted that the age of onset for type 2 diabetes has droppedprogressively during the last 20 years, and common riskfactors such as obesity and being overweight have reachedvirtual epidemic proportions among adolescents in the US [4].Quite alarmingly, type 2 diabetes is estimated to account for8–45% of all new cases of diabetes in children andadolescents [4]. Thus, the “adult” label for type 2 diabetes isquickly becoming anachronistic.

Racial and ethnic differences in the age-associatedprevalence of diabetes have long been realized. In particular,the American Indian population has the highest rate ofdiabetes, >18% in recent surveys [3]. Rates among non-Hispanic blacks (15%), Hispanic/Latino-Americans (14%),and non-Hispanic whites (8%) are not much lower than this,and recently an increased prevalence has also been notedamong Asians and Asian-Americans [3].

Three separate epidemiological studies have shown thatpatients with major depressive disorder (MDD) have a much higher subsequent relative risk of developing type 2diabetes [5–7]. MDD has been observed to precede thedevelopment of type 2 diabetes, with a mean of 8.7 yearsbetween the onset of depressive symptoms and a diagnosisof type 2 diabetes [8].

At the same time, patients with both type 1 and type 2diabetes have a higher relative risk of developing mooddisorders, and MDD (and its variants, including dysthymia,bipolar disorder, and seasonal affective disorder) has beenshown to be 3–4 times more prevalent in patients withdiabetes than in the general population [9]. Diabetic patientswho are at greatest risk for developing depression are typicallywomen, patients with lower educational or socioeconomicstatus, and those with physical disabilities [10]. Significantcorrelations have been observed between deterioratingmood and poor glycemic control [11]. Children/adolescentswith type 1 diabetes have a 2–3-fold greater prevalence rateof depression [12], and this may be a prolonged, unremitting,and ultimately lethal (through suicide) course of illnessbecause of its early age of onset.

The Bidirectional Relationship betweenDiabetes Mellitus and Depression

Sanjay J Mathew and Susan BurdDepartment of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Major depressive disorder and related mood disorders are associated with poor metabolic control, poor adherence to medicationand diet, a reduced quality of life, and an increase in overall healthcare expenditure in patients with diabetes mellitus. In turn,inadequate management of diabetes in mood disorder patients may exacerbate psychiatric symptoms, contribute to persistentfatigue, lethargy, and neurovegetative symptoms, and diminish response to both psychological and somatic treatments. Thisarticle will discuss the complex bidirectional relationship between these two chronic and disabling multifactorial illnesses,offering several pathophysiological hypotheses regarding this relationship, as well as reviewing treatment approaches for thedepressed patient suffering from comorbid diabetes mellitus. The primary focus of this article is type 2 diabetes mellitus,although examples discuss type 1, or “juvenile-onset” diabetes. Finally, the relationship between depression and diabetes isdiscussed within the context of broader cardiovascular disease risk factors. Depression: Mind Body 2006;2(4):130–3.

Address for correspondence: Sanjay J Mathew, One Gustave Levy Place,

Box 1217, New York, NY 10029, USA. Email: [email protected]

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Pathophysiology of comorbid diabetes and depressionWhat are the moderating and mediating factors that influencethe development and persistence of type 2 diabetes inpatients with mood disorders? Behavioral and lifestyle factors(sedentary lifestyle, dietary factors, poor adherence totreatments), as well as associated cardiovascular problems,undoubtedly play a significant role in increasing an individuals’vulnerability to the development and maintenance of this disorder.

Since MDD generally precedes the onset of diabetes,careful attention paid to depressed, non-diabetic individualscould provide information regarding the development of thiscondition (Table 1). The study of asymptomatic persons whoeventually go on to develop diabetes has yielded importantclues regarding its pathogenesis. Biological factors thatpredate the clinical onset of type 2 diabetes include [1,13]:

• Insulin resistance in muscle, fat, and liver cells. • Abnormal beta-cell functioning in the pancreas.• Excess accumulation of intracellular triglycerides

in muscle and liver.

A unifying hypothesis underlying these factors isabnormal mitochondrial function. In a landmark study, ratesof mitochondrial adenosine triphosphate (ATP) synthesis inskeletal muscle were found to be decreased by 30% in agroup of lean, insulin-resistant children whose parents hadtype 2 diabetes, compared with controls with normal insulinsensitivity who were matched for physical activity [14]. Aninherited defect in mitochondrial oxidative phosphorylationwas hypothesized to result in lipid accumulation andcontribute to insulin resistance in muscle [14]. Interestingly,recent work using magnetic resonance spectroscopy inpatients with mood disorders has also implicated impairedmitochondrial oxidative phosphorylation [15].

One clinically salient moderating variable for thedevelopment of diabetes is the impact of childhoodtraumatic experiences. While several decades of researchhave now documented the fact that childhood trauma(including neglect and sexual and physical abuse) poses asignificant risk for the development of major depression[16], more recent epidemiological surveys suggest that earlyadverse experiences may also be a risk factor for adult-onsetdiabetes [17,18]. For example, individuals reporting maternalemotional or physical abuse during childhood had higher ratesof self-reported diabetes in adulthood (Midlife Developmentin the US survey, n=3032) [17]. A separate, larger studyshowed an association between childhood neglect specifically,and not abuse per se, and increased risk of diabetes(National Comorbidity Survey, n=5877) [18]. A fundamental

limitation of these surveys, although intriguing andpotentially informative about causal pathways to illness, is the retrospective nature of the self-reported abuse.

Some interesting work has investigated the role ofchildhood abuse and stressful life experiences as markers ofvulnerability to depression. One prominent study examinedthe relationship between a functional polymorphism of theserotonin transporter and the risk of developing majordepression in relation to stressful life events [19]. In thislarge, prospective, longitudinal study of a representativebirth cohort from New Zealand, subjects were genotyped for a functional serotonin transporter polymorphism andassessed for magnitude of self-reported stressful life events, including maltreatment. In the “resilient” genotype (l/l genotype), no matter how severely they experiencedmistreatment, the relative risk of developing depression was significantly decreased compared with the group withthe vulnerable genotype (s/s genotype). This studydemonstrated that a gene–environment interaction mayexplain an individuals’ vulnerability to developing depressionin the wake of stressful life events. Genetic variability inserotonin function may be relevant to the expression ofdiabetes in depressed patients; serotonin (5-HT) transporterpolymorphisms modulate human blood glucose control [20],and metabolic syndrome is associated with reduced brainresponsiveness to serotonin [21].

Brain mechanisms in diabetesHistorically, diabetes has been viewed as a pancreatic orendocrine disorder, not a brain disorder. One reason for thisview was that a peptide the size of insulin would be toolarge to cross the blood–brain barrier, and thus glucoseregulation in the brain would be insulin independent.However, more recent research has found that the brain isnot insulin insensitive; in fact, brain insulin activity isnecessary for normal glucose homeostasis. Furthermore,discrete brain pathology has been found in humans with

Table 1. Monitoring diabetes in depressed patients.

Glycosylated hemoglobin: measures the average level of glycemia over the preceding 2–3 months

Frequency: 2×/year if treatment goals are met and patienthas stable glycemic control; 4×/year if glycemic control is unstable

Values: <7% for patients in general (<6% is normal, without significant hypoglycemia)

Additional laboratory tests: fasting serum glucose, LDL, HDL, triglycerides

HDL: high-density lipoprotein; LDL: low-density lipoprotein.

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diabetes and in animal models, while brain mechanismsunderlying insulin resistance have been documented [1].

There are intimate brain–peripheral organ pathways that serve to maintain homeostatic regulation of energyexpenditure [22]. Specific hypothalamic neurons respond to adiposity-related signals via hormones such as leptin.These hormones are secreted in proportion to energy storesand circulating nutrients, and adaptive changes in energyexpenditure and hepatic glucose production result inresponse to these inputs. As weight gain progresses,increased insulin resistance is observed along with increaseddemand for pancreatic insulin secretion, and a subsequentincreased risk of type 2 diabetes [22].

Hippocampal regions such as the dentate gyrus (criticalto neurogenesis), deficits in gray matter density, andhypothalamic nuclei have been implicated in diabetes [23].Excess secretions of neurotransmitters in conjunction withlong-chain polyunsaturated fatty acid deficiency, especiallyomega-3 fatty acids, were found to damage neurons in thehypothalamus as well as insulin receptors in the brain [24].Finally, diabetes may result in changes in hippocampalsynaptic plasticity. These alterations in plasticity parallelfindings in major depression and the speculated mechanismof action of antidepressants, such as selective serotoninreuptake inhibitors (SSRIs), which may work by increasingsynaptic plasticity and neurogenesis [25].

Implications for treatmentPatients with comorbid depression and diabetes typicallyshow an improvement after treatment with antidepressants,but primarily with respect to depressive symptoms.However, glycemic control, as indexed by glycosylatedhemoglobin A1C (HbA1C), is uncertain with long-termantidepressant treatment.

A recent paper by Lustman et al. featured one of thelargest investigations to date of SSRI treatment in patientswith depression and diabetes [26]. A sample of 152 patientswho had received open-label sertraline for 16 weeks weresubsequently randomized in a discontinuation arm tosertraline or placebo for up to 1 year. The major finding wasthat depression recurrence was diminished and survival wasincreased four-fold in the sertraline group compared withthe placebo group. Surprisingly, the short-term impact ofglycemic control was positive (i.e. after 4 weeks of open-label treatment with sertraline, glycosylated HbA1C actuallydecreased), although long-term data suggested no differencein standard diabetic measures (blood glucose levels, HbA1C)between the placebo and sertraline-treated groups.

Katon et al. asked the question: does enhancing thequality of depression care improve both depression anddiabetes [27]? A total of 329 patients with both diabetes

and depression were randomized to two groups. One groupreceived treatment as usual and the other was randomizedto Pathways case management, which provided educationaland adherence support [27]. The somewhat surprisingfinding was that the Pathways collaborative care modelimproved depressive symptoms but did not result inimproved glycemic control [27].

In choosing a drug to treat patients with diabetes and depression from among the different classes ofantidepressants, it is important to consider which drugscause weight gain and hypoglycemia. Certain monoamineoxidase inhibitors, tricyclic antidepressants (TCAs),mirtazapine, and atypical antipsychotics (most notablyclozapine and olanzapine) may not be optimal for treatingthis patient population as they can result in hypoglycemia,greater insulin sensitivity, weight gain, and/or increasedHbA1C [28].

Beyond standard drugs for the treatment of depressionand diabetes, new agents soon to gain US Food and DrugAssociation approval might offer promising new directionsfor patients. Rimonabant (Sanofi-Aventis, Bridgewater, NJ, USA) is the first in a class of selective CB-1 receptor (partof the endocannibinoid system) blockers, and are found inbrain and adipose tissue. The endocannibinoid system hasbeen implicated in body mass regulation, insulin resistance,and lipid metabolism, and it is hoped that varied applicationsof this drug, including treatment of the mood and anxietydisorders associated with metabolic syndrome and/ordiabetes, might be possible.

Diabetes in the context of cardiovascular risk statusWhile this review has focused on type 2 diabetes, this illnessshould be examined in the context of a broader generalmedical, cardiovascular, and metabolic profile. It is now wellestablished that major depression is a risk factor for coronaryartery disease and poor cardiovascular outcomes in patientswith established heart disease [29]. The INTERHEART studyof modifiable risk factors for acute myocardial infarction (MI)identified psychosocial factors as stronger predictors forincident MI than classic risk factors such as diabetes,smoking, hypertension, and obesity [30]. Both behavioral(dietary factors, non-adherence to medications, poor socialsupport, lack of exercise) and biological mechanisms(increased platelet activation, increased catecholamine levels,inflammatory processes, alterations in cardiac autonomictone) may explain the associated risk between depressionand cardiovascular disease [29]. SSRIs were found to be safeand effective in the treatment of depressed patients withacute coronary syndromes by the SADHART (SertralineAntidepressant Heart Attack Trial) [31], although larger

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prospective studies are necessary to evaluate the role ofantidepressant pharmacotherapy on cardiovascular outcomes.

Metabolic syndrome, or syndrome X, is characterized byabdominal obesity, atherogenic dyslipidemia, hypertension,insulin resistance, inflammation, and prothrombotic states(Table 2) [32]. An important link between metabolicsyndrome and MDD is the accumulation of increased intra-abdominal visceral fat [33,34], which, along withincreased prothrombotic factors such as plasminogenactivator inhibitor-1 (PAI-1) and factor VIII activity [35], may represent crucial factors contributing to the increasedcardiovascular mortality observed in MDD patients.

Conclusion In patients with diabetes, the presence of comorbiddepression is associated with an increased morbidity andmortality rates [36]. Diabetes is recognized as a disease withdiscrete brain pathology, and brain mechanisms underlyinginsulin resistance have recently been identified.

Antidepressant medications that are weight-neutralshould be recommended as first-line agents for comorbiddepression and diabetes, although these medications mightnot improve glycemic control. Behavioral therapies thatpromote weight reduction through regular exercise anddietary modification are critical to the long-term success ofall treatments in these patients. Finally, diabetes should beviewed within the context of the larger cardiovascular andmetabolic risk profile of the patient, and regular monitoringis critical for patients with one or more risk factors.

DisclosuresDr Mathew is a member of the Speakers’ Bureau for AstraZeneca,

Cephalon Inc., and Pfizer. Dr Burd has no relevant financial relationships

to disclose.

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9. Anderson RJ, Freedland KE, Clouse RE et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001;24:1069–78.

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17. Goodwin RD, Weisberg SP. Childhood abuse and diabetes in the community. Diabetes Care 2002;25:801–2.

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20. Yamakawa M, Fukushima A, Sakuma K et al. Serotonin transporter polymorphisms affecthuman blood glucose control. Biochem Biophys Res Commun 2005;334:1165–71.

21. Muldoon MF, Mackey RH, Korytkowski MT et al. The metabolic syndrome is associatedwith reduced central serotonergic responsivity in healthy community volunteers. J Clin Endocrinol Metab 2006;91:718–21.

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26. Lustman PJ, Clouse RE, Nix BD et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch GenPsychiatry 2006;63:521–9.

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29. Whooley MA. Depression and cardiovascular disease: healing the broken-hearted. JAMA 2006;295:2874–81.

30. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associatedwith myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet 2004;364:937–52.

31. Glassman AH, O’Connor CM, Califf RM et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701–9.

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Table 2. Characteristics of metabolic syndrome [29].

The Third Report of the National Cholesterol EducationProgram Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (ATP III,NHLBI) defines metabolic syndrome as three or more of the following abnormalities:

• Waist circumference ≥102 cm (40 inches) in men and ≥88 cm (35 inches) in women

• Serum triglyceride level ≥150 mg/dL• HDL cholesterol level <40 mg/dL in men

and <50 mg/dL in women• Blood pressure ≥130/85 mmHg• Fasting glucose level ≥110 mg/dL

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CLINICAL REVIEWSCommentary and Analysis on Recent Key Papers

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

EPIDEMIOLOGY

Social inequalities in response to antidepressanttreatment in older adultsCohen A, Houck PR, Szanto K et al. Arch Gen Psychiatry 2006;63:50–6.

Low socioeconomic status (SES) has repeatedly been shownto be associated with elevated rates of morbidity andmortality throughout all stages of life for both physical andpsychiatric disorders. Higher rates and increased persistenceof depression have also been seen with low SES; however,research into the effect of SES on treatment outcomes indepression has been inconclusive. The authors of this studyexplored the effects of two aspects of SES – education andincome – on the efficacy of antidepressant treatment inelderly patients with major depressive disorder.

All 248 subjects had been participants in one of two open-label, National Institute of Mental Health-funded studies.Data were used from 145 of 169 subjects aged ≥59 yearswho took part in the first study examining the efficacy ofnortryptyline hydrochloride and interpersonal psychotherapyin late-life depression. Data were also gathered from 103 of116 total subjects aged >69 years who had participated in asecond research project, exploring the efficacy of paroxetine

and interpersonal psychotherapy. Depression outcomes werecollated during the short-term and continuation phases of thestudies, which lasted up to 26 weeks.

The 17-item Hamilton Rating Scale for Depression(HAM-D17) was used to assess for depression, response totreatment (HAM-D17 ≤10), remission (HAM-D17 ≤6), andsuicidality. The authors measured SES using levels ofeducation and income. Several baseline clinical anddemographic characteristics were also analyzed, includingconcurrent medical burden measured using CumulativeIllness Rating Scale–Geriatric. Three forms of regressionanalysis were used to evaluate the association between SESand time to response or remission of depression.

The high- (n=50), middle- (n=158), and low- (n=40)income subjects showed response rates of 78%, 77%, and80%, and medial response times of 7.4, 7.0, and 9.1 weeks,respectively. Remission was achieved in 44%, 47%, and48% of subjects, respectively.

Hazard ratio (HR) comparisons revealed a significantdifference between probable treatment response in high-and middle-income subjects compared with low-incomepatients, following adjustment for demographic variables.Factoring in clinical characteristics in addition to SES anddemographic variables revealed that middle-income subjectswere more likely to respond to depression treatment thanlow-income participants (HR=1.8). When examined as asingle aggregate, high- and middle-income subjects weresignificantly more likely to respond to treatment than low-income participants (HR=1.61).

Suicide ideations were consistently higher in low-incomesubjects compared with those in the middle- or high-economic groups, even after adjustment for baseline clinicalcharacteristics. Specifically, the likelihoods of suicideideations in middle- and high-income subjects were 0.48and 0.39 times, respectively, that of the reported suicidalityin low-income participants. Combining middle- and high-income groups reveals that this cohort is 0.46 times as likelyas low-income subjects to report suicide ideations.Additional analysis revealed that suicide ideations and lowSES were independent predictors of probable response to

This study examined the association betweensocioeconomic status and response to depressiontreatment in patients aged ≥59 years. The authors usedpooled data from the open-label phase of two studies ofthe efficacy of interpersonal psychotherapy with eithernortryptyline hydrochloride or paroxetine. Analysis of thedata revealed that middle-income patients respondedbetter to antidepressant treatment than those on a lowincome. Suicide ideation was also less common in high-and middle-income patients than in low-income patients.These data suggest that older adults on low incomesreceiving treatment for depression have a less favorableoutcome than their higher-income counterparts.

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antidepressant treatment. The study also showed that number of years of education was not a significant predictorof treatment response or suicidal ideations during treatment,and that number of years of education and income were notrelated to remission rates.

It could be concluded that low-income subjects were less likely to respond to depression treatment, but only after accounting for certain demographic and clinicalcharacteristics. Moreover, high- and middle-income subjectshad lower rates of suicidality than their lower-incomecounterparts. However, the study was limited by severalfactors. Subjects were pooled from open-label trials, whichmeant that there was no placebo arm to the data. Theincome category was based on census data and may nothave indicated subjects’ actual income. In addition, as all theparticipants were aged ≥59 years, it is difficult to generalizethese results to younger populations.

Address for reprints: A Cohen, Department of Social Medicine, HarvardMedical School, 641 Huntingdon Avenue, Boston, MA 02115, USA.Email: [email protected]

Association of body mass index with suicidemortality: a prospective cohort study of more than one million menMagnusson PK, Rasmussen F, Lawlor D et al.Am J Epidemiol 2006;163:1–8.

Being overweight or obese carries significant medical risks,and may also have important associations with morbidityand mortality rates in psychiatric illnesses. However, previousstudies have found that results differ for men and women.More than 40 000 individuals were interviewed in a USsurvey of major depression, suicidal ideation, suicideattempt, and body mass index (BMI), and the resultsrevealed a positive association between BMI and depressionand suicidal ideation in women, but an inverse association in men [1].

Magnusson and colleagues examined data on BMIassessed at 18–19 years of age, psychiatric diagnoses,parental socioeconomic data, and suicide death informationfrom 1 299 177 men conscripted to the Swedish militaryfrom 1968 to the end of 1999. Men with a severe, chronicmedical condition or documented handicap that excludedthem from the military were not captured in this dataset.

From the nearly 1.3 million men, almost 19 millionperson–years were covered. The overall suicide rate was 16.2

per 100 000 person–years (0.24% or 3075 total suicides from1968–1999). Mean BMI was 21.8 kg/m2 and 1.9% of subjectswere obese. Over the study period the prevalence of obesityincreased from 1% for men born in the 1950s to 2.8% formen born between 1970 and 1981. Overall, higher BMIcorrelated with a lower suicide rate. For every BMI increase of 5 kg/m2, the risk of suicide decreased by 13% (95%confidence interval 7–18%). This inverse correlation remainedsignificant even when excluding men with baseline psychiatricillness. Furthermore, this correlation was similar for suicidesthat occurred within 5 years of study entry, 5–10 years, and>10 years after baseline measurements.

The strengths of this study include the large sample size,prospective follow-up design, and measurement of suicidedeaths instead of suicide behaviors. Coupled with the studyby Carpenter et al. [1], these results indicate that theinteractions between weight and suicide are different in menand women. These results do not mean that increasedweight is a protective factor against suicide for men, butrather that weight loss, depression, and suicide may haveoverlapping etiologies in men. The differential interaction inwomen needs further study.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 generalpopulation study. Am J Public Health 2000;90:251–7.

Address for reprints: F Rasmussen, Child and Adolescent Public Health Epidemiology Group, Department of Public Health Sciences,Karolinska Institute, Norrbacka, SE-171 76 Stockholm, Sweden. Email: [email protected]

Depressive symptoms and cognitive decline in late lifeGanguli M, Du Y, Dodge H et al.Arch Gen Psychiatry 2006;63:153–60.

Cognitive impairment is a common feature of majordepression, and major depression may predict the futuredevelopment of dementia in older adults. The authors aimedto determine whether depressive symptoms predictedcognitive impairment in a population-based communitystudy. Cognitive function was prospectively examined every2 years for 12 years in 1265 older adults (aged ≥67 years)without baseline dementia. The study controlled for baselinedepressive symptoms, as measured by the modified Centerfor Epidemiological Studies – Depression Scale (mCES-D).Depression was defined as a mCES-D score of ≥5.

Baseline depressive symptoms did not predict cognitivedecline in the older adult without dementia in thiscommunity sample, in contrast to the significant effects reported in at-risk groups (those with majordepression or dementia).

Based on data from nearly 1.3 million men and 19 millionperson–years, higher body mass index was correlatedwith a lower suicide rate in men, which is the inverse of previous findings in women.

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The mean sample age was 74.6 years and 60.8% werefemale. Subjects with depression at baseline had significantlylower cognitive functioning than individuals withoutdepression. Of 1265 subjects, 171 (13.5%) developeddementia during the 12-year follow-up. Eventual dementiasufferers had lower mean baseline cognitive scores.However, depressive symptoms did not correlate with anydecline in cognitive scores, not even in the subjects whodeveloped dementia.

Overall mortality rate during the 12-year follow-up was50.4%, and baseline depression was a risk factor for early(between follow-up visits two and three), but not later,mortality in the study (odds ratio 1.94).

Depressive symptoms have been reported to have asignificant effect on cognitive function in an at-risk sample(i.e. in patients with major depression or dementia).However, this was not seen in a community sample ofsubjects where depressive symptoms were less prevalent,and subjects did not have or were not at risk for dementia.

Address for reprints: M Ganguli, Western Psychiatric Institute and Clinic,3811 O’Hara St, Pittsburgh, PA 15213-2593, USA. Email: [email protected]

Perspectives on depression, mild cognitiveimpairment, and cognitive declineSteffens DC, Otey E, Alexopoulos GS et al. Arch Gen Psychiatry 2006;63:130–8.

Evidence suggests that late-life depression and cognitiveimpairment both increase the risk of developing dementia.However, these two phenomena are, for the most part,investigated along two separate avenues of research. Mildcognitive impairment (MCI) is a term that has been used todescribe the state between normal cognition and dementia.Subjects are often excluded from studies of depression if theyhave cognitive impairment, and studies of MCI frequentlyomit patients with depression. Hence, there is little researchpublished on the prevalence of the concomitance of

cognitive impairment and depression. The study authors alsonote that there is a paucity of research on the effect of thesetwo phenomena on the risk of future dementia.

This article offers a summary of the 2003 NationalInstitute of Mental Health (NIMH) conference “Perspectiveson Depression, Mild Cognitive Impairment, and CognitiveDecline”, wherein discussion focused on the gaps that existin our knowledge of depression and MCI, and what the bestuse of research funding would be to improve these deficits.Participants included grantees from the National Institute onAging, NIMH, and the National Institute of NeurologicalDisorders and Strokes in the US.

Researchers have some disagreement with regard to thedefinition of depression in the elderly, as non-dysphoric ordepression with intermittent symptoms may be prevalent inthe population but not well characterized by the DSM-IVcriteria for a major depressive episode. When the authors ofthis article refer to depression, they include these forms intheir discussion.

MCI has been subcategorized into amnestic and non-amnestic subtypes. Studies suggest that the amnesticsubtype progresses to Alzheimer’s disease and non-amnesticMCI tends to develop into non-Alzheimer dementias.However, there is no consensus regarding these subtypes ofMCI among clinicians. The study authors used the phrase“mild cognitive impairment” when discussing a subtype,and the term cognitive impairment for the more generalstate that is not considered to be normal aging.

Despite the finding that many older depressed patientsalso have cognitive impairment, this association is not welldefined. Several analyses have shown that the combinationof cognitive impairment and depression is substantial in theelderly population, with one study suggesting that 33–60%of older patients developed major depressive episodes at orafter the onset of cognitive impairment [1].

Conference members identified several factors thatinfluence the reported co-occurrence of MCI and depressionacross studies:

• The definition and measurement of cognitive impairmentmay influence reported rates.

• Patient selection has a significant impact, as most studiesof dementia and depression exclude subjects with seriousmedical illness.

• Cultural differences in the perception of depression andthe expectation of normal aging may also have affectedthe studies.

The committee noted that divergent paths of research onbiological markers of depression and cognitive deficits needto be reconciled. Cognitive research has focused significantly

The “Perspectives on Depression, Mild CognitiveImpairment, and Cognitive Decline” conference wasarranged by the National Institute of Mental Health todiscuss depression and cognitive impairment. The aim ofthe conference was to identify gaps in our understandingof these areas that significantly impact on public health,and to offer suggestions as to how research investment can be allocated more efficiently. The recommendation of representatives from several government agencies was that greater collaboration between researchersinvestigating depression and those studying memorydisorders is required.

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on temporal lobe structures, while depression research hasconcentrated on the basal ganglia and prefrontal cortex.Emerging evidence suggests that these regions of the brainare implicated in both disorders, and therefore integratingthese research foci may be justified. The conferenceconcluded with acknowledgement by the attendees fromthe various organizations present that cognitive disordersand depression have a serious impact on public health. 1. Zubenko GS, Zubenko WN, McPherson S et al. A collaborative study of the emergence

and clinical features of the major depressive syndrome of Alzheimer’s disease. Am J Psychiatry 2003;160:857–66.

Address for reprints: DC Steffens, Department of Psychiatry, Duke University School of Medicine, Campus Box 3903, Durham, NC 27710, USA.

CLINICAL PRACTICE

Relapse of major depression during pregnancy in women who maintain or discontinueantidepressant treatmentCohen LS, Altshuler LL, Harlow BL et al. JAMA 2006;295:499–507.

Research has suggested there is a high level of depressionrelapse in non-gravid patients who discontinue antidepressantmedication; however, the risk in pregnant women has notbeen determined. A better understanding of the incidence ofrelapse would be significant in discussing the risk–benefitassessment of continuing antidepressant medications (i.e.exposing the fetus to the medication) versus discontinuingtreatment (i.e. the risks of untreated depression) duringpregnancy. This study explored the difference in the risk of

depression relapse during pregnancy between women whomaintained antidepressant treatment and those whodiscontinued medication. The study authors also observeddifferences in time-to-relapse between groups.

In total, 201 women were recruited through threedifferent centers specializing in psychiatric conditions duringpregnancy. All subjects were currently or had recentlyreceived antidepressant medication, were at <16 weeksgestation, had a history of major depression prior tobecoming pregnant, and were euthymic for >3 months prior to their last menstrual period. The study wasprospective and naturalistic in design. Longitudinal datawere gathered from March 1999–April 2003. The study wasnot randomized, and treatment decisions were madeindependently of participation in the study. All participantswere assessed utilizing the Structured Clinical Interview,Hamilton Rating Scale for Depression, and the ClinicalGlobal Impressions Scale. Subjects were placed into fourcategories based on their medication status: medicationdecreased below optimal dose; increased above optimaldose for ≥1 week; maintained on medication throughoutstudy period; and discontinued for ≥1 week.

Of the 201 subjects, 12 were lost to follow-up, eightchose to discontinue from the study, 13 miscarried, and fiveelectively terminated their pregnancies. The mean age ofdepression onset was 18.8 years, 20% of subjects haddepression of >20 years duration, 48% had depression of<14 years duration, 40% had ≥5 prior episodes ofdepression, and 53% had comorbid psychiatric illness.

Overall, 43% of the women in the study had a relapse ofdepression. Within the four subcategories the relapse rateswere as follows:

• 26% of women who continued their medication.• 68% of those who discontinued their medication.• 45% of subjects who increased their medication.• 35% of those who decreased their medication.

Of those women who decreased or discontinued their medication, 61% (n=60) restarted treatment during the pregnancy.

The study was limited as it did not have a randomizeddesign – the study authors felt this would have beenunethical in a study of antidepressant use in pregnantwomen. As described above, the study participants had extremely severe depression, and it is possible therelapse rate may have been lower in subjects with less severe illness.

Address for reprints: LS Cohen, Perinatal and Reproductive Psychiatry,Massachusetts General Hospital, WACC 812, 15 Parkman Street,Boston, MA 02114, USA. Email: [email protected]

Historically, pregnancy has been regarded as offering“protection” from depression. However, little researchhas been published on the relapse rates in women withpre-existing depression and their use of medicationduring pregnancy. This prospective, naturalistic studyassessed the risk of depression relapse in 201 pregnantwomen who either continued or stopped theirantidepressant medication during pregnancy. The studyrevealed that 43% of all study participants experienced a relapse. Of the 82 patients who continued theirmedication, 26% experienced a relapse compared with68% of the 65 subjects who stopped their treatment.This study suggests that pregnancy is not “protective”with regard to depression, as has been historicallyunderstood. Euthymic women receiving ongoingantidepressant medication should be informed of the risk of relapse if they discontinue their medication.

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Long term outcomes from the IMPACT randomizedtrial for depressed elderly patients in primary careHunkeler E, Katon W, Tang L et al.BMJ 2006;332:259–63.

The IMPACT (Improving Mood Promoting Access toCollaborative Care Treatment) program is an interventionaimed at improving the psychiatric and functional outcomesof depressed (Diagnostic and Statistical Manual of MentalDisorders, 4th edition [DSM-IV] major depressive disorder,with or without dysthymic disorder) older adults, whocommonly seek psychiatric care from their primary carephysicians. Older (aged ≥60 years, 65% female, n=1801)ethnically diverse adults were randomly assigned to acollaborative care intervention (depression care manager,primary care physician, and psychiatrist) or standard care(antidepressants, counseling by primary care physician, andreferral to specialty mental health care) for 1 year, andassessed at the end of the treatment year (12 months), andagain at 18 and 24 months. Initial response differences at 12 months favored collaborative care [1]. In the presentarticle, Hunkeler and colleagues report on the longer-termfollow-up at 18 and 24 months to determine whether thedifferences in response were sustained.

Patients treated with collaborative care had higher ratesof antidepressant use at 12, 18, and 24 months comparedwith those receiving standard care. Depressive symptomswere improved, and physical function and quality of life were better, for the collaborative care group compared withthe standard care group at 12, 18, and 24 months, evenconsidering gender, age, ethnicity, severity of depression,and medical comorbidity. Use of counseling was higher in the collaborative care group at 12 months, but not at 18 or 24 months.

Other studies have demonstrated the positive impact ofcollaborative care on depression outcomes. Public awarenessof this study has resulted in IMPACT being advocated as amodel program for mental health care in the US.1. Unutzer J, Katon W, Callahan CM et al. Collaborative care management of late-life

depression in the primary care setting. A randomized controlled trial. JAMA2002;288:2836–45.

Address for reprints: EM Hunkeler, Kaiser Permanente, Division ofResearch, 2000 Broadway, 2nd Floor, Oakland, CA 94612, USA. Email: [email protected]

Systematic detection and multidisciplinary care of depression in older medical inpatients: a randomized trialCole MG, McCusker J, Elie M et al. CMAJ 2006;174:38–44.

Major depressive disorder occurs in up to 30% of elderlyinpatients, and has been associated with poorer outcomes.Treatment offers many benefits; however, up to 90% ofthese patients are not diagnosed with depression duringtheir hospital stay. The study authors examined a strategy ofsystematic detection to determine its efficacy in reducingsymptoms of depression and improving outcomes.

Patients screened were aged ≥65 years and had beenadmitted to medical services via the emergency room of aprimary acute care hospital in Montreal (QC, Canada).Enrolled subjects scored ≤4 on the Short Portable MentalStatus Questionnaire and were further assessed using theDiagnostic Interview Schedule.

Patients were randomized to either the standard care orintervention group. The intervention group receivedtreatment for 24 weeks including assessment and treatmentby a psychiatrist and subsequent follow-up care by aresearch nurse and the patient’s family physician. Treatmentinvolved supportive psychotherapy and antidepressantmedication. Control subjects were informed they sufferedfrom depression and were directed to talk to their physicianabout treatment, but no additional systemic interventionswere made. All subsequent consultations for psychiatry werehonored, consistent with standard practice. Subjects wereevaluated at baseline, 3 months, and 6 months, andmeasures of physical illness, alcoholism, depression, activitiesof daily living, health services utilization, suicide, and suicideattempts were collected.

This randomized clinical trial examined the efficacy of a strategy of depression detection and treatment in1500 medical inpatients, aged ≥65 years, admitted to a general medical service. Patients (n=157) who hadmajor depression and consented to enter the study wererandomized to receive either standard care or the studyintervention. The intervention involved consultation andtreatment by a psychiatrist, and follow-up by a researchnurse and the subjects’ primary care provider. Data weregathered at 3 and 6 months on a variety of outcomes,including depressive symptoms and medical outcomes.Amongst the 64 subjects who completed the study, nodifference was seen between the groups at the end of 6 months, suggesting that the system under examinationwas no more beneficial to patients than standard care for this population.

Collaborative care (from a depression care manager,primary care physician, and psychiatrist) in the primarycare setting improves compliance with antidepressanttreatment in older depressed adults, resulting in improveddepression and better physical functioning and quality of life. The goal is to make collaborative treatment thestandard of care.

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Out of 1500 patients who were initially screened, 225(15%) had major depression. Of these, 157 patients agreed toparticipate in the study; 79 were randomized to the standardcare group and 78 to the intervention group. Thirty-six(22.9%) of the study died prior to the 6-month follow up visit,57 (36.3%) withdrew, and 64 (40.8%) completed the study.Seventy-four (94.9%) patients in the intervention group and21 (26.6%) in the standard care group received a consultationfrom a psychiatrist. At 6 months, there was no differencebetween the standard care and experimental group on any ofthe primary outcome measures of the study.

This study was unable to show the benefits of systematicdetection and multidisciplinary care of elderly inpatients withdepression. However, a high number of subjects withdrew ordied before the study could be completed. The same teamof attending physicians was managing both sets of patients,which also may have led to contamination of standard careby the experimental program.

Address for reprints: MG Cole, Department of Psychiatry, St Mary’sHospital Center, 3830 Lacombe Avenue, Montréal, QC H3T 1M5,Canada. Email: [email protected]

A 20-week randomized controlled trial of estradiolreplacement therapy for women aged 70 years andolder: effect on mood, cognition and quality of lifeAlmeida OP, Lautenschlager NT, Vasikaran S et al. Neurobiol Aging 2006;27:141–9.

Estrogen replacement therapy (ERT) has been shown inlimited studies to improve cognitive scores, decrease therisk of dementia, and improve mood. However, recentinvestigations suggest that the findings of these earlystudies may be misleading. Specifically, the WHIMS

(Women’s Health Initiative Memory Study) found a two-fold increase in the rate of dementia in women treatedwith hormone replacement therapy (HRT) compared withthose who did not receive HRT. The study also showedthat there was no improvement in mood of subjectstreated with HRT. It is conceivable that the effects of ERTon mood may be age-dependent and different to thosereported in the WHIMS. This current study is the first of itskind to explore the effects of estradiol on cognition, mood,and quality of life (QoL) in a population of women aged≥70 years.

The study was double-blind and placebo-controlled indesign. Subjects randomly allocated to the treatment groupreceived estrogen for a total of 20 weeks, with a gradualescalation and de-escalation of dose in order to minimize sideeffects. Of the 278 women who were screened for the study,115 met entry criteria and were randomized into the study.

Subjects were assessed for cognitive function andmental state using the Cambridge Examination for MentalDisorders of the Elderly. Additional cognitive testsadministered included Block Design and the CaliforniaVerbal Learning Test II. Symptoms of depression weremeasured utilizing the Beck Depression Inventory andanxiety symptoms were assessed with the Beck AnxietyInventory. The Short Form-36 Health Survey was used toassess QoL and adverse events were quantified using theGreene Climacteric Scale. Blood tests, including apoproteinE genotype determination, total plasma homocysteine, andmeasures of unconjugated 17 β-estradiol, were performed.

The 115 women were randomized to either the estradiol(n=58) or placebo group (n=57) for 20 weeks. Twenty-ninesubjects did not complete the study; of these, 22 discontinuedthe study protocol and seven were lost to follow-up.

There were no significant differences in measures ofQoL, anxiety, or depression between groups. Women inthe estrogen treatment group had improved immediatememory of faces compared with control subjects, but this effect disappeared after Bonferroni method adjustmentfor multiple comparisons. There was no significantdifference between groups in any of the other cognitivetests administered.

Total plasma concentration of estradiol did, as expected,substantially increase in subjects in the treatment group.Women in the experimental group were four times as likelyas those in the placebo group to leave the study due to sideeffects, the most common being breast tenderness andvaginal itchiness.

The results of this study suggest that estradiolreplacement is not effective in improving mood symptoms,QoL, or cognitive function in older women. The authorsnote that the study had 90% power to detect differences

Research into the effects of estrogen replacement therapy (ERT) on mood has led to contradictory results. Observational studies show it improvescognition, quality of life (QoL), and mood; however,the controlled Women’s Health Initiative trial did notfind improvements in any of these factors, and actuallyreported an increase in the risk of dementia. Little datahave been published on the effects of ERT on womenat higher risk of cognitive decline (≥70 years old). This double-blinded, placebo-controlled study exploredthese issues in 115 women who were randomized toreceive either placebo or estradiol, and were assessedfor changes in mood, cognition, and QoL. Resultsshowed no difference between groups in any outcomemeasured. This study suggests that high levels ofestrogen replacement do not significantly impact on any of the above three clinical variables.

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between the experimental and placebo groups. The clinicalsignificance of these findings may be limited as the majorityof women did not have low mood scores to begin with, andthere was therefore little room for improvement.

Address for reprints: OP Almeida, School of Psychiatry and ClinicalNeurosciences, The University of Western Australia (M573), 35 Stirling Highway, Crawley, Perth, WA 6009, Australia. Email: [email protected]

Response to fluoxetine and serotonin 1A receptor(C-1019G) polymorphism in Taiwan Chinese major depressive disorderHong C, Chen T, Yu YW et al.Pharmacogenomics J 2006;6:27–33.

Genetic research has moved toward identifying phenotypicdifferences between psychiatric patients, such as treatmentresponsiveness in depressed patients. Most of the work inthis area has focused on the polymorphisms of the serotoninsystem of receptors and transporters.

Hong and colleagues studied polymorphisms in 224Taiwanese unipolar depressed patients given fluoxetine for 4 weeks. The following polymorphisms were investigated:

• C–1019G polymorphism of the 5-hydroxytryptamine 1Aautoreceptor (HTR1A C–1019G).

• Serotonin transporter gene-linked polymorphic region(SERTPR).

• Variable-number tandem-repeat polymorphisms in intron 2of the serotonin transporter gene (STin2).

• Serotonin 2A receptor (T102C) polymorphism.• Tryptophan hydroxylase (A218C) polymorphism.• G-protein beta3 subunit (C825T) polymorphism.

These polymorphisms were chosen based on priorfindings from other research groups who had foundassociations with selective serotonin reuptake inhibitorantidepressant response.

Only 36.2% of patients met the response criteria of 50%improvement in Hamilton Depression Rating Scale score.The mean final dose of fluoxetine was 25.8 mg/day. In terms of the HTR1A C–1019G polymorphism, thosehomozygous for the C allele (C/C genotype) had a greaterresponse to fluoxetine than G allele carriers (G/C or G/Ggenotypes); the odds ratio was 4.4. Long variant

homozygotes of SERTPR (l/l genotype) had a greaterresponse to fluoxetine than short variant carriers (s/l or s/sgenotypes), with an odds ratio of 8.6. Other polymorphismresponse associations were not replicated by this study.

This study extends the expanding literature on applyinggenetic research to phenotyping response differences inpsychiatric patients. As response was determined relativelyearly (at 4 weeks, compared with typical clinical trials of 8 weeks) and overall response was low (36%), someeventual responders were likely missed; thus, these results aremore aptly defined for early responders. This study is alsolimited by the lack of a placebo comparison. Nevertheless,these results point to the need for a prospective trialpredicting response from baseline genotyping, with theultimate goal of individualizing treatment.

Address for reprints: S-J Tsai, Department of Psychiatry, Taipei VeteransGeneral Hospital and National Yang-Ming University, No. 201, Shih-PaiRoad, Sec 2, Taipei 11217, Taiwan. Email: [email protected]

COMORBIDITIES

Prevalence and correlates of restless legssyndrome: results from the 2005 National Sleep Foundation pollPhillips B, Hening W, Britz P et al.Chest 2006;129:76–80.

Restless legs syndrome (RLS) has gained increasingimportance in public awareness since the recent approval ofthe first medication for its treatment by the US Food andDrug Administration. The National Sleep Foundationconducts a yearly telephone interview of US adults toevaluate the prevalence and comorbidities of sleep disorders.Phillips and colleagues report on the National SleepFoundation Sleep in America 2005 poll results for RLS.

The entry question of the poll was, “In the past year,according to your own experiences or what others tell you,how often did you have unpleasant feelings in your legs likecreepy, crawly, or tingly feelings at night with an urge to movewhen you lie down to sleep?” A high rate of respondentsendorsed this symptom at least a few nights per week.

If respondents also endorsed these feelings as worse atnight than during the daytime, the diagnosis of RLS wasdefined as likely (9.7% of the entire sample). Functionalproblems (including daytime fatigue, missing work, and

Data from the National Sleep Foundation Sleep inAmerica 2005 poll indicates a nearly 10% prevalence of restless legs syndrome among adults in the US.

C allele homozygotes of the serotonin 1A receptor andlong variant homozygotes of the serotonin transporterhave a greater response to fluoxetine. These resultsadvance the potential utility of genetics in phenotypingpsychiatric illness, in particular treatment response.

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missing social events) were more common in individuals atrisk of RLS. The likelihood of suffering from this syndromewas higher in southern states and lower in northeasternstates. Out of eight queried medical conditions, the rates ofRLS were higher in six conditions (depression, anxietydisorder, hypertension, arthritis, diabetes, andgastroesophageal reflux disease). This suggests that RLS iscommonly comorbid or aggravated by many otherconditions, or possibly that the poll lacks diagnosticspecificity. However, other studies have found prevalencerates of approximately 10% for RLS, and patients with RLSoften have a family history of the disorder. Overall, theavailable data suggest that RLS has a high prevalence.Dopamine agonists have demonstrated efficacy as a therapyfor this disorder.

Address for reprints: B Phillips, Fifth Floor, Kentucky Clinic, Division ofPulmonary, Critical Care and Sleep Medicine, University of KentuckyCollege of Medicine, 800 Rose Street, Lexingon, KY 40536-0028, USA.Email: [email protected]

Clinical depression and risk of out-of-hospitalcardiac arrestEmpana JP, Jouven X, Lemaitre RN et al. Arch Int Med 2006;166:195–200.

Previously published research has shown an associationbetween depression and coronary heart disease-relatedmortality. Research into the association between depressionand sudden cardiac death has been limited by studies wherefew cardiac arrest (CA) events occurred and which involved select populations. Little has been published that

adequately characterizes the relationship betweendepression and CA in the general population. The authorsstudied this relationship overall and in specific subgroupsutilizing data from a case-controlled, population-basedstudy of out-of-hospital CA.

Information was gathered from patients enrolled in theGroup Health Cooperative of Puget Sound in westernWashington State (USA). Enrollees (n=2228) who hadexperienced an out-of-hospital CA between 1980 and 1994were identified. Out-of-hospital CA was defined as a suddenpulseless condition with no known non-cardiac condition.Subjects were excluded if they had a prior non-cardiaccondition that was life threatening, including brain tumor,liver disease, and end-stage renal disease. Randomly chosenenrollees (n=4164) acted as controls. An index date wasrandomly assigned based on the distribution of the date ofCA in the experimental group. Clinical physician-diagnoseddepression was defined in this study as either the use ofantidepressant medication at the index date or diagnosis ofdepression within a year of this index date by a physician.Subjects were categorized as having no depression,depression, or severe depression (either a referral to a mentalhealth clinic or hospitalization for depression). Informationon various cardiac diagnoses and measures of cardiac well-being was also collated.

Of the entire study population, 3641 had a prior historyof heart disease, and 92.9% were Caucasian. Subjects withdepression were more likely to be hypertensive, diabetic,have congestive heart failure, be current smokers, beunemployed, or involved in a clerical occupation.

Depression and severe depression were more common inCA cases than in controls. The risk of CA in patients withdepression was almost two-fold greater than in thosewithout depression (odds ratio [OR]=1.88) and this ORremained elevated after accounting for several cardiacvariables, including previous diagnosis of heart disease. Therisk increase exhibited a graded manner, with a greaterincrease observed with severe depression (OR=1.77) than inless severe illness (OR=1.30) when compared with controls.This graded increase in risk was still seen when the risk ofCA was directly compared between patients with depressionand those who suffered severe depression (OR=1.36).

This study offers evidence that clinical depressionincreases the risk of out-of-hospital CA, and that this riskincreases with the severity of the depression. The study waslimited by the fact that depression is often unrecognized inprimary care, and thus subjects with depression may havebeen misclassified as not being depressed.

Address for reprints: JP Empana, INSERM Avenir-U258, Hôpital PaulBrousse, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex,France. Email: [email protected]

The authors of this case-controlled, population-based study investigated the association between depressionand sudden cardiac death. Data were gathered fromsubjects enrolled in a health maintenance organization inthe state of Washington (USA). Random enrollee controlpatients (n=4164) were compared with 2228 enrolleesaged 40–79 years who experienced out-of-hospitalcardiac arrest (CA) between 1980 and 1994. Depressionwas defined by the use of antidepressant medication or diagnosis by a physician 1 year prior to the CA, while severe depression was classified as hospitalizationor referral to a mental health clinic for depression.Subjects with depression had a higher odds ratio (OR) of having a CA (OR=1.88), an effect that remained after accounting for confounding variables (OR=1.43).The risk of CA was increased in both depressed(OR=1.30) and severely depressed participants(OR=1.77). These data suggest that clinical depressionmay be independently associated with CA.

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Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatmentJorde R, Waterloo K, Storhaug H et al.J Clin Endocrinol Metab 2006;91:145–53.

Hypothyroidism is clearly associated with cognitivedysfunction and increased risk of depressive disorders. Studieshave found that patients with subclinical hypothyroidism,defined as elevated levels of thyroid-stimulating hormone(TSH) but normal levels of free T3 and T4, may also beassociated with cognitive dysfunction and depressivesymptoms. Jorde and colleagues examined whether treatmentof subclinical hypothyroidism with T4 supplementation wouldimprove cognitive function and depressive symptoms.

Eighty-nine patients with subclinical hypothyroidism(TSH 3.5–10.0 mIU/L; reference range 0.20–4.20 mIU/L)were compared with 154 age- and gender-matchedeuthyroid control subjects using a battery of 14 cognitivetests, the Beck Depression Inventory (BDI), and the GeneralHealth Questionnaire (GHQ). Sixty-nine of the patients wererandomly assigned and treated with T4 supplementation in adouble-blind fashion for 1 year, and then reassessed usingthe same series of neuropsychological tests.

Mean TSH in the subclinical hypothyroidism group was5.57 mIU/L compared with 1.79 mIU/L in the control group.While age was inversely related to cognitive performance,there were no significant cognitive differences between thesubclinical hypothyroidism and control groups. Paradoxically,subclinical hypothyroidism subjects had statistically betteremotional functioning according to GHQ scores, andnumerically, but not statistically, higher BDI scores. After 1 year of intervention (dose titrated to target TSH of 0.5–1.5 mUI/L), subjects given T4 did not differ from thosegiven placebo in any measured parameter (cognitive,emotional, or physical symptoms).

This study did not find subclinical hypothyroidism to beassociated with significant cognitive deficits, and T4supplementation did not result in any cognitive or emotionalchanges beyond that of placebo. However, severallimitations of this study may have masked potential findings.The TSH range used in this study overlapped with thelaboratory reference range; previous studies have

investigated subjects with higher mean TSH levels. Subjectswere notified of their TSH levels and were allowed to seektreatment outside the study. Additionally, anyone alreadyreceiving T4 supplementation was excluded. Therefore, thisstudy could have missed subjects who may have hadcognitive or emotional symptoms and who soughttreatment. Placebo-controlled studies are necessary toaddress the potential utility of T4 supplementation and/orT3 supplementation for subclinical hypothyroidism inpatients with higher TSH levels (e.g. TSH ≥4.2), given thatother studies have found associations between subclinicalhypothyroidism and cognitive and depressive symptoms.

Address for reprints: R Jorde, Institute of Clinical Medicine, University of Tromso, 9037 Tromso, Norway. Email: [email protected]

PATHOGENESIS

Increased hippocampal plaques and tangles inpatients with Alzheimer disease with a lifetimehistory of major depressionRapp MA, Schnaider-Beeri M, Grossman HT et al. Arch Gen Psychiatry 2006;63:161–7.

Plaque and tangle formation, especially in the hippocampusand temporal lobes, are considered the hallmark change thatoccurs in Alzheimer’s disease (AD). It has been noted that alifetime history of major depressive disorder (MDD) increasesthe risk of clinically diagnosed AD, and MDD has beenassociated with memory deficits in the elderly by severalstudies. Imaging analyses in the geriatric population have

Plaque and tangle formation have been characterized as the hallmark pathological changes that occur inAlzheimer’s disease (AD). Although there is evidence thatmajor depression can impact these changes, no researchhas been published on neuropathological interactionsbetween the two disorders. The authors of this studycompared post mortem examinations of the brains of 50 patients with AD and a history of major depressionwith those from 52 patients with AD only. The resultsrevealed that patients with both disorders had higherlevels of plaque and tangle formation than those with AD alone. Those who had been diagnosed with AD while suffering from co-occurring major depressivedisorder had more pronounced neuropathologicalchanges in the hippocampus area. Utilizing an ADneuropathological rating scale, the authors discoveredthat those patients with both disorders had a more rapid cognitive decline than those with AD alone.

In this study, subclinical hypothyroidism (defined bythyroid-stimulating hormone [TSH] 3.5–10.0 mIU/L butnormal free T4 and T3) was not associated with cognitiveor emotional deficits, and T4 supplementation did notimprove cognitive or emotional functioning. However,TSH levels of the study group overlapped with those ofthe control group (reference range 0.20–4.2 mIU/L).

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revealed a correlation between MDD and volume loss in thehippocampus. Additional research has also suggested arelationship between MDD and the pathological processesthat lead to AD; however, no study to date has explored ahistory of MDD as a factor in the progression of AD. Theauthors explored this issue with the hypothesis that plaquesand tangles would be more pronounced in patients withMDD and AD than in those with AD alone.

The cohort selected was part of a large study of AD, withthe subjects screened from residents and new admissions tothe Jewish Home Nursing Home (New York, NY, USA).Patients were screened using the Mini-Mental Status Exam(MMSE) and the Clinical Dementia Rating Scale. Afterpatients were screened for dementia, the clinical diagnosis of AD was determined through specific research andDiagnostic and Statistical Manual of Mental Disorders ThirdEdition (DSM-III) or DSM-IV criteria. The history andpresence of MDD was ascertained by examining medicalrecords, the Geriatric Depression Scale, and standardizedquestionnaires based on the Structured Clinical Interview forDSM-IV Axis I disorders.

The researchers acquired post mortem data on 102 subjects with AD. Of these, 44 patients also had alifetime history of MDD while 51 did not. The remainingseven could not be classified. Eleven subjects had beenexperiencing MDD at the time of baseline assessment. Afterthe death of a patient, an autopsy was performed thatincluded neuropathological assessment of various parts ofthe brain. The extent of the lesions was determined usingthe Consortium to Establish a Registry for AD (CERAD)neuropathological battery.

The mean age of death for the 95 patients in the finalstudy group was 81.36 years, and the mean MMSE scorewas 12.37 at the last assessment prior to death. The mostcommon causes of death were pneumonia, cardiovascularfailure, and renal failure, with no differences seen betweenpatients with or without MDD. Post mortem analysisrevealed that 83 subjects could be classified as havingdefinite AD, eight subjects had probable AD, and 10 wereclassified as having possible AD. MDD was found to beequivalently distributed throughout these categories. TheMMSE scores of subjects with AD and a lifetime history of MDD at baseline were slightly higher than those with AD alone.

Post mortem analysis also showed that subjects with ADwho had never experienced MDD had less neuritic plaques(NP) and neurofibrillary tangles (NFT) than those with ADand a past history of MDD. The mean annual cognitivedecline was greater in those with a history of MDD than inthose without such a history (1.86 vs. 1.15 mean annualizeddecline in MMSE score).

Eleven of the 44 subjects with a lifetime history of MDD were depressed at the time of baseline assessment.These 11 patients had higher mean CERAD ratings than ADsubjects with a history of MDD but not active depression atbaseline assessment. Analysis revealed that the subjects whowere depressed at baseline had a larger proportion of NFTand NP in the hippocampus. Mean CERAD scores for bothNP and NFT in the hippocampus were higher in all subjectswith AD and MDD, whether the depression was active atbaseline or not.

This study showed that there is an association betweendepression history and differences in NFT and NP in thehippocampus of subjects with AD, as more NFT and NPwere found in the hippocampus of subjects with MDD thanin those without. Further analysis suggested that subjectswho had both AD and MDD experienced a more rapidcognitive decline than those who did not have depression.The study was limited; without hippocampal volumetric sizedata it is difficult to assess whether the changes observedwere a result of increased AD neuropathological densitycaused by impaired neurogenesis due to MDD or whetherthe findings reflected an increase in NFT and NP.Furthermore, since the study was performed in very oldsubjects, the findings cannot be extrapolated to patientswith earlier onset AD.

Address for reprints: MA Rapp, Department of Psychiatry, Mount SinaiSchool of Medicine, 1 Gustave L Levy Place, Box 1230, New York, NY 10029, USA. Email: [email protected]

Alterations in 5-HT1B receptor function by p11 in depression-like statesSvenningsson P, Chergui K, Rachleff I et al. Science 2006;311:77–80.

Medications that alter serotonin metabolism or reuptake areused in several psychiatric disorders. Fourteen differentserotonin receptors have been identified, of which a number also have multiple splice variants. Serotonin 1B

This study revealed that serotonin 1B receptor (5-HT1B)interacts with p11, a protein that translocates its bindingpartner to the plasma membrane. p11 was shown to increase cell membrane localization of the 5-HT1B

receptor. Over-expression of p11 in mice increased 5-HT1B receptor function, and led to recapitulation of some behaviors seen after antidepressant treatment.Both electroconvulsive therapy and antidepressanttreatment caused increases in p11 levels in rodent brains.Lastly, p11 knockout mice exhibited a depression-likephenotype, and had a reduced response toantidepressants and 5-HT1B receptor antagonists.

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(5-HT1B) receptors function as both autoreceptors andheteroreceptors on many neurons, and have been implicatedin the pathophysiology of numerous psychiatric disorders,including depression and anxiety.

The authors presented evidence from a yeast two-hybridscreening assay that showed p11 interaction with 5-HT1B

receptors, but not with other serotonin or dopamine receptors.p11 was shown to co-localize with 5-HT1B receptors, and thep11 mRNA distribution in the brain resembled that of 5-HT1B

receptor mRNA. p11 mRNA expression was found to beincreased in the cortex by long-term administration ofimipramine, traylcypromine (another tricyclic antidepressant),and electroconvulsive therapy, but not haloperidol, diazepam,or risperidone. p11 mRNA was also down-regulated in theanterior cingulate cortex of patients with major depressivedisorder. In accordance with the increased mRNA expression,p11 protein levels increased in the cortex after administrationof imipramine and electroconvulsive therapy.

Many aspects of 5-HT1B receptor regulation and signalingwere characterized using cell culture experiments. COS-7cells that were co-transfected with p11 and 5-HT1B receptorshad higher 5-HT1B receptor expression levels on theirsurfaces than COS-7 cells transfected with 5-HT1B receptorsalone. COS-7 cells co-transfected with both p11 and 5-HT1B

receptors also had more forskolin-induced cyclic adenosinemonophosphate formation blockade by serotonin than cellsexpressing the 5-HT1B receptors only.

As the results suggested that p11 increases as a result ofantidepressant treatment, the authors explored whether p11also affected behaviors in the mouse model. Transgenic micethat over-expressed p11 behaved in a similar way to micegiven antidepressants, while p11 knockout (KO) mice wereshown to have fewer 5-HT1B receptors.

It is known that serotonin reduces glutamate release at the terminals of certain neurons via 5-HT1B receptors. Theresearchers monitored the amplitude of field excitatory post-synaptic potentials evoked by electrical stimulation ofglutamatergic fibers. Serotonin was able to mediate an effect inthe wild-type mice, but not the p11 KO mice. 5-HT1B receptorsare also known to act as autoreceptors and to inhibit serotoninrelease, and it was found that the p11 KO mice had increasedlevels of serotonin metabolism and turnover. Experimentsthat assessed exposure to antidepressants in p11 KO micecompared with controls suggested that p11 mediatesbehavioral responses to imipramine via 5-HT1B receptors,and that p11 KO mice have a depression-like phenotype.

This study offers significant evidence that p11 may play arole in the molecular mechanisms that malfunction in depression.

Address for reprints: P Greenguard, Laboratory of Molecular andCellular Neuroscience, The Rockefeller University, New York, NY 10021,USA. Email: [email protected]

Cognitive profile of subcortical ischaemic vascular diseaseJokinen H, Kalska H, Mantyla R et al.J Neurol Neurosurg Psychiatry 2006;77:28–33.

Vascular dementia is a major cause of cognitive impairmentand dementia, and has a large range of clinical presentationsbased on the specific subtype. Subcortical ischemic vasculardisease (SIVD) is a subtype of vascular dementia, characterizedby magnetic resonance imaging findings of extensive cerebralwhite matter lesions and lacunar infarcts in deep grey andwhite matter. Clinical findings have not been clearly defined;however, involvement of frontal–subcortical circuits predictsmore severe executive, but less severe memory and spatialdysfunction, in contrast to Alzheimer’s disease.

Jokinen and colleagues assessed the neuropsychologicalfunction (speed of mental processing, executive function,short-term memory, immediate recall, delayed recall, verbalintellectual functions, and visuospatial functions) of:

• Patients with SIVD (n=85; mean age 71.7 years, mean years of education 8.3).

• Younger, better educated, other stroke patients (n=238;mean age 69.8 years, mean years of education 9.8).

• Younger, neurologically healthy controls (n=38; meanage 67.4 years, mean years of education 9.4).

SIVD patients had more cortical and central atrophy, andmore medial temporal lobe atrophy than was seen incontrols; SIVD patients also had greater medial temporallobe atrophy and higher depression scores than other strokepatients. Rates of dementia did not differ between any ofthe three groups.

Overall, cognitive function in all domains was lower in theSIVD patients than in the controls, even after taking intoaccount age and education. SIVD patients had lower executivefunction and delayed memory recall compared with otherstroke patients, after considering age and education. Correctingfor depression scores did not affect the differences between theSIVD and other stroke patients; however, the delayed memoryrecall difference was accounted for by the difference in medialtemporal lobe atrophy between these groups.

Subcortical ischemic vascular disease is a subtype ofvascular cognitive impairment and has specifically definedstructural imaging findings (extensive cerebral white matterlesions and lacunar infarcts in deep grey and white matter).The results of this study indicate that this disease isassociated with worse depressive symptoms, greaterimpairments in executive function, and more delayedmemory than is seen in other stroke patients.

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SIVD is a relatively homogeneous subtype of vascularcognitive impairment with specifically defined structuralimaging findings. The results of this study indicate depressivesymptoms, impairments in executive function, and delayedmemory beyond that observed for the heterogeneous group ofgeneral stroke patients. These changes were observed as earlyas 3 months after the acute stroke.

Address for reprints: H Jokinen, Department of Neurology, HelsinkiUniversity Central Hospital, PO Box 302, FIN-00029 HUS, Helsinki,Finland. Email: [email protected]

Frontal white matter anisotropy and symptomseverity of late-life depression: a magneticresonance diffusion tensor imaging studyNobuhara K, Okugawa G, Sugimoto T et al.J Neurol Neurosurg Psychiatry 2006;77:120–2.

Structural and functional imaging studies have implicatedthe prefrontal cortex and anterior paralimbic circuit in thepathophysiology of major depressive disorder. Magneticresonance diffusion tensor imaging (DTI) measures themagnitude and directionality of tissue water movement,which is greatest along axonal tracts and least across andperpendicular to axonal tracts. Thus, DTI can provide anindex of the microstructural integrity of white matter tracts,and has been used to evaluate white matter tract integrity inschizophrenia and depression.

The present study enrolled 13 older adults (mean age62.8 years) with unipolar depression who were receivingantidepressants, and 13 age- and gender-matched controls.Nobuhara and colleagues examined diffusion-weightedimages in predetermined regions of interest:

• Bilaterally in the frontal white matter at 8 mm aboveanterior commisure–posterior commissure (AC–PC) plane,at the AC–PC plane, and at 8 mm below the AC–PC plane.

• Bilaterally in temporal, parietal, and occipital white matter.• The genu and splenium of the corpus callosum.

Fractional anisotropy (FA) is an index of water mobility ordiffusion anisotropy and thus white matter integrity, suchthat lower values suggest decreased white matter integrity.

FA values were lower in frontal and temporal regions indepressed subjects compared with healthy control subjects,but not in the parietal, occipital, or corpus callosal whitematter regions of interest. Depression severity, measured by Hamilton Depression Rating Scale scores, were inverselycorrelated with FA in the frontal cortical white matter 8 mm below the AC–PC plane, consistent with orbitofrontalcortex dysfunction (r=–0.58; p=0.04 uncorrected formultiple comparisons).

Despite the small sample size and exploratory nature ofthis study, these results are consistent with current hypothesesof anterior paralimbic – including orbitofrontal – circuitinvolvement in depression. Correlations with depressionseverity suggest state effects, but studies in euthymicpatients are needed to assess the longitudinal effects ofunipolar depression.

Address for reprints: K Nobuhara, 10–15 Fumizono-cho, Moriguchi City,570-8506, Japan. Email: [email protected]

Patients with depression in later life have decreasedfractional anisotropy in frontal and temporal white matter tracts, compared with matched controls. Thisfinding is consistent with reduced orbitofrontal whitematter tract integrity and increased pathology in late-life depression.

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The annual meeting of the Association of EuropeanPsychiatrists (AEP) was well attended, with approximately2700 participants from 62 countries present. The meetingconcentrated on treatment issues, which are the primaryfocus of this report.

Brain stimulationBrain stimulation is a promising area for the development of new treatments for depression. Malek Bajbouj (Charité-Univeritätsmedizin, Berlin, Germany) discussed vagus nervestimulation (VNS) as a therapy for treatment-resistantdepression (TRD). The efficacy of VNS is currently beingdebated. In an open study of 60 patients, only 15%remitted during the acute phase, with another 27%remitting after 1 year, and a further 22% after 2 years. Thisrelative lack of short-term efficacy was also demonstrated inanother trial, with no significant differences seen betweenthe treatment and control conditions. However, anobservational study did show better results in the long-term.Side-effects included hoarseness, cough, paresthesias, anddyspnea, although these disappeared over time. The efficacyof VNS appears to depend on the intensity and duration ofthe intervention, and Dr Bajbouj stressed that predictors forsuccessful treatment are necessary to improve efficacy.

Markus Kosel (University Hospital, Bonn, Germany)discussed the potential benefits of magnetic seizure therapy(MST). As with electroconvulsive therapy (ECT), MST aimsto generate seizures in the brain; however, as this is a non-invasive intervention, the procedure may have fewerside-effects than ECT. The application is similar, with therapythree times a week for 10–12 sessions. Dr Kosel discussed a case study of TRD and described a good response to MSTin this patient. However, the limited power of the MSTdevice posed a problem. As was found in ECT treatment,seizures are a prerequisite for the antidepressant effect, butnot every seizure improves depressive symptomatology.

A new technique was introduced by Robert Berman (NY State Psychiatric Institute, New York, NY, USA): focal

electrically administered seizure therapy (FEAST). FEAST isdesigned to have enhanced spatial targeting compared withECT, and therefore improved efficacy and decreasedcognitive side-effects. In an experiment performed onmonkeys, it was possible to induce focal seizures withoutunwanted motor effects.

Dr Kosel also discussed deep brain stimulation – wherean electrode is implanted in the nucleus accumbens of thebrain – as a therapy for TRD. Patients’ depression improvedduring the study-period and relapsed after the device wasswitched off for several weeks, providing proof of efficacyfor this therapy. There were no reported symptoms of maniaor other psychiatric syndromes. The nucleus accumbens waschosen as the site of electrode implantation because of itsrole in motivation and drive; indeed, an increase in both ofthese traits was found.

Pharmacological treatments for depressionOlder techniques were also reviewed alongside newdevelopments. Manfred Ackenheil (University of Munich,Munich, Germany) discussed how to choose the rightantidepressant treatment for the right patient. A meta-analysis by Michael Thase and colleagues (University ofPittsburgh Medical Center, Pittsburgh, PA, USA) found nodifferences between various antidepressant medications in thetreatment of depression with comorbid anxiety. Dr Ackenheilalso referred to agomelatine (a melatonine agonist) as apromising new antidepressant that has added efficacy insleep disturbances, and minimal side effects. Hans-JürgenMöller (University of Munich, Munich, Germany) delivered a similar lecture on new developments in antidepressantmedications, discussing the well-known underdiagnosis andundertreatment of depression, especially in primary care;however, this situation is better in specialized mental healthcare. A naturalistic German study of 686 depressedinpatients found that only 23% of patients showed noresponse and 54% achieved remission while receiving abiological treatment (mostly combined with psychotherapy).

14th Annual Meeting of the Associationof European Psychiatrists (AEP)

Nice, France, 4–8 March, 2006

Jan SpijkerDe Gelderse Roos, Mental Health Care, Arnhem, and Trimbos Institute, Utrecht, The Netherlands

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The success rate is remarkable for this population; however,in this study the mean duration of inpatient treatment was61 days, which is longer than usual. Dr Möller showed apreference for the antidepressants with a dual action, andindicated that venlafaxine and duloxetine are more efficaciousthan other antidepressants. He also referred to a Cochranemeta-analysis from Cipriani et al., where the results pointedto selective serotonin reuptake inhibitors (SSRIs) as the mostefficacious treatment for depressed outpatients [1].

Siegfried Kasper (University of Vienna, Vienna, Austria)and Peter Falkai (University of Saarland, Saarbrücke,Germany) opened a discussion of SSRIs and suicidality. Datafrom studies of children and adolescents have found a smallbut significant increase in suicidality after startingantidepressant treatment (see also Baldessarini et al. [2]);however, in adults there is limited evidence to support thisassociation. There is more reason to expect the opposite, i.e.that antidepressants prevent suicide. Recent meta-analyseshave shed some light on this matter. Fergusson et al. foundan association between suicidal behavior and SSRI treatment[3], in contrast with a review from Khan et al. [4]. Studyfindings showed that suicidality in depressed patients is at itspeak just before starting antidepressant treatment and notafter this event; however, antidepressants are still potentiallydangerous drugs and can have lethal effects.

Depression and physical illnessDepression and physical illness frequently co-occur in patients,and Paul Mackin (University of Newcastle, Newcastle, UK)performed a literature review on this subject, producing

>64 000 references. Dr Mackin then focused on cardiovasculardisease (CVD) and metabolic disease, and found (from 15 prospective studies) that an association between depressionand CVD was present in the majority of patients. Depressionpredicts for CVD and some studies have even found adose–response relation with coronary calcifications, carotidatheroscleroses, increased inflammatory processes, andreduced autonomic function. In a further 10 studies includedin the analysis, a strong association between depression andobesity was identified, especially in depressed adolescents.As a consequence of obesity, the risk for diabetes mellitusalso increased, as was determined by another 11 studies.Mechanisms of this association are thought to involve thehypothalamic–pituitary–adrenal axis, lifestyle, and the use of psychotropic drugs. Depression was also found toindependently increase the risk for metabolic disease. Thislecture made a very convincing argument that somaticillnesses in depressed patients should not be overlooked.

Enhancing treatment for depressive disorders is anenormously important goal, and this congress presentedsome interesting new possibilities while enriching ourknowledge of the existing ones.

References1. 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 GenPsychiatry 2006;63:246–8.

3. Fergusson D, Doucette S, Cranley Glass K et al. Association between suicide attempts and selective serotonin reuptake inhibitors: a systematic review of randomised clinicaltrials. BMJ 2005;330:396–403.

4. Khan A, Khan S, Kolts R et al. Suicide rates in clinical trials of SSRIs, other antidepressants,and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790–2.

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The American Psychiatric Association annual meeting is thelargest psychiatric conference in the world, bringing togetherleaders in this profession and providing an internationalforum for debate of the latest scientific advances and howto best integrate this knowledge to continually improvepatient care.

New augmentation strategies in depression for better outcomesJonathan Alpert (Massachusetts General Hospital, Boston,MA, USA) chaired the industry-sponsored symposiumentitled “New augmentation strategies in depression forbetter outcomes.” Polypharmacy, defined as two or moremedications to treat the same or a comorbid condition, is common. Despite the increased risk of adverse events,drug–drug interactions, medication errors, and patientnonadherence, rational polypharmacy is frequently requiredto address residual symptoms after initial treatment. Up to60–70% of patients have residual depressive symptomsafter initial treatment with an antidepressant. The basicfoundations of polypharmacy rational include:

• Targeting similar neurotransmitter mechanisms (e.g. fluoxetine plus buspirone).

• Targeting complementary neurotransmitter mechanisms(e.g. citalopram plus bupropion).

• Second medication addressing adverse effects of theprimary medication (e.g. paroxetine plus sildenafil)

• Medications treating comorbidities (e.g. sertraline plus zolpidem).

Lithium, liothyronine (T3), and bupropion augmentationof antidepressants have been validated by numerousrandomized clinical trials. There are >50 studies supporting a beneficial effect of lithium at plasma levels 0.4–0.6 mmol/L,but clinical use has been limited due to potential adversethyroid and renal effects and a low therapeutic index. T3 hasundergone >25 trials as augmentation therapy in major

depressive disorder (MDD). Bupropion is empiricallysupported and commonly used by clinicians to augmentother antidepressant medications. However, many patientsstill remain depressed after these validated combinations.

The STAR*D (Sequenced Treatment Alternatives toRelieve Depression) trial was conducted to compare differenttreatment strategies in treatment-resistant patients, andresults were reviewed at this meeting. STAR*D investigatedoutpatient treatment of acute major depression in primarycare and psychiatric settings, with the goal of identifying the most suitable “next choice” after incomplete responseto initial antidepressant treatment. Patients were first treated with citalopram for up to 12 weeks; nonremitterswere then randomized to a range of antidepressant switchor augmentation strategies. Only approximately 30% ofsubjects remitted with citalopram treatment alone. Switchingto another antidepressant caused remission in approximately20% of patients, while augmentation with bupropion-SR orbuspirone was efficacious in 30% of the initial nonremitters.A major limitation of the augmentation arm of STAR*D wasthe lack of placebo control group. Further novel strategieswere discussed at the meeting and are shown in Table 1.

Psychotherapies are likewise validated in combinationwith antidepressants for the treatment of patients withMDD, benefiting acute response and maintaining remission.Combined psychotherapy and medication is superior toeither intervention alone, based on studies involvingcognitive therapy in various forms (cognitive therapy,cognitive–behavioral therapy, well-being therapy, cognitive–behavioral analysis system of psychotherapy, mindfulness-based cognitive therapy) and interpersonal therapy. Overall,treatment of depression typically requires a combinedtherapy approach to attain the goal of remission.

Interrupting the cycle of vascular disease and depressionSteven Roose (New York State Psychiatric Institute, NewYork, NY, USA) chaired the industry-sponsored symposium

159th Annual Meeting of the AmericanPsychiatric Association (APA)

Toronto, ON, Canada, May 20–25, 2006

Po Wang and Alan SchatzbergDepartment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

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entitled “Interrupting the cycle of vascular disease anddepression”. This session covered:

• Potential mechanisms underlying the interactionbetween vascular disease and depression.

• Comorbidity and treatment considerations of vasculardisease and depression.

• The concept of vascular depression.• The relationship between depression and diabetes mellitus.

Cardiovascular disease and depression are among the topcauses of medical mortality and morbidity. The presence ofdepression is a well-established predictor of myocardicalinfarction (MI), cerebrovascular events, reduced survivalafter MI, and development of diabetes. Hypothalamus–pituitary–adrenocortical (HPA) axis hyperactivity might havea role in both depression and vascular disease, andhypercortisolemia can lead to insulin resistance and vascularreactivity. An elevated immune response (increased levels ofC-reactive protein and interleukin-6 [IL-6]) may also be acommon feature in both depression and cardiovasculardisease, and IL-6 could mediate insulin resistance. Finally,some antidepressants (e.g. paroxetine and nortriptyline)have been shown to decrease platelet “stickiness”, as wellas to affect central nervous system (CNS) targets, thereforeinfluencing both depression and vascular disease.

Myocardial infarction and depressionThe SADHART (Sertraline Antidepressant Heart AttackRandomized Trial) investigated post-MI depression by

randomizing 369 patients with depression during the post-MI period to treatment with either 50–200 mg sertraline orplacebo for 24 weeks. Sertraline was efficacious in patientswith a prior history of depression, but not in patients whodeveloped their first depressive episode after the MI.

Stroke and depressionDepression occurs in 10–27% of patients post-stroke.Depression predicts poorer rehabilitation, increased disability,and increased mortality following stroke, which may be relatedto biological (common cerebral deficits, e.g. executive orlanguage functions) and psychosocial mechanisms.Antidepressant treatment can benefit the outcome ofdepression and stroke; however, in a meta-analysis of sevenpharmacotherapy and two psychotherapy trials, clearefficacy was not demonstrated, although this may be due tothe high threshold of complete depression remissionrequired by the analysis. In some placebo-controlled trials,nortriptyline has shown an early and sustained response [1],while fluoxetine had a delayed response, in the treatment of post-stroke depression [2].

Diabetes and depressionDiabetes and depression show a bidirectional relationship:depression is 3–4 times more common in individuals withdiabetes than in the general population, and depressionoften precedes the onset of diabetes. Although thebiological links between depression and diabetes are stillbeing explored, the psychological link is clearer (poorertreatment adherence, weight management by diet and

Table 1. Novel antidepressant drug augmentation strategies.

Strategy Drug Notes

New Olanzapine Double-blind studies in MDDantipsychotic Risperidonemedications Ziprasidone

New Lamotrigine Lamotrigine has better efficacy data in bipolar depressionanticonvulsants Divalproex Divalproex may target agitation in MDD

Selective Amphetamines Used for anergia, amotivationdopamine Bromocriptine No double-blind trialsagonists 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 patientsDHEAHydrocortisone

Other Modafinil Modafinil 100–200 mg/day

DHEA: dehydroepiandrosterone; MDD: major depressive disorder.

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exercise, and quality of life). Interestingly, controlled clinicaltrials of antidepressants or cognitive behavioral therapy fordepressed patients with diabetes improved glycemic control [3].A recent placebo-controlled maintenance trial for individualswith diabetes whose depression responded to open-labelsertraline found that a good initial open-treatment responseand continued euthymic mood were associated with improvedlevels of glycosylated hemoglobin for >1 year [4].

Young Investigators’ Poster SessionA broad range of topics were covered in the YoungInvestigators’ Poster Session. A sampling of just a few of theposters is given below.

Cognitive and social functioning in recovery from depression: results from a population-based, 3-year follow-upAiraksinen and colleagues (Karolinska Institutet, Stockholm,Sweden) examined 76 individuals with a Diagnostic andStatistical Manual of Mental Disorders-IV (DSM-IV)diagnosis of MDD, identified from a population-basedsample. Patients were administered social-functioning andepisodic-memory scales at baseline and at 3-year follow-up.Social functioning was noted to improve when depressivesymptoms improved. Episodic-memory scores throughoutthe study were lower than expected from normative dataand irrespective of an improvement in depression. Thissuggests that cognitive dysfunction may persist for up to 3 years after an acute major depressive episode.

Modafinil augmentation for fatigue associated with fibromyalgiaChlebowski and colleagues (State University of New York,Syracuse, NY, USA) examined 98 consecutive rheumatologypatients with fibromyalgia who were given modafinil (meandose 162 mg/day). Fatigue improved by a mean of 28%,and modafinil was generally well tolerated.

Prevalence of metabolic syndrome in VA bipolar patientsCardenas and colleagues (University of California in LosAngeles, CA, USA) found that 49% of patients at the WestLos Angeles Veterans Affairs Hospital (CA, USA) presentingfor treatment of bipolar disorders had metabolic syndrome.This is approximately twice the rate of metabolic syndromeamong the general population.

Hippocampal volume in post-traumatic stressdisorder: a meta-analysisSood and colleagues (Maricopa Integrated Health System,Phoenix, AZ, USA) conducted a meta-analysis of the results

from 19 published studies analyzing hippocampal volumes insubjects with post-traumatic stress disorder (PTSD), traumawithout PTSD, and control subjects. Patients with PTSD hadsmaller bilateral hippocampal volumes compared withcontrol subjects. However, no differences were seen involume between individuals with PTSD and those withtrauma without PTSD, suggesting that trauma itself may beassociated with regional brain changes.

Advances in research: an Update for the Clinician SessionDavid Kupfer (University of Pittsburgh Medical Center,Pittsburgh, PA, USA) chaired the Advances in Research: anUpdate for the Clinician Session.

Floyd Bloom (Neurome, Inc., La Jolla, CA, USA) discussedthe fastest advancing areas of research in psychiatry andneuroscience: genomics, biological imaging, and computer-assisted data mining. The mouse genome and transgenic micecan provide a framework and research platform to helpunderstand the human CNS. Mouse strains can be createdthat experience high levels of anxiety and depression(represented by a range of strain-specific performances on theForced Swim Test), develop earlier Alzheimer’s-like amyloidplaques, or express or lack specific genes of interest (so called“gene knock outs” e.g. mice deficient in glucocorticoidreceptor expression in the forebrain).

Katherine Wisner (University of Pittsburgh, Pittsburgh, PA,USA) reviewed use of selective serotonin reuptake inhibitor(SSRI) antidepressants during pregnancy. Given thewidespread use of antidepressants, many children are bornafter intrauterine exposure to SSRIs. Early studies found noincrease in the risk of intrauterine fetal death or major physicalmalformations associated with first trimester exposure;however, a current focus of controversy is data suggestingthat fetal paroxetine exposure may be associated with cardiacmalformations. More recent studies have addressed latertrimester exposure and adverse reproductive outcomes,including fetal growth changes and behavioral teratogenicity(finding no difference in cognitive function, verbalcomprehension, expressive language, mood, arousability,activity, behavior problems, or temperament).

Chambers et al. found that late exposure to fluoxetine wasassociated with a lower birth weight than early or no exposure [5]. However, this study did not control for animprovement in depressive symptoms; therefore, mothersremaining on antidepressants during late pregnancy may havehad depression that required continued treatment. Dr Wisner suggested that neonatal syndrome, a conditioncharacterized by difficulty in feeding and sleeping, irritability, prolonged crying, tremors, and seizures, may berelated to either acute serotonin exposure (e.g. fluoxetine)

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or antidepressant withdrawal (e.g. paroxetine withanticholinergic effects). For mild symptoms, behavioralinterventions (small and frequent feeds, increased physicalcontact, and psycho-education for the mother) are advocated.Identifying the source of the symptoms (excessive serotoninexposure versus anticholinergic withdrawal) will guidepharmacotherapy choices for more severe symptoms.

SSRI antidepressant exposure (after the 20th week ofgestation), but not tricyclic antidepressant exposure, hasbeen suggested to increase the risk of persistent pulmonaryhypertension (PPH; or persistent fetal circulation). Out of 377women whose infants had PPH, 14 had been exposed toSSRIs after the 20th week of gestation, whereas in thecomparison group of 836 matched women, six had beenexposed to SSRIs after the 20th week of gestation [6]. SSRIexposure therefore increases the risk of PPH by as much assix-fold over the rare occurrence rate of PPH in the generalpopulation. Although the relative risk is great, the absoluterisk is low; however, the mortality rate of PPH is high.

Jeffrey Lieberman (Columbia University, New York, NY,USA) discussed the rationale and initial outcome measures of CATIE (Clinical Antipsychotic Trials in InterventionEffectiveness). CATIE was designed to address differences in efficacy among second generation antipsychotics(olanzapine, quetiapine, risperidone, ziprasidone) andperphenazine (representing first-generation antipsychoticmedications) in approximately 1500 patients withschizophrenia. In Phase I of the trial, patients were randomlyassigned to treatment. Patients who chose not to remain onthe first randomly assigned medication were given a secondrandomized drug, which included open clozapine treatment(Phase II). The primary hypothesis was that newantipsychotic medications would be more effective than theolder antipsychotic, perphenazine. The primary outcomemeasure was “all-cause discontinuation”. A total of 74% ofpatients switched from the first medication assigned.Olanzapine was statistically better than other medications inmaintaining patients in the randomization. Perphenazine wasas effective, and unexpectedly, its extrapyramidal adverseeffects were not more severe than, the second generationantipsychotics. In Phase II, inefficacious medication switcheswere randomized to open clozapine or an antipsychotic notused in Phase I. Clozapine was the most effective medicationin Phase II, while risperidone was best for patients who hadswitched for tolerability reasons. Olanzapine produced thegreatest increases in weight and plasma glucose and lipidlevels, while quetiapine’s adverse effects included elevatedplasma glucose and lipids. Risperidone caused elevatedplasma glucose and prolactin concentrations, but weight didnot increase appreciably and plasma lipid levels decreased.Ziprasidone use was associated with weight loss and

decreases in plasma lipid concentrations; no patient onziprasidone discontinued treatment due to weight gain or metabolic adverse effects. The anticipated superiority of the second-generation antipsychotics over olderantipsychotic medications was not demonstrated by this trial.Clozapine was reported as having superior efficacy afterinefficacy switches. Overall, switching to other treatmentswas common.

Therapeutic neuromodulation: methods and mechanisms This symposium consisted of four talks and a discussion thatfocused on new techniques of brain stimulation in depression.

Mark Demitrack (Neuronetics, Inc., Malvern, PA, USA)opened the symposium noting that most medication therapiesfor depression have been developed in “easy-to-treatdepression”, i.e. patients without a prior history of poortreatment response. Few of the currently approved therapieshave been studied in refractory patients. Given that STAR*Dfound only 30% of patients achieved remission after 12weeks of citalopram therapy, and an additional 25–30%remitted with an augmentation or switch strategy, new andmore effective therapies are needed for the large percentageof patients who do not achieve a full response. One approachhas been to use electroconvulsive therapy, which, althoughvery effective, has high relapse rates post-cessation.Additionally, follow-on maintenance drug therapy is lesseffective in patients who did not previously respond tomedication than in patients with a history of prior goodresponse. Along with the relatively low response rates toestablished therapies, treatment discontinuation due toadverse events is also common. Thus, better-toleratedtreatments need to be developed.

Philip Janicak (University of Illinois at Chicago, Chicago, IL,USA) reviewed data on vagus nerve stimulation (VNS). TheVNS Therapy System™, (Cyberonics, Inc., Houston, TX, USA) is currently the only implantable devise approved for thetreatment of major depression. Current US Food and DrugAdministration (FDA) approved indications are for treatment-resistant and recurrent depression. The device, which isimplanted in the side chest wall and has an electrode wrappedaround the vagus nerve, appears to stimulate a number of keybrain regions via afferents to the brain.

The pivotal study compared active with sham VNS in a totalof 220 patients. All subjects were chronically depressed (≥2years) or had ≥4 lifetime episodes of depression. The averageduration of the current depressive episode was 4 years. A thirdhad received electroconvulsive therapy in the current episode,and 50% in current or past episodes. Patients had also received 2–6 adequate trials of antidepressant treatment in the present episode.

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Treatment involved 2 weeks of stimulus adjustmentfollowed by 5 weeks of active versus sham treatment. All other medications were unchanged. Response wasdefined as a ≥50% reduction in the Hamilton Rating Scalefor Depression (HAM-D). A response rate of 15% was seenin the active group compared with 10% in the shamcondition (p=0.25).

Sham patients were then crossed over to active treatmentwhile treated patients continued to receive active therapy. By1 year, 30% of patients had responded to VNS treatment. A refractory group was subsequently followed for 1 year atthe same sites and under standard treatment conditions. A significantly lower response rate of 13% was seen in thiscomparison group. This comparison was part of the basis forthe approval of VNS treatment.

Side effects included voice alteration in approximately70% of patients and surgical complications occurred in <2%of cases. To date, approximately 1100 patients in the US havebeen implanted with the VNS treatment device for refractoryor recurrent depression.

Elliott Richelson (Mayo Clinic, Jacksonville, FL, USA)discussed recent studies of the biological basis of VNS fordepression treatment. A number of possible mechanismswere reviewed, including depolarization of key areas in thebrain and promotion of neurogenesis. Of particularimportance is that electrical stimulation may help reverseabnormalities in circuits involving the anterior cingulate,prefrontal cortex, and amygdala.

John Reardon (Hartford Hospital, Hartford, CT, USA)discussed rapid transmagnetic stimulation (r-TMS). There havebeen multiple small studies suggesting that 3–4 weeks oftherapy are more effective than 1–2 weeks, and havehighlighted the left prefrontal cortex as a useful site ofapplication. He then presented the first results from amulticenter study of 300 unipolar, nonpsychotic patients witha history of nonresponse to medication. Patients were aged18–70 years, and had received treatment 5 days/week for 6 weeks. Primary efficacy was improvement at 4 weeks andchange in the Montgomery-Asberg Depression Rating Scale(MADRS) was used to measure the primary outcome. Anaverage point decrease of 5.2 was seen in the active groupcompared with 3.4 in the sham condition (p=0.057).

Using a categorical definition of decrease in MADRS totalscore of ≥50%, a response rate of 18% was seen in the activegroup compared with 11% in the sham treatment group(statistically significant). Categorical and continuous outcomesobserved on the HAM-D were significantly better in the activetreatment group than in sham-treated patients. Crossing overfrom sham to active treatment in the next phase of the studyresulted in an overall 42% response rate. Side effects includedheadache (57%), application site pain (35%), and muscle

twitching (21%), but these were all manageable.Discontinuation rates due to side effects were 4–5% and3–4% in the active and sham conditions, respectively.

Alan Schatzberg (Stanford University School of Medicine,Stanford, CA, USA) served as the discussant, and emphasizedthe need to develop more effective and better-toleratedtreatments for depression since adverse events from currenttherapies are still highly problematic. Dr Schatzberg alsopresented recent data on alleles for the 5-HT2a receptor andpromoter variants for the 5-HT transporter, which may predictfor discontinuation of paroxetine treatment due to sideeffects. These genes are currently under a patent application(on which Dr Schatzberg is a named inventor).

Recent STAR*D data point to low response rates (15%) atPhase III (using nortriptyline or mirtazapine monotherapy, oraugmentation with T3 or lithium) of the clinical trials inpatients who did not respond to Phases I and II. Thus,response rates in the r-TMS and VNS trials do not seem as low when considered in the light of the recent STAR*D results. Background expected response rate must always be considered when assessing these refractory trials. The significant MADRS findings in the r-TMS study used categorical rather than continuous measure,suggesting efficacy in a specific type of patient. Greaterattention needs to be directed towards developing predictorsof response for the various fields of antidepressant treatment.Overall, data from the r-TMS multicenter trial suggest thetreatment showed efficacy.

Lastly, these new devices require further study tomaximize stimulus parameters, in particular VNS and thefrequency of therapy (3 times/week rather than 5 times/weekas for r-TMS).

DisclosuresDr Schatzberg is co-founder of Corcept Therapeutics and a Consultant

for Forest Laboratories, Eli Lilly, and Neuronetics, Inc. Dr Wang has

financial affliations with Abbott Laboratories, AstraZeneca, Bristol-Myers

Squibb, Elan Pharmceuticals, Eli Lilly, GlaxoSmithKline, Janssen

Pharmaceutica, Pfizer, Sanofi Aventis, Shire Laboratories, and Wyeth.

References1. Robinson RG, Schultz SK, Castillo C et al. Nortriptyline versus fluoxetine in the treatment

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-strokedepression – a three-month double-blind placebo-controlled study with an open-label long-term follow up. J Neurol 2003;250:347–51.

3. 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.

4. Lustman PJ, Clouse RE, Nix BD et al. Sertraline for prevention of depression recurrence in diabetes mellitus. Arch Gen Psychiatry 2006;63:521–9.

5. Chambers CD, Johnson KA, Dick LM et al. Birth outcomes in pregnant women takingfluoxetine. N Engl J Med 1996;335:1010–5.

6. Chambers CD, Hernandez-Diaz S, Van Marter LJ et al Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579–87.

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