VOLUME 3 NUMBER 1 2006 DEPRESSION: Mind and Body Advances in the Understanding and Treatment of Depression and its Physical Symptoms

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

Bipolar Disorders in Women Wendy Marsh and Mytilee Vemuri

Diagnosing and Treating Comorbid Mood Disorders and Obsessive-Compulsive Disorder Lorrin M Koran

Pharmacogenetics of Major Depression: From Research to Clinical Practice Alessandro Serretti and Paolo Olgiati

A Case Study of Refractory Major Depression with a Delayed Response to Vagus Nerve Stimulation John P O’Reardon, Kiran B Bapatla, and Umair Aktar

www.depressionmindbody.com

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the ACCME through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal opportunity university. Depression: Mind and Body is supported by an unrestricted educational grant from Cyberonics, Inc.

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

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

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

Editorial Policy Depression: Mind and Body is an independent journal published by Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editor-in-Chief, Editorial Advisory Board, and the Editors. Before publication, all material submitted to the journal is subjected to rigorous review by the Editor-in-Chief, Editorial Advisory Board, Editors, and/or independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and conflict of interest. Aims and Scope Depression: Mind and Body is designed to bring a critical analysis of the world literature on depression, written by clinicians, for clinicians, to an international, multidisciplinary audience. Our mission is to promote better understanding of the treatment of depression across the global healthcare system by providing an active forum for the discussion of clinical and healthcare issues. Leading Articles - These major review articles are chosen to reflect topical clinical and healthcare policy issues in depression. All contributions undergo a strict editorial review process. Clinical Reviews - The most important papers from the best of the international literature on depression are systematically selected by an internationally recognized panel of experts. The Editors then prepare concise and critical analyses of each paper, and, most importantly, place the findings into clinical context. Meeting Reports - Depression: Mind and Body also provides incisive reportage from the most important international congresses. Publisher’s Statement ©2006 Remedica Medical Education and Publishing. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission of the copyright owners. While every effort is made by the publishers and editorial board to see that no inaccurate or misleading data, opinions, or statements appear in this journal, they wish to make it clear that the material contained in the publication represents a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the board, publishers, and any supporting company accept no responsibility for the consequences of any such inaccurate or misleading data or statements. Neither do they endorse the content of the publication or the use of any drug or device in a way that lies outside its current licensed application in any territory. Depression: Mind and Body (ISSN 1479-5035) is published four times a year by Remedica Publishing Ltd and distributed by USA Mail Agent Pronto Mailers Association, 544 Lincoln Boulevard, Middlesex, NJ 08846. Subscription price $170 per year. Periodicals Postage Paid at Middlesex NJ. POSTMASTER: Please send address changes to Remedica Publishing Ltd, 544 Lincoln Boulevard, Middlesex NJ 08846-2439. Remedica Medical Education and Publishing Ltd., Commonwealth House, 1 New Oxford Street, London WC1A 1NU, UK. Telephone: +44 (0)20 7759 2999 Fax: +44 (0)20 7759 2951 Email: [email protected] Editorial Team: Emma Beagley, Scott Millar Editorial Director: Reghu Venkatesan Publishers: Ian Ackland-Snow, Simon Kirsch Design and Artwork: AS&K Skylight Creative Services ISSN 1479-5035 Dear Colleagues, Contents Welcome to the first issue of the third volume of Depression: Mind and Body. Leading Articles Bipolar Disorders in Women In this issue, the first two articles concentrate on disorders Wendy Marsh and Mytilee Vemuri 2 comorbid with depression, with the third article providing insights into the pharmacogenetics of depression treatment. Diagnosing and Treating Comorbid Wendy Marsh and Mytilee Vemuri (Stanford University Mood Disorders and Obsessive-Compulsive Disorder School of Medicine, Stanford, CA, USA) consider the Lorrin M Koran 12 epidemiology of bipolar disorders in women, describing gender differences in presentation, clinical course, and issues Pharmacogenetics of Major Depression: concerning the treatment of bipolar disorder during From Research to Clinical Practice pregnancy and lactation, among others. Alessandro Serretti and Paolo Olgiati 19

Lorrin Koran (Stanford University Medical Center, Stanford, Case Study CA, USA) elaborates on the association between A Case Study of Refractory Major Depression obsessive–compulsive disorder (OCD) and mood disorders, with a Delayed Response to Vagus Nerve Stimulation with concurrent major depression reported in as many as John P O’Reardon, Kiran B Bapatla, 39.5% of patients with OCD. The article discusses the and Umair Aktar 32 diagnosis of OCD, its comorbidity with different mood disorders, and treatment courses for patients. Clinical Reviews Epidemiology 35 In the third article of this issue, Alessandro Serretti and Paolo Olgiati (University of Bologna, Bologna, Italy) review the Clinical practice 40 pharmacogenetics of a patient’s response to treatment for major depression, highlighting the genes encoding metabolic Comorbidities 45 enzymes, monoamine transporters, and receptors that can Meeting Report influence response to antidepressant drug trials. The 19th European College of John O’Reardon, Kiran Bapatla, and Umair Aktar (University Neuropsychopharmacology (ECNP) Annual Congress of Pennsylvania, Philadelphia, PA, USA) provide a case study Paris, France, 16-20 September, 2006 46 of a patient suffering from treatment-resistant depression (TRD) who experiences a suggested delayed response to vagus nerve stimulation (VNS) therapy. This case underlines the importance of further long-term trials of VNS therapy in patients with TRD.

As always, the clinical reviews provides a concise read of the most important papers recently published in the world literature on depressive disorders. Following this, Dr Serretti details the highlights of the recent 19th European College of Neuropsychopharmacology Annual Congress from Paris, France.

We hope you enjoy this issue, and indeed this third volume, and welcome any comments or suggestions you may have concerning the journal to help us provide a useful and relevant review of current topics.

AF Schatzberg, MD Editor-in-Chief Bipolar Disorders in Women

Wendy Marsh and Mytilee Vemuri Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

Gender differences exist in bipolar disorder; notably, women experience a higher rate of depressive episodes than men. This article reviews the epidemiology and comorbidity of gender differences in bipolar disorder, and details the influence of the reproductive phases (e.g pregnancy and post partum) on the clinical course. Finally, clinically important issues in treating mood episodes during the different reproductive phases are discussed. Depression: Mind and Body 2006;3(1):2–11. LEADING ARTICLE

Presentation and epidemiology Suicide risk Bipolar I, II, and spectrum disorders In bipolar disorder, both genders share similar risks for life- The presentation of bipolar disorders in women shares threatening suicidal acts [13]. Suicide risk is greater in mixed similarities as well as noticeable differences compared with mania than in classic mania [19], and the risk is similar that in men. Bipolar I disorder affects 1–2% of the between men and women with mixed mania [15]. The population and exists in equal proportion among both increased risk of suicide in mixed mania is associated with genders [1,2]. In aggregate, bipolar I, bipolar II, and bipolar a higher number of depressive symptoms [20]. spectrum disorders have an estimated 3.9–6.4% lifetime prevalence [2,3]. However, within the bipolar spectrum, Comorbidities bipolar II occurs more often in women [4,5] and patients Approximately 65% of individuals with bipolar disorder have with bipolar II experience more depressive episodes than a comorbid psychiatric or physical condition [21]. Women those with bipolar I [6]. have higher rates of medical and psychiatric comorbidity Similar to the greater prevalence of unipolar depression in than men, both in the general population and in bipolar women of reproductive age than in men, depressive disorder populations. Women with bipolar disorder have a symptomatology is more prominent in women than in men greater prevalence of thyroid disease, obesity, bulimia, and with bipolar disorders. Most studies [4,7–9], though not all anxiety disorders than men [22,23]. [10,11], have found that women with bipolar disorder Substance use disorders are a significant comorbid experience more depressive episodes than men with this condition in bipolar disorder. While men with bipolar condition, with the depressive episodes being longer in duration disorder have greater rates of alcohol misuse than women and more likely to be treatment refractory [12]. Women with [24,25], women with bipolar disorder have four times the bipolar disorder present more often with depression and rate of alcohol misuse and seven times the rate of other remain misdiagnosed with unipolar depression longer than substance misuse than women from the community [11,26]. men [13]. Even within mood elevation episodes, women suffer more depressive symptoms than men and experience Reproductive phases and the clinical course a greater occurrence of dysphoric and mixed mania [14,15]. of bipolar disorder Menarche Rapid-cycling bipolar disorder The literature addressing the relationship of menarche and Women disproportionately experience rapid-cycling, the course of bipolar disorder is limited. One study of bipolar accounting for 58–92% (mean 71%) of patients diagnosed disorder in women found the mean age of onset to be with rapid cycling bipolar disorder [16,17]. The rapid-cycling 20 years and the mean age of menarche 13 years [27]. pattern is predominated by depressive episodes [18], Nonetheless, a high proportion (18%) of women with providing further evidence of the disproportionate amount bipolar disorder experienced their first affective episode of depression experienced by women. within 1 year of menarche [27].

Address for correspondence: Wendy Marsh, Stanford University School Menstrual cycle and hormonal contraception of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. Mood changes across the menstrual cycle are common, Email: [email protected] although the severity, timing, and type vary [8,28–31].

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Women with bipolar disorder have been reported to have an post partum period is twice as high as that for non-pregnant increased suicide rate, severity of suicidal intent, and rate of women [35]. For women with bipolar type I who have hospitalization during the premenstrual to menstrual phases discontinued lithium during pregnancy, the risk of a mood of the menstrual cycle [32]. Approximately two-thirds of recurrence is 70% in the first 3 months post partum [33]. In women with bipolar disorder report exacerbations, with a a retrospective study of women with bipolar I, II, or NOS, predominant risk for depression, during the menstrual cycle Freeman et al. reported that 67% of women, most not phase [29,30]. However, in a study of women with rapid- receiving treatment, developed a mood episode within cycling bipolar disorder, no significant association was found 1 month of delivery [27]. Additionally, women with bipolar between mood exacerbations and the menstrual cycle [28]. disorder have a 100-fold higher risk of developing a post Experts debate whether hormonal contraception has partum psychosis than women with no previous psychiatric either detrimental or beneficial effects on mood, and data illness [36]. are limited in support of either position. In a self-report of 33 women with bipolar disorder exposed to hormonal Lactation contraception, 52% indicated no mood effect, 12% The current literature contains no information on whether indicated mood improvement, 21% indicated mood breastfeeding influences mood in women with bipolar disorder. worsening, and 15% could not recall any mood effect [27]. A longitudinal study found a modest decrease in Peri- and post-menopause depressive burden in those taking hormonal contraceptives While data are scarce in bipolar disorder, prospective compared with those who were not [30]. evidence indicates that the menopausal transition in women without bipolar disorder is a period of susceptibility to Pregnancy depression [37]. Women with bipolar disorder have reported Illness history and severity are thought to be predictive of increased emotional disturbances and increased cycling bipolar course during pregnancy, and depressive or during the perimenopause [29,38]. In another study, 55% of dysphoric-mixed symptoms are more common than manic post-menopausal women with bipolar disorder reported symptoms during this period [33]. However, pregnant perimenopausal worsening of mood episodes, and all 55% women with bipolar disorder are either frequently under- experienced increased depressive symptoms during diagnosed or do not receive a diagnosis until years after perimenopause [27]. Longitudinal analysis found a high rate pregnancy [27]. Diagnosis during pregnancy may be subject of depression (68%) over an average 16.8 months in to a complicated symptom overlap of depression and perimenopausal age women treated for bipolar disorder pregnancy, such as fatigue and sleep disturbance. [39]. Worsening of depression may not be alleviated in the The majority of studies suggest that pregnancy is not a post-menopausal years [29]. time of increased mood stability. Women with bipolar I disorder who discontinued lithium and were followed Treatment considerations through pregnancy had similarly high rates of mood Menarche recurrence as their non-pregnant matched controls (52% vs. The treatment of bipolar disorder during the time of 58%) [33]. Rates of recurrence were much lower for both menarche should follow the standard of care for pregnant and non-pregnant groups treated with lithium. adolescents. No literature currently exists regarding unique Freeman et al. found similar rates of mood exacerbations in treatment of bipolar disorder during menarche. pregnant women with bipolar I, II, and not otherwise specified (NOS) disorders as those in non-pregnant women Menstrual cycle with bipolar disorder [27]. In contrast, Grof et al. reported Lithium that untreated women with bipolar I disorder had fewer Women of reproductive age appear to be at an increased mood episodes during pregnancy than during pre-pregnancy risk of lithium-associated hypothyroidism, although the or post partum [34]. Any protective effects of pregnancy are effects on the menstrual cycle are less clear. The prevalence likely to be limited, particularly if treatment is discontinued. of hypothyroidism in women undergoing lithium treatment was reported as being 14% vs. 5.5% in men [40]. Post partum The post partum period is a time of high risk for women Antiepileptic agents with bipolar disorder, particularly in those who discontinue Valproate has been implicated in the development of treatment during pregnancy. In women with bipolar I polycystic ovarian syndrome (PCOS), which is characterized disorder, the risk of having a mood episode recurrence in the by menstrual irregularities and hyperandrogenism. Women

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 3 WENDY MARSH AND MYTILEE VEMURI

with PCOS experience hirsutism, acne, and anovulation with Risk of teratogenicity is highest during the first an endocrine profile of elevated testosterone and luteinizing trimester, when organ genesis and potential teratogenicity hormone and low to normal follicle stimulating hormone. leading to major malformations occurs. Some experts Obesity and insulin resistance are common. recommend avoiding medication altogether, if clinically An association between high rates of PCOS and valproate feasible [52]. Others recommend gradual taper of use has been found in women treated for epilepsy [41–43], medication prior to pregnancy for mild to moderate illness, but the data in women treated with valproate for bipolar and continuation for severe illness [53]. Reintroduction of disorder are limited and currently yield mixed results. In medication during the second or third trimesters, when bipolar disorder, valproate is associated with more menstrual teratogenic risk is lowest, may be prudent to prevent abnormalities than lithium and other mood stabilizers mood episodes in pregnancy or post partum. Alternatively, [44,45]; however, a higher prevalence of PCOS in bipolar re-introduction of medication could be postponed until women treated with valproate has not been found [46]. the re-emergence of symptoms. Hence, risk–benefit The other antiepileptic mood stabilizers, including analyses involving consultation with the patient are crucial lamotrigine, carbamazepine, and oxcarbazepine, are less to determine the value each woman places on the risks likely to cause hyperandrogenism than valproate [47,48]. of fetal exposure to medication versus the risks of a potential mood episode. General guidelines proposed by Antipsychotics experts include [52,53]: First-generation antipsychotics and risperidone are associated with hyperprolactinemia in women with bipolar • Prenatal counseling allowing for adequate education disorder [49]. The clinical manifestations of increased about possible risks of treatment versus risks of prolactin are galactorrhea, irregular menses, infertility, and foregoing treatment. sexual dysfunction. Prolactin levels should therefore be • Monotherapy if possible, or alternatively streamlining the monitored [50]. To date, there are no published data medication regimen. regarding second-generation antipsychotics and the • Use of the minimum effective dose. menstrual cycle. • Frequent follow-up, and separate treatment plans for pregnancy and post partum (differing periods of risk). Oral contraceptives • Evaluating the need for post partum prophylaxis. In women with clear premenstrual worsening of mood • Sleep regulation and social support, particularly during episodes, oral contraceptives were helpful in one study [51]. the post partum period. However, commonly used hormonal contraceptives of estrogen and progesterone reduce lamotrigine plasma levels Figure 1 shows a proposed algorithm on the treatment by a mean of 49%; therefore, monitoring lamotrigine serum decision-making process for bipolar illness during pregnancy levels may be worthwhile [52]. Additionally, carbamazepine [56]. Mood stabilizers confer specific cautions and guidelines and topiramate induce hepatic cytochrome P450 activity in pregnancy. These are described below and summarized and increase metabolism of hormonal contraceptives. in Table 1.

Pregnancy Lithium Treatment during pregnancy requires a risk–benefit analysis The overall rate of major malformations in lithium-exposed for both the mother and the fetus. Many mood stabilizers fetuses is estimated at 4–12% compared with 2–4% in have teratogenic potential and should be used with caution unexposed fetuses [57]. Specifically, the risk of Ebstein’s during pregnancy. Such concerns may lead clinicians to anomaly, characterized by the downward displacement of recommend against pregnancy altogether [53], or lead to the tricuspid valve into the right ventricle and right under-treatment, which itself poses risks to the fetus and ventricular hypoplasia, is elevated in lithium-exposed mother. Depression during pregnancy is associated with low infants [35,58]. While the rate of Ebstein’s anomaly in birth weight, preterm delivery, and low Apgar scores [33,54], lithium-exposed infants is 20–40-fold higher than in the as well as high-risk health behaviors, such as substance general population (1:2000 vs. 1:20 000–1:40 000) [59], the misuse or decreased prenatal care [55]. Adverse events can absolute risk is believed to be low. also result from untreated mania if a pregnant patient Other possible effects of lithium exposure to the fetus engages in impulsive, high-risk behavior [56]. Furthermore, include thyroid difficulties, nephrogenic diabetes insipidus, under-treatment during pregnancy may lead to a need for transient neurodevelopmental deficits, premature delivery, higher doses of medication should a relapse occur [33]. macrosomia, hypotonia, and respiratory difficulties [60].

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Figure 1. Suggested approach to the bipolar patient who wishes to conceive or who is pregnant.

Pregravid?

Yes No

• Discuss planned conception Already pregnant? • Review risks associated with conceiving on medication • Discuss risk for relapse off medication Yes • Discuss alternatives to current medication, including psychotherapies, less teratogenic psychotropics, and ECT 1st trimester?

No

Wanting to conceive? 2nd and 3rd trimester?

Yes No Yes Yes

• Consider tapering off Continue medication until • Discuss specific • Continue medications medication if prior closer to decision to medication and its risk if patient is taking them illness was of mild– conceive for teratogenicity and mood is stable moderate severity • Consider switching to a • Discuss risk for and without multiple relatively safer alternative post partum relapse hospitalizations (e.g. from valproate to • To decrease risk for • If patient conceives, lithium) if no history of post partum relapse, continue off medication treatment nonresponse discuss restarting until 2nd trimester or to the safer alternative medications at end of throughout pregnancy • Assess current mood 3rd trimester if mood is if mood is stable and length of wellness, stable and patient is not • If relapse occurs before as well as severity on medication patient conceives or in of prior illness • Restart medications if 1st trimester, restart • Discuss increased mood is unstable and medication trial, choosing potential for relapse with patient is not already least teratogenic option adrupt discontinuation on medications • Continue medication of a mood stabilizer • Discuss lactation and through attempts at • Consider continuing medication use conception if prior medication in 1st course was characterized trimester if prior course by multiple was characterized by hospitalizations or multiple admissions, marked morbidity impaired judgment, or suicidal ideation

ECT: electroconvulsive therapy. Reprinted with permission from [56].

Resolution of such side effects has been observed in clearance increase during pregnancy and rapidly shift after childhood, suggesting relative long-term safety of lithium in delivery, lithium levels should be monitored and doses adjusted comparison with other mood stabilizers [58]. frequently [62]. Higher lithium concentrations during delivery Treatment with lithium during pregnancy requires careful have been associated with more perinatal complications. monitoring as lithium equilibrates completely across the Decreased maternal doses prior to delivery may mitigate such placenta [61]. Divided daily doses are recommended in order complications [61]. In addition, diuretics should be avoided in to maintain stable serum levels. As plasma volume and renal pregnancy due to both their potential to cause sodium

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 5 WENDY MARSH AND MYTILEE VEMURI 200 mg/day ≤ steady levels [104] Vitamin K, 10–20 mg/day in last month Vitamin and intramuscular of pregnancy supplementation for neonate [112,113] Consider folate supplementation Fetal echocardiography week 16–18 [64] Fetal echocardiography Fetal ultrasound and echocardiography in weeks 16–18 [113] 3–5 mg/day [113] Perinatal complications associated with highmaternal lithium levels [104] during pregnancy at delivery [61] Suspend dose 24–48 h prior to delivery or at onset of labor [61] Adequate hydration, avoid diuretics with medication [59] hypotonicity [101,102] suspected [35,75,108] Hypoglycemia [110] 3–5 mg/day [113] aly comparisons 0.5–1.0%, 20–40 times the rate in general population [64] [103] Hypothyroidism diabetes Nephrogenic monitoring of lithium levels [104] Frequent inspidus [101,102] dose during increasing May require clearance renal due to increased pregnancy 2.8–11% [59,100] anom Rate of Ebstein’s delivery than at and distress/cyanosis Divided daily doses (3–4) to maintain and increased dose [65] and increased 2.2–8.2% [65,72,74]Fetal anticonvulsant neural tube syndrome, defects, including spina delay [75]bifida, craniofacial defects,fingernail hypoplasia [75] weight [76]than other antiepileptic hyperbilirubinemia, head Decreased circumference with [114] resolved discontinuation of K, 10–20 mg/day in last month Vitamin [115,116] breastfeeding supplementation for neonate [112,113] and intramuscular of pregnancy Consider folate supplementation 3–5 mg/day [35,113] drugs [57] “Fetal anticonvulsant [107] syndrome” Major malformation rate with polytherapy increases 6–20.3% [65,67,74] bifida spina of Rate 1–6% [105] Neural tube defects Mental 5-9% [105,106] retardation [35,108] retardation suspected symptoms [106] Withdrawal Liver toxicity [109] [112] or more) Divided daily doses (three Consider folate supplementation Low fibrinogen levels [111] AFP at 14–16 weeks [113] 2.9–3.2% approximately Maintain doses [65,78] with monotherapy Cleft lip/palate in 8.9 per [80] 1000 exposures polytherapy with valproate Avoid category*D Rates of major malformation Not reported Higher weight “Floppy baby”: respiratory teratogenicity Minimum therapeutic dose, monotherapy complications associated use in pregnancy D Rate of major malformation, Developmental Lower birthC Hepatic toxicity and less teratogenic In theory, Minimum therapeutic dose, monotherapy Unknown Unknown Unknown Minimum therapeutic dose, monotherapy D Rates of major malformations, Lower IQ [71] Growth Heart rate decelerations [108] Minimum therapeutic dose, monotherapy C Rates of major malformation Unknown Minimum therapeutic dose General risks/guidelines for use of mood stability in pregnancy. Table 1. Table Medication FDA riskLithium Organ dysgenesis Neurobehavioral Growth effects Neonatal complications Recommendations and guidelines for Carbamazepine Oxcarbazepine Valproate Lamotrigine

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depletion [63] and their paradoxical antidiuretic effects when co-administered with lithium [58]. Fetal ultrasound and echocardiography are recommended at 16–18 weeks gestation to assess for cardiac malformations [64].

Antiepileptic drugs Information about the use of antiepileptic drugs (AEDs) in pregnancy largely comes from epilepsy registries. Women with epilepsy are known to experience a fetal major malformation rate slightly above that of the general population. However, there is limited evidence available to guide treatment in women with bipolar disorder. limbs if exposed in first trimester [118] Valproate Valproate is a known human teratogen. The overall rates of serious adverse outcomes, including major malformations associated with in utero exposure to valproate monotherapy, are estimated from various international pregnancy registries as being between 6.2–20.3% [65–68]. Numerous studies have demonstrated a dose-dependent effect of valproate exposure in utero with serious adverse neonatal outcomes, cannot be ruled out; Category D: positive evidence of risk; X: contraindicated with doses ≥800–1500 mg/day implicated [69]. Valproate confers a risk of neural tube defects, specifically spina bifida, the prevalence of which is estimated at 1–6% [70]. Children exposed to valproate in utero have demonstrated lower verbal IQ scores compared with children exposed to other AEDs or not exposed to medications [71]. Valproate has also been implicated in intrauterine growth retardation, heart deceleration, irritability, and abnormal tone [35]. Vitamin K is necessary for the development of clotting factors and mid-facial development. Valproate may cause fetal vitamin K deficiency and maternal supplementation in the last month of pregnancy and neonatal treatment with vitamin K is recommended by most experts; however, strong evidence is lacking in support of this practice [72]. Polytherapy with valproate is associated with higher rates of malformations than any AED in monotherapy (8.8% with carbamazepine and 9.6% with lamotrigine) [65]. Since valproate has folate antagonistic properties, folate supplementation is recommended, although currently no evidence demonstrates that this strategy is protective. second-generationantipsychotic risk– no greater of malformation include macrosomia, Possible sequelae of GDM in children syndrome, distress hypoglycemia, jaundice, respiratory polycythemia, and hypocalcemia [117] rates of malformationthan the general population [84,118] Possible risk for limb [118] birth than in non-exposed groups Higher rates of preterm malformations [118] Consider ultrasound with emphasis on Carbamazepine The rate of malformation associated with carbamazepine exposure is estimated at 2.2–8.2% [66,74], and is generally

BC Limited data available forCCCC above that of theC of clozapine- or olanzapine-exposed pregnancies Case reports general population in GDM [82,83] resulted reported. [81,82] Minimum therapeutic dose Similar or slightly higher Unknown Lower median birthweight than in non-exposed groupsthought Minimum therapeutic dose to Monitor for GDM be lower than that with valproate [74]. Craniofacial defects, developmental delay, and reductions in birthweight have been found in offspring exposed to carbamazepine in utero [75,76]. Maternal risks from carbamazepine (agranulocytosis, hepatic failure, and

Continued from overleaf. Clozapine Olanzapine Risperidone Quetiapine Aripiprazole Ziprasidone First-generation antipsychotics (e.g. haloperidol) studies show no risk; Category B: evidence of risk in humans; C: *FDA risk categories: Category A: controlled in pregnancy; [35]. FDA: US Food and Drugs Administration; GDM: gestational diabetes mellitus. Adapted from Stevens–Johnson syndrome) are highest in the first 8 weeks

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of therapy; therefore, initiating treatment after conception is which is consistent with the malformation rates of the problematic [77]. As noted above, the teratogenic risk general population [74,84]. increases with concomitant exposure to valproate [65]. The metabolic side effects of antipsychotics are of growing Like valproate, carbamazepine may cause fetal vitamin K concern. While case reports have described the occurrence of deficiency, and maternal supplementation and neonatal gestational diabetes and obesity in pregnant women treated treatment are recommended (see valproate) [35]. with olanzapine and clozapine [82,83], larger studies have not described an increased incidence of gestational diabetes Oxcarbazepine in treated versus untreated populations [81]. In theory, oxcarbazepine may be less teratogenic than the other AEDs as it has no epoxide metabolites; however, there First-generation antipsychotics are no data confirming this. Like valproate and carbamazepine, Older antipsychotics, particularly chlorpromazine, have oxcarbazepine can also interfere with vitamin K metabolism significant data regarding use during pregnancy due to their and supplementation is recommended. role in treating hyperemesis gravidarum, nausea, and psychosis in pregnant women. Studies suggest equal to Lamotrigine slightly higher rates of malformations among exposed Lamotrigine exposure is likely to confer some risk of offspring [84]. Higher rates of anomalies in chlorpromazine- teratogenicity, but less than other known mood stabilizing exposed pregnancies may be influenced by the underlying AEDs. Monotherapy rates of malformation were first illness, since rates of malformation in women with psychosis demonstrated as negligible [67], but later were reported as are also elevated above the general population [35]. Other ranging 2.9–3.2% [78]. However, recent data indicate a high neonatal side effects are consistent with the extrapyramidal rate of cleft palate and cleft lip in children exposed to side effects of the medications, including tongue-thrusting, lamotrigine in utero. Preliminary information from the North tremor, and hypertonicity [85]. American Antiepileptic Drug Pregnancy Registry suggests a prevalence rate of oral cleft cases of 8.9 per 1000, which is Omega-3 fatty acids higher than oral cleft reported rates of 0.5–2.14 per 1000 Minimizing the use of medications during pregnancy has in pregnant women not taking lamotrigine [79]. Additionally, generated interest in non-medication therapeutics and genito-urinary and gastrointestinal malformations have been supplements, such as omega-3 fatty acids. While a few small associated with lamotrigine exposure [65]. studies of omega-3 fatty acids appear to show promise for use Greater rates of malformation have been reported in treating depression, the data are less clear for bipolar with doses >200 mg/day [65]. Malformation rates with disorder and the risk for mood elevation [86]. lamotrigine polytherapy are higher, and estimated at 9.6% when co-administered with valproate [65]. Therefore, Electroconvulsive therapy minimizing doses to <200 mg/day is recommended, although Electroconvulsive therapy (ECT) has relatively few side some women may require higher doses of lamotrigine later effects for pregnant patients. The risks are generally in pregnancy. Concentration-to-dose ratios have been shown associated with anesthetic, intubation, and medications used to decrease in the second and third trimesters, possibly during the procedure. For severe cases of mood episodes due to increased renal clearance of the medication [80]. during pregnancy, the risks of ECT may be fewer than those associated with pharmacological management or untreated Second-generation antipsychotics illness [35]. Limited information exists to guide the safe prescribing of atypical antipsychotics in pregnancy. In the largest and only Psychotherapy prospective comparison study performed to date, McKenna Psychotherapy can provide numerous benefits to the pregnant et al. compared patients exposed to atypical antipsychotics patient, including improvement in coping strategies, assistance (n=151) with an age-matched control group [81]. The in medication compliance, and social support. However, there rates of major malformations were comparable in both are no studies describing the role or efficacy of psychotherapy groups (0.9% vs. 1.5%), as were the rates of reported in pregnant women with bipolar disorder [52]. complications during labor and neonatal complications. The majority of published cases of atypical antipsychotic Post partum use during pregnancy concern olanzapine. Data from Treatment in the post partum period requires a shift in the Eli Lilly (Indianapolis, IN, USA) case registry indicate risk–benefit analyses. Risks of in utero exposure are a major malformation rate of one in 96 exposed cases, exchanged for risks of exposure via lactation if a woman

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chooses to breastfeed. Moreover, there is an increased risk Table 2. Mood-stabilizing medication safety ratings of a severe mood episode in the post partum period that in lactation. calls for aggressive relapse prevention and treatment. Medication Hale lactation AAP recommendation [93] risk category [99] Medication prophylaxis Lithium L4 Significant adverse effects, Adding lithium in the post partum period has led to a use with caution decrease in relapse rates from 50% to 10% [87,88]. Adding valproate in the post partum period has not shown similar Valproate L2 Usually compatible with breastfeeding effectiveness in preventing relapses [89]. A small study demonstrates some promise for the use of olanzapine in Carbamazepine L2 Usually compatible with breastfeeding post partum prophylaxis for bipolar disorder [90], but further investigation into this area is needed. Oxcarbazepine L3 Not reviewed Lamictal L3 Unknown effects, Hormonal interventions may be of concern Rapid decreases in estrogen and progesterone after delivery Olanzapine L2 Not reviewed have been implicated as contributors in post partum mood Quetiapine L4 Not reviewed episodes. Hormone treatments in the post partum period have been proposed, but further investigation is required to Ziprasidone L4 Not reviewed determine their efficacy. Aripiprazole L3 Not reviewed Risperidone L3 Not reviewed Psychosocial interventions Haloperidol L2 Unknown effects, Sleep regulation for the mother should be emphasized as may be of concern irregular sleep may precipitate a mood episode [91].

Furthermore, sleep dysregulation in fathers in the post AAP: American Academy of Pediatrics; L2: safer; L3: moderately safe; partum period is also associated with mood relapses [92]. L4: possibly hazardous. Many new mothers report benefit from additional home support and childcare in the first few months. A woman Lithium may consider foregoing breastfeeding in order to minimize Lithium should be avoided, if feasible, in breastfeeding sleep disruption and stress, as well as to facilitate mothers. It is excreted in breast milk in a higher proportion medicated treatment. (10–50%) than most other psychotropic medications [84,86], and has been reported in infant electrocardiogram Lactation changes, cyanosis, lethargy, murmur, and hypotonia [96]. The American Academy of Pediatrics (AAP) encourages breastfeeding because of its immunological benefits. The AEDs AAP Committee on Drugs has published breastfeeding Valproate and carbamazepine are tolerated by the infant guidelines; however, data on medications commonly used and are considered by the AAP to be compatible with for bipolar disorder are limited [93]. For psychotropic breastfeeding [93]. However, both agents have been medication, evidence is often drawn from case studies and associated with hepatic dysfunction, therefore, checking liver lacks long-term follow-up [94]. enzymes, bilirubin, and white blood cell count is advisable [97]. Nonetheless, it is known that medication passage is Lamotrigine, although comparatively safe during pregnancy, generally higher through the placenta during pregnancy has relatively high infant serum levels in breastfeeding than through the breast milk. While no psychotropic drugs (25–30% of the mother’s), and data on the adverse effects are determined to be absolutely safe for the breastfeeding are sparse [94]. infant, with few exceptions the amount of central nervous system drug passed from mother to infant via breast Antipsychotics milk averages <10% [95]. Concern should be heightened Data are similarly sparse for second-generation antipsychotics for premature infants, those with metabolic disorders, or [94]. It appears that combining antipsychotic medications, as those with inherited disturbances. Breastfeeding does not noted with chlorpromazine or haloperidol, may increase the prevent conception and birth control options should be likelihood of adverse effects, including declining scores on discussed. Lactation safety ratings of various drugs are developmental testing [97]. Clozapine should probably be presented in Table 2. avoided because of the risk of agranulocytosis [94].

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 9 WENDY MARSH AND MYTILEE VEMURI

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DEPRESSION: MIND AND BODY Vol 3 No 1 2006 11 LEADING ARTICLE Stanford, CA94305-5721,USA.Email:[email protected] of Psychiatry, OCDClinic,Room2363,401QuarryRoad, Room2363, Address forcorrespondence: LorrinMKoran,Emeritus Professor highlighted andthearticleconcludeswithseveralchallengesforfuture. patient failstorespondadequatelytreatmentarediscussed.Theusefulnessofprovidingeducationalmaterialsfor patients considered whenchoosingtheinitialtreatmentcourseforapatient,whichmedicationstouse,andnextsteps totakeifa of theapproachestoconsiderwhenoneorbothconditionsfailadequatelyrespondtherapy. Factorsthatshouldbe treatment approachesforpatientswithOCDwhopresentdifferent co-occurringmooddisorders,followedbyadescription and mooddisordersinpatientgeneralpopulationsamplesarealsoreviewed.Finally, the articlediscussesinitial of OCDanditssubtypes,includingseveralthatmaybeindicatorsfortreatmentresponse.Studiesthecomorbidity ofOCD ascertainment bias,ashighratesofcomorbidityarealsofoundinepidemiologicalsamples.Thisarticledescribesthe diagnosi common inpatientswithmooddisordersthanthegeneralpopulation.Thisassociationisnotmerelyareflectionof dysthymia andbipolardisorderhavebeenreportedtobeashigh20%21.5%,respectively. Conversely, OCD ismore Concurrent majordepressionhasbeenreportedinasmany39.5%ofpatientswithOCDandlifetimeprevalencerates The associationbetweenobsessive-compulsivedisorder(OCD)andmooddisordershasbeenrecognizedforoveracentury. Department ofPsychiatryandBehavioralSciences,Stanford UniversityMedicalCenter, Stanford, CA,USA Lorrin MKoran Compulsive Disorder Mood Disorders andObsessive- Diagnosing andTreating Comorbid both conditions. treatment ofpatientsunfortunateenoughtosuffer from disorders inpatientswithOCDand diagnosis ofOCDanditssubtypes,theprevalence ofmood close attentionofclinicians.Thisarticlewillreview the and mooddisorders iscommonenoughtowarrantthe OCD istherarer disorder. However, theassociationofOCD with mooddisorders havecomorbidOCD,inpartbecause those suffering from OCD.Asmaller proportion ofthose suffered from obsessionsandcompulsions[2]. Bénédict AugustinMorel describedbipolarpatientswhoalso disorder begantoberecognized, theFrench psychiatrist “religious melancholy.” Inthe19thcentury, whenbipolar topic, heincludedcasesofOCDamongthosesuffering from upon ancientandmedievalwritingssomehowrelated tohis Anatomy ofMelancholy[1],compilingandcommenting published hiscomic,cathartic,encyclopedictome,The 1621, whenRobertBurton,anOxford collegedon, (OCD) andmooddisorders haslongbeenrecognized. In An associationbetweenobsessive-compulsivedisorder 12 Today, mooddisorders are knowntobecommonin vice versa D EPRESSION , andthe : M N AND IND B “compulsions” ofpathological gamblingorcompulsive by rulesorproper procedures. Incontrasttothe termed rituals–are usuallyrepetitive, excessive,andguided reviewing of listsorconversations.Compulsions–also compulsions includecompulsive counting,praying,and anxiety ordistress brought onbyobsessions.Mental thought, avertafeared event,ordiminishtheassociated patient feelsdriventocarryoutinorder toundoadangerous negative eventsoranticipatedfailures. obsessions anddepressive ruminationsmayconcernpossible self-criticism, failures, guilt,orpessimism;however, both usually experiencedasego-dystonic,anddonotcenter on uncertainty. Unlikedepressive ruminations,obsessionsare distress. Theyare commonlyassociatedwithdoubtingor thoughts, impulses,orimagesthatcausemarkedanxiety describes obsessionsasintrusive,persistent,unwanted as predominantly troubled bycompulsions[4].DSM-IV-TR predominantly affected byobsessions,andaboutone-fifth by obsessionsandcompulsions,alittlelessthanone-third as clinicians ratedabouthalfofthepatientsasequallytroubled and compulsions(Table 1)[3].IntheDSM-IVfieldtrial, markedly distressing, orsignificantlyimpairingobsessions OCD ischaracterizedbythepresence oftime-consuming, The diagnosisofOCDanditssubtypes ODY Compulsions are mentalorphysicalactionsthatthe Vol 3No12006 Depression: MindBody 2006; 3 (1):12–8. is s DIAGNOSING AND TREATING COMORBID MOOD DISORDERS AND OCD

Table 1. DSM-IV diagnostic criteria for 300.3 buying disorder [5], they are never pleasurable; they merely obsessive–compulsive disorder. reduce anxiety. Given the differences between the treatments A. Either obsessions or compulsions: that are effective, the results of brain imaging studies, as well as the absence of high rates of co-occurrence [6], a close Obsessions as defined by: biological relationship between pleasure-driven impulse • Recurrent and persistent thoughts, impulses, or images that are experienced, at some time during the disturbance, control disorders and OCD is unlikely. as intrusive and inappropriate and that cause marked Although their manifestations are richly particularized anxiety or distress by each patient, the morbid themes of obsessions and • The thoughts, impulses, or images are not simply compulsions are few: aggression, harm avoidance, excessive worries about real-life problems contamination, distasteful sexual ideas, religious or moral • The person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other concerns, hoarding, need for symmetry or order, need thought or action to know, and fear of illness. The patient often exhibits • The person recognizes that the obsessional thoughts, a proclivity to inflate estimates of danger, assume impulses, or images are a product of his or her own mind unrealistic degrees of responsibility for feared but (not imposed from without as in thought insertion) extremely unlikely events, and achieve perfection, a “just Compulsions as defined by: right” feeling, or certainty [5]. • Repetitive behaviors (e.g. hand washing, ordering, To screen for OCD a clinician might ask questions such checking) or mental acts (e.g. praying, counting, repeating words silently) that the person feels driven to as: Do you clean or wash a lot? Do you have to check things perform in response to an obsession, or according to over and over? Do you have unpleasant thoughts that you rules that must be applied rigidly can’t get rid of? Do you have trouble discarding things? Do • The behaviors or mental acts are aimed at preventing you have troubling thoughts about sexual or religious or reducing distress or preventing some dreaded event matters? Are you concerned about neatness or symmetry? or situation; however, these behaviors or mental acts either are not connected in a realistic way with what Several subtypes of OCD have been proposed as they are designed to neutralize or prevent or are indicators of prognosis or treatment response. DSM-IV clearly excessive criteria recognize that some OCD patients might lack insight B. At some point during the course of the disorder, the and still merit this diagnosis rather than a diagnosis of a person has recognized that the obsessions or compulsions psychotic disorder. In the DSM-IV field trial, 8% of patients are excessive or unreasonable. Note: This does not apply lacked insight at the time of examination and 5% had never to children. had insight into the irrationality of their symptoms [4]. C. The obsessions or compulsions cause marked distress, Limited or absent insight is associated with poorer response are time consuming (take ≥1 h/day), or significantly interfere to serotonin reuptake inhibitors (SRIs) in most studies [7], but with the person's normal routine, occupational (or academic) not all [8]. The degree of insight is also related to outcome in functioning, or usual social activities or relationships. some studies of cognitive behavioral therapy (CBT) [9], but D. If another Axis I disorder is present, the content of not others [10]. Most studies [11,12], but not all [13], the obsessions or compulsions is not restricted to it (e.g. indicate that OCD patients whose predominant or only preoccupation with food in the presence of an eating disorders; hair pulling in the presence of trichotillomania; symptom is hoarding are less responsive to treatment than concern with appearance in the presence of body patients with other predominant symptoms. The presence of dysmorphic disorder; preoccupation with drugs in the chronic motor tics was associated with poorer response in a presence of a substance use disorder; preoccupation with controlled trial of fluvoxamine [14], but not in a controlled having a serious illness in the presence of hypochondriasis; trial of clomipramine [15]. preoccupation with sexual urges or fantasies in the presence of a paraphilia; or guilty ruminations in the The symptoms of major depression may differ somewhat presence of major depressive disorder). in patients with OCD compared with those suffering from major depression alone. A recent study compared E. The disturbance is not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) depressive symptoms in 52 subjects with pure major or a general medical condition. depression with those in 52 patients suffering from OCD and Specify if: depressive symptoms of equal severity, as measured by the With Poor Insight: if, for most of the time during the current Montgomery Asberg Depression Rating Scale (MADRS; episode the person does not recognize that the obsessions eligibility score ≥20) [16]. The study found that subjects with and compulsions are excessive or unreasonable. comorbid depression and OCD scored significantly and

Reprinted with permission from [3]. substantially higher on the MADRS items for inner tension (anxiety) and pessimistic thoughts, and significantly and

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substantially lower on the items reflecting vegetative induced switches into hypomania or mania in OCD patients symptoms, i.e. sleep and appetite. who were constitutionally vulnerable to such mood switches. The California HMO study reported that 6% of The prevalence of mood disorders in patients those with clinically recognized OCD had also been with OCD diagnosed with bipolar disorder [22]. Clinical studies, whose results are strengthened by the use of Epidemiological studies confirm the high rates of structured interviews, report that patients with OCD exhibit comorbid mood disorders in individuals with OCD. The high rates of current and lifetime mood disorders. Reported lifetime prevalence rate for major depression among rates of concurrent major depression range from 14% to those with OCD in the Epidemiological Catchment Area 39.5%, and lifetime rates from 36% to 55%. Epidemiological study was 32% [25]. In the Cross National Study [26], rates studies report lifetime rates ranging from 12% to 60%. The of comorbid depression ranged from 12% (Korea) to broad agreement between clinical and epidemiological results 60% (Germany), with age- and sex-adjusted odds ratios suggests that the high rates of major depression in patients >3 in all seven countries when compared with the risk in with OCD are not simply a result of ascertainment bias, i.e. a the general population. A German epidemiological study of greater propensity for individuals with OCD and major >4000 adults reported that half of the 20 individuals with depression to seek care than for those with OCD alone, OCD had a history of major depression [27]. A community although such bias has probably influenced the comorbidity survey in Zurich, Switzerland, reported a 1-year prevalence rates reported in clinical studies of OCD. However, of comorbid major depression in 20% of those with OCD epidemiological data are too limited to allow firm conclusions in a sample of subjects aged 19–20 years, who were for the apparently elevated lifetime rates of dysthymia (15%) interviewed six times over the next 20 years, but this rate and bipolar disorder (15% to perhaps 30%) in OCD patients. did not exceed the rate in the control group [28]. With regard to major depression, a study of 100 patients The prevalence of comorbid dysthymia in samples from with DSM-III-R OCD reported 31% to have concurrent the general population is less studied; however, the German major depression [17]. In a Turkish study of 147 DSM-III-R epidemiological study reported a lifetime prevalence of 15% OCD outpatients, concurrent major depression was observed among 20 individuals with a lifetime diagnosis of OCD [27]. in 39.5% and past episodes reported in 36% [18]. A study of Epidemiological data concerning bipolar disorders in 77 OCD outpatients identified current major depression in subjects with OCD are also limited. The authors of the Zurich 16%, and a lifetime prevalence of 55% [19]. Among 63 study noted that their results were in clear conflict with those OCD patients enrolling in a CBT study, 14.3% had current of other studies and hypothesized that “our repeated major depression [20]. A Dutch chart review study of 120 interviews enabled us to identify a far higher number of hidden consecutive OCD outpatients revealed a point prevalence of bipolar cases, and to correct the over-diagnosis of depression” 37% for comorbid depression, with a higher prevalence in [28]. However, they utilized a much broader definition of women than in men (48% vs. 15%, respectively) [21]. In a bipolar spectrum than is usual. Significantly higher rates of study of recorded, but not uniformly established, clinical bipolar II disorder were reported in the individuals with OCD diagnoses in a population of 1.7 million persons aged 6–65 than in the remaining subjects (30% vs. 12%), and there were years treated within a California health maintenance strikingly higher rates of “all bipolar disorders” (53% vs. 24%). organization (HMO), 56% of adults with clinically recognized The German epidemiological study reported a much lower OCD were also diagnosed with major depression [22]. bipolar disorder rate of 15% (three of 20 individuals with With regard to dysthymia, a study of OCD patients who OCD, including one diagnosed with “hypomania”) [27]. enrolled in a CBT trial reported a current comorbidity rate of In the converse situation, where patients with major 14.3% [20], and a study of Turkish OCD patients reported depression or bipolar disorder are examined for comorbid a lifetime prevalence of 20% [18]. OCD, clinical studies using structured interviews suggest that Bipolar disorder is also over-represented in OCD patients. rates of OCD are elevated. General population rates of current The Turkish OCD study reported a past episode of mania OCD range from 0.6% to 1.1%, and lifetime prevalence rates in 3% of OCD patients [18]. An Italian study of from 1.5% to 2.5% [5]. By contrast, a Finnish study of 315 consecutive OCD outpatients reported that 15.7% had 269 patients (83% outpatients) with major depression lifetime comorbid bipolar disorder [23]. In a later study of reported current OCD in 7%, and noted an average rate of 79 consecutive OCD patients by the same research group, 5% for current comorbid OCD in a review of five other studies 3.8% had a lifetime diagnosis of bipolar I disorder and [29]. A study of 479 depressed outpatients reported a current 17.7% a diagnosis of bipolar II disorder [24]. The authors OCD (DSM-IV) diagnosis in 9.0% and a lifetime OCD noted that some of these cases may represent medication- diagnosis in 11.7% [30]. In a study of bipolar patients, current

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OCD (DSM-IV) was diagnosed in 24 of 360 (6.7%) bipolar I for the treatment of OCD, citalopram and escitalopram have patients and three of 115 (2.6%) bipolar II patients [31]. been found effective in large, European multi-center trials, Lifetime prevalence rates were 10.9% and 7.0%, respectively. and offer the advantage of fewer drug interactions than Another group reported an OCD (DSM-IV) lifetime prevalence some SSRIs [40,41]. Non-SRI antidepressants, with the rate of 9% among 288 bipolar patients [32]. In the possible exceptions of venlafaxine [42,43] and mirtazapine Epidemiological Catchment Area study, the lifetime prevalence [44], are not effective for OCD. In choosing between SRIs, rate of OCD among subjects with bipolar disorder was 21.0% factors to consider include potential drug interactions, side compared with a rate of 2.5% in the general population [33]. effects, past treatment response, and concurrent general medical conditions, but does not include efficacy [5]. Treatment considerations Data on potential drug interactions can be accessed from No large controlled trials have been expressly designed to several websites [45,46]. Paroxetine, although effective, is answer questions regarding the best treatment approach for the SSRI most strongly associated with weight gain [47]. It is patients with OCD and concurrent mood disorders. As a possible that due to genetic similarities, the response of first- result, reasonable approaches are inferred from studies degree relatives to particular medications may predict the incidentally including subjects with a comorbidity, from small likelihood of the patient’s response, but no definitive or even controlled trials and uncontrolled observations, and from the strongly suggestive data are currently available. literature on treating the comorbid conditions. Treatment of OCD is likely to require higher doses of In uncomplicated OCD, both SRIs and CBT in the form medication than treatment of major depression, and to take of exposure and response prevention (ERP) are well- longer to bring about a clinically meaningful response, e.g. supported first-line treatments [5,34–36]. Evidence suggests 6–10 weeks vs. 3–4 weeks [4,48,49]. OCD patients may that for some patients with uncomplicated OCD, combining benefit from higher doses than those recommended by the an SRI and CBT is more effective than either treatment as manufacturers [50,51], and some clinicians prefer a weekly monotherapy [37,38], but combination treatment is not increase in dose to reach the maximum recommended, if always necessary. Clinical considerations influencing the comfortably tolerated, rather than waiting 4–8 weeks to choice of monotherapy versus combined drug and evaluate the therapeutic effect at each intermediary dose. psychotherapy include: Despite the observation that OCD often requires higher SRI doses, treatment outcome has not been associated with • The patient’s preferences and capabilities. plasma levels of clomipramine [52], fluoxetine [53], • The nature and severity of the symptoms. fluvoxamine [54], or sertraline [55]. • The presence of comorbid psychiatric and medical In uncomplicated OCD, some studies suggest that a conditions, and their manner of treatment. combination of medication and CBT may be more effective in • The availability of psychotherapy. sustaining outcomes in the first few months after treatment • The patient’s past treatment history and current discontinuation [56], but no carefully controlled long-term medication regimen. outcome data are available. Maintenance treatment of OCD with SRIs is advisable as continued efficacy has been For a patient whose OCD (or comorbid major demonstrated, and discontinuation or switch to placebo may depression) is severe and limits his or her ability to engage in quickly lead to relapse [57]. Moreover, one study has reported CBT, starting treatment with an SRI alone in order to a poorer response with reinstatement of the study medication diminish symptom severity may ultimately enhance the than was seen with initial treatment [58]. patient’s ability to cooperate with more demanding therapy If uncomplicated OCD does not respond to initial SRI regimens. In treating patients with OCD and a comorbid treatment, a switch to one or more trials of different SRIs mood disorder, the clinical considerations that would should be considered, along with a number of influence treatment decisions for either condition if present augmentation or combination strategies [48,49,59]. If not in isolation must be kept in mind. previously provided, ERP or, with less evidentiary support, SRIs have demonstrated efficacy in treating cognitive therapy [35], should also be considered. In uncomplicated OCD and should be used if pharmacotherapy patients who show only a partial or no response to is elected as a first step [5]. Meta-analyses suggest that treatment, addition of a second-generation antipsychotic clomipramine is more effective than fluoxetine, fluvoxamine, drug is currently the only augmentation strategy supported or sertraline [34,39], but head-to-head trials comparing by multiple, double-blind, placebo-controlled trials [60]. clomipramine with these SSRIs have found their efficacies to (This augmentation strategy may also alleviate comorbid be comparable [39]. Although not FDA-approved in the US major depression [61]).

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Combining an SSRI with modest doses of clomipramine response in patients with both disorders [78]. Results from a has been successful in improving OCD response in open trials case series suggest that when an SRI relieves OCD and [5,63]; however, care must be taken when combining simultaneously worsens major depression, the depression this drug with fluvoxamine, fluoxetine, or paroxetine, since may respond to the addition of an antidepressant that these can inhibit clomipramine metabolism and produce inhibits norepinephrine reuptake [77]. However, the addition dangerously high levels in the plasma. In uncomplicated OCD, of the noradrenergic antidepressant desipramine to SRIs in a small, very short-term, double-blind, placebo-controlled trials double-blind, placebo-controlled trial in treatment-resistant and case reports support augmentation with once-weekly oral OCD did not improve OCD response [79]. morphine [64] or dextro-amphetamine [65,66]; limited data Co-occurring major depression has been associated with a support the role of these medications in the treatment of less satisfactory outcome in many ERP monotherapy trials of major depression [67–69]. However, in this author’s opinion, patients with OCD [80,81], and limited evidence from these treatments are to be considered far down the hierarchy controlled trials supports the use of ERP in combination with of possible interventions and should be avoided in patients fluvoxamine [82] or imipramine [83] in such cases. with contraindications to their use, such as a history of alcohol Unfortunately, therapists trained in ERP are in short supply or substance abuse, and certain medical conditions such as and, additionally, no studies have yet examined how to cardiovascular compromise. In addition, the precautions, combine ERP with other psychotherapies demonstrated to be evaluations, periodic review of treatment efficacy, and effective for major depression, such as CBT, interpersonal documentation recommended by the American Academy of therapy, or short-term psychodynamic psychotherapy [74]. Pain Medicine should be followed [70]. Given the different psychotherapeutic techniques required for In this author’s experience, clinical practice is enriched by OCD and major depression, combining them within a remembering that the word, “doctor,” derives from the Latin, treatment session could be a formidable task. Thus, in cases of “docere,” to teach. Providing patients with information and comorbid OCD and major depression (and possibly access to educational materials regarding the nature of their dysthymia), combining an SRI with psychotherapy aimed at disorders and the treatments being considered has frequently one rather than both disorders may be a more feasible first been of substantial benefit, diminishing guilt and unfounded step, and can be followed by additional treatment once an worries, and enhancing cooperation with medical care. The improvement in symptoms has been achieved. Obsessive-Compulsive Foundation and the Depression and Treatment-resistant depression may respond to drug Bipolar Support Alliance, as well as the National Institute of switches or augmentation strategies, including switches to Mental Health, are excellent sources of educational tricyclic antidepressants bupropion, lamotrigine, buspirone, to information [71–73]. combination/augmentation treatment with these agents or with lithium or thyroid hormone, or to a trial of Treating OCD comorbid with major depression electroconvulsive therapy [84–88]. A good response of OCD In cases where OCD is complicated by comorbid major to therapy with a given SRI may be lost when a switch is made depression, the clinician must evaluate and plan for treatment because of little or no response of the patient’s major of the major depression in accordance with published depression; similarly, antidepressant effect may be lost when a guidelines [e.g. 74] and other expert opinions [e.g. 62,75,76], decision is made to switch SRIs due to poor OCD response. while considering the modifications that might be necessary There are currently no studies that provide good estimates of to simultaneously or sequentially treat the OCD. Summarizing these risks. Augmentation strategies for depression are not and reviewing these treatment approaches to major expected to interfere with response of the patient’s OCD to depression is beyond the scope of this article. If a patient’s continued SRI treatment, although drug interactions and OCD or major depression fails to respond robustly to an additive side effects should always be considered. adequate trial of the initial pharmacotherapy, the clinician should look to augmentation/combination strategies with Treating OCD comorbid with dysthymia additional drugs, combined psychotherapy with medication, A review of available controlled trials [89] and a more recent or switching medications as outlined previously. controlled trial [90] suggest that pharmacotherapy with an The presence of major depression does not generally SSRI may be more effective than psychotherapy for treating predict a poorer response of OCD to SRI treatment [6,39], OCD comorbid with dysthymia. It also indicated that although occasionally, SRI treatment may relieve the OCD evidence for the superiority of combined medication and but worsen the patient’s depression [77]. A recent study psychotherapy to monotherapy with either modality alone is suggests that this may reflect differences in the limited. The review of controlled trials concluded that efficacy neurobiological substrates for OCD and major depression in treating dysthymia is equivalent across antidepressant

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drug classes, but SSRIs are better tolerated than tricyclic References antidepressants [89]. Thus, patients with OCD complicated 1. Burton R. The Anatomy of Melancholy (reprinted). New York, NY, USA: New York Review, 2001. by dysthymia might reasonably be first treated with an SSRI 2. Morel BA. Traite des Maladies Mentales. Paris, France: Librairie Victor, 1860. alone, or an SSRI plus ERP. 3. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (Copyright 2000). American Psychiatric Association. 4. Foa EB, Kozak MJ, Goodman WK et al. DSM-IV field trial: obsessive-compulsive disorder. Treating OCD comorbid with bipolar disorder Am J Psychiatry 1995;152:90–6. Erratum in: Am J Psychiatry 1995;152:654. A history of episodic OCD, i.e. a course marked by periods of 5. Koran LM. Obsessive-Compulsive and Related Disorders in Adults: A Comprehensive Clinical Guide. 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Lifetime-comorbidity of obsessive compulsive disorder of the life cycle and remove them.”[97]. In the 21st century, and subclinical obsessive-compulsive disorder in Northern Germany. Eur Arch Psychiatry perhaps physician participation in “the larger political and Clin Neurosci 2001;251:130–5. 28. Angst J, Gamma A, Endrass J et al. Obsessive-compulsive severity spectrum in the social life of our time” is even more urgently needed – our community: prevalence, comorbidity, and course. Eur Arch Psychiatry Clin Neurosci more effective treatments are still not available to all. 2004;254:156–64. 29. Melartin TK, Rytsälä HJ, Leskelä US et al. Current comorbidity of psychiatric disorders among DSM-IV major depressive disorder patients in psychiatric care in the Vantaa Disclosures depression study. J Clin Psychiatry 2002;63:126–34. 30. Zimmerman M, Chelminski I, McDermut W. 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18 DEPRESSION: MIND AND BODY Vol 3 No 1 2006 LEADING ARTICLE e 19 (1):19–31. 3 2006; Vol 3 No 1 2006 Vol In recent years it has become possible to perform In recent on the literature This paper summarizes the emerging ODY is the study of genetically based, inter-individual variability in is the study of genetically based, inter-individual and susceptibility to drug-induced adverse drug response [10]. Suitable genes for study code for either effects of mechanism to the drug’s pharmacodynamic (related to drug metabolism) action) or pharmacokinetic (related focus is on genetic – the research targets protein of or function polymorphisms that influence the structure The most common variation, the the encoded protein. is a single base single-nucleotide polymorphism (SNP), which occurs at a change in the sequence of the gene, of about one in every 1000 bases. Fewer than frequency significance. Other 10% of SNPs have functional of tandem repeats polymorphisms, such as variable number of the by the number of repeats alleles differ (VNTR), where much less common. same sequence, also exist but are systems [11]. genome-wide scans using microarray Genome-wide analysis and the candidate gene approach and [12]. The former is hypothesis-free complementary are number of leads to the identification of an ever-increasing which can then be confirmed by classical predictors, association studies. Thus, if genetic factors currently – one study account for a small variability in AD response that 12.5% of the variance was explained by a reported (5-HT [5-hydroxytryptamine]) model including serotonin (TPH) genes as transporter and tryptophan hydroxylase to selective 5-HT reuptake of the response predictors could genetic profiling inhibitors (SSRIs) [13] – in the future, be used to customize AD treatment in bipolar and pharmacogenetics of major depression B IND AND : M Depression: Mind Body EPRESSION D

Address for correspondence: Alessandro Serretti, Institute of Psychiatry, Serretti, Alessandro for correspondence: Address Carlo Pepoli 5, 40123 Bologna, Italy. University of Bologna, Viale Email: [email protected] The introduction of antidepressant drugs (ADs) has of antidepressant The introduction These of mood disorders. the treatment revolutionized 30–40% of and well tolerated; however, effective agents are (>50% response patients do not show a significant on the Hamilton Rating Scale for score in baseline reduction to [HAM-D]) to a first AD, while 60–70% fail Depression of <7 on the 17-item HAM-D) (a score achieve full remission a higher rate has been associated with [1]. Partial remission functional impairment, and greater recurrence, of depression some mood a worse quality of life [2,3]. Although can occur within the first 2 weeks of AD improvement the placebo this from to separate it is difficult treatment, medication with antidepressant [4]. Initial treatment effect be continued for at least 4–8 weeks before should therefore [5]. response switching to another AD in cases of insufficient a benefit During this period, many patients may not perceive the likelihood of premature increasing treatment, from it may exacerbate discontinuation [6]. Furthermore, requiring hopelessness, a risk factor for suicidal behavior, in patients to stay in hospital for longer periods and resulting and minimize costs, patient suffering reduce higher costs. To be desirable to know in advance whether it would therefore has effort research great A a drug is likely to be effective. of successful AD treatment been made to identify predictors been reported have in AD response [7]. Inherited differences of since the 1960s [8,9], and have established the role moderators. Pharmacogenetics genetic factors as treatment with the monoamine hypothesis of depression, a number of genes coding for metabolic enzymes, monoamine transporters, of genes coding for metabolic enzymes, hypothesis of depression, a number with the monoamine a marginal role, except for Pharmacokinetic genes appear to play been shown to influence AD response. and receptors have of tricyclic antidepressants. At present, the therapeutic response and tolerability affect cytochrome P450 2D6 variants, which in the next few years genome-wide of the variability in AD response. However, genetic factors account for a small proportion perhaps to the identification of an increasing number of outcome predictors and scans with microarray systems will lead treatment. fulfill the promise of individualized AD Although major depression is regarded as the prototype of treatable mental disorders, up to one-third of patients fail to of treatable mental disorders, up to is regarded as the prototype Although major depression driven. In accordanc runs in families and is in part genetically drug (AD) trial. AD response respond to a first antidepressant Alessandro Serretti and Paolo Olgiati Alessandro Serretti of Bologna, Bologna, Italy University Institute of Psychiatry, From Research to Clinical Practice Clinical to Research From Pharmacogenetics of Major Depression: of Major Pharmacogenetics ALESSANDRO SERRETTI AND PAOLO OLGIATI

unipolar disorder, correlating the biological mechanisms expressed in peripheral organs such as the gut, pineal gland, underlying depressive symptoms with the discovery of genes spleen, and thymus, and less frequently in the brain. A that can influence AD treatment outcome. biallelic SNP at position 218 (TPH1 A218C) was reported to influence gene transcription, with carriers of the rarer Candidate genes related to monoamine systems A allele showing decreased serotonin synthesis [21]. The Our theoretical understanding of depression neurobiology is presence of this allele may predispose to suicidal behavior rooted in the monoamine hypothesis. In its original form, this [22,23] and to a worse response to SSRI treatment (Table 1) theory stated that the biological basis for depression was a [13,24]; however, the latter association was not confirmed in deficiency in brain norepinephrine [14]. This was supported by recent Asian studies [25–27]. An independent US study drugs that caused norepinephrine depletion and induced reported no effect of the TPH1 A218C SNP on fluoxetine depressive states, while agents that increased norepinephrine treatment, but a significant effect of three different levels showed antidepressant or psychostimulant effects. TPH1 polymorphisms [28]. Tph2 was discovered in the Further study demonstrated the role of serotonin and dopamine mouse some years ago, when Tph1 knockout animals still neurotransmission; thus, it became evident that all monoamine had normal levels of 5-HT in serotonergic brain areas [29]. systems are involved in depression neurobiology [15,16]. In fact, Tph2, unlike Tph1, seems to be selectively expressed Monoamine neurotransmitters are synthesized from their in many more brain areas [30,31]. In humans, TPH2 variants precursors in the nerve cell body and stored at the nerve have been associated with major depression [32] and terminal in vesicles. An action potential arriving at the suicidal behavior [33]. Ongoing research on AD response terminal activates calcium currents and precipitates the has yielded both positive [28,34] and negative [35] simultaneous release of neurotransmitter molecules from results (Table 1). many vesicles by fusing the membrane of the vesicles with that of the nerve terminal. Neurotransmitters diffuse across Catechol-O-methyltransferase the synaptic cleft and bind briefly to receptors, activating All monoamines are oxidized; catecholamines are then them and causing physiological responses. In order to avoid methylated by catechol-O-methyltransferase (COMT). The persistent receptor activation, neurotransmitters are quickly COMT gene has been mapped to chromosome 22 pumped back into the presynaptic nerve terminals by protein (22q11.1-q11.2) [36]. Lachman and collaborators reported a carriers (reuptake) or destroyed by enzymes near the functional G to A SNP at codon 158 in membrane-bound receptors. The neurotransmitter–receptor interaction triggers COMT (and in position 108 in soluble COMT), leading to a a cascade starting with the activation of G-proteins, Val to Met substitution [37]. It has been shown that the Met synthesis of second messengers, phosphorylation of protein allele results in a 3–4-fold lower enzymatic activity than the kinases, and culminating in the up-regulation of genes Val allele [38]. This polymorphism has been associated with encoding neurotrophic factors. different psychiatric disorders, suicidal behavior, and Adaptive changes in the expression of monoamine personality traits [39]. Two recent studies point to Met/Met receptors and alterations in intracellular transduction homozygosity predicting a worse response to mirtazapine pathways that are activated by neurotransmission have been and citalopram (Table 2) [40,41]. suggested as potential mechanisms of action of ADs [17]. Recently, it has emerged that different AD treatments can Monoamine oxidase A stimulate neurogenesis, which is thought to mediate their Monoamine oxidase A (MAOA) catalyzes monoamine therapeutic effects [18]. Many genes involved in these oxidation. The MAOA gene – localized to chromosome processes have been analyzed as candidates in the study Xp11.23 [42] – is thought to influence the mechanism of of antidepressant response. action of SSRIs through an interaction with 5-HT transporter protein (SERT) [43]. A VNTR polymorphism located 1.2 kb Tryptophan hydroxylase upstream of the MAOA coding sequences was reported to Tryptophan hydroxylase (TPH) catalyzes the rate-limiting affect transcription of the MAOA promoter [42], and has step of 5-HT biosynthesis. Long-term treatment of rats with been associated in recent literature with bipolar disorder SSRIs has been shown to upregulate mRNA and protein [44], suicidality [45], and some personality features [46]. levels of TPH [19], supporting the involvement of this Two studies reported no influence on AD treatment efficacy enzyme in the pharmacological action of ADs. TPH has two [25,47]; however, more recently, the three-repeat variant of isoforms, TPH1 and TPH2. TPH1 is ubiquitous. Its gene the MAOA VNTR was positively associated with AD (TPH1 in humans, Tph1 in the mouse) – localized to treatment outcome in women in a sample of Chinese chromosome 11 (11p15.3-p14) [20] – is predominantly inpatients with major depressive disorder (Table 2) [48].

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Table 1. Serotonergic genes and antidepressant response. Polymorphism Author Study design Results TPH1 (A218C) Serretti et al. 2001 [13] n=216; BP + MDD; fluvoxamine Slower response with A/A genotype Serretti et al. 2001 [24] n=121; BP + MDD; paroxetine Worse response with A allele Yoshida et al. 2002 [25] n=55; MDD/Japan; fluvoxamine No association Ham et al. 2005 [26] n=93; MDD/Korea; various ADs No association Hong et al. 2006 [27] n=224; MDD; fluoxetine No association Peters et al. 2004 [28] n=96; MDD; fluoxetine TPH1 associated with general response TPH2 Peters et al. 2004 [28] n=96; MDD; fluoxetine TPH2 associated with specific response Zhang et al. 2005 [34] n=306; 87 MDD; controls; Association with resistant depression various ADs (TPH2 G1463A) Garriock et al. 2005 [35] n=182; 97 MDD; controls; No association with resistant depression various ADs (TPH2 ExonXI) HTR1A (C1019G) Lemonde et al. 2004 [94] n=118; MDD; AD + pindolol Worse response with G/G genotype versus flibanserin Serretti et al. 2004 [95] n=262; MDD + BP; fluvoxamine Worse response with G-allele (BP) Arias et al. 2005 [61] n=130; MDD; citalopram Worse response with G/G genotype Hong et al. 2006 [27] n=224; MDD; fluoxetine Better response with C/C genotype Yu et al. 2006 [96] n=222; MDD; fluoxetine Better response in C/C females HTR1A (Asp-Gly) Suzuki et al. 2004 [97] n=65; MDD; fluvoxamine Better response with Asp allele Yu et al. 2006 [96] n=222; MDD; fluoxetine No association HTR2A (T102C) Minov et al. 2001 [101] n=173; MDD; various ADs Better response with C allele Cusin et al. 2002 [47] n=443; MDD + BP; No association fluvoxamine or paroxetine Hong et al. 2006 [27] n=224; MDD; fluoxetine No association HTR2A (C-1420T) Cusin et al. 2002 [47] n=443; MDD + BP; Marginal association of T/T genotype fluvoxamine or paroxetine with worse response HTR2A (-1438A/G) Sato et al. 2002 [103] n=55; MDD; fluvoxamine No association Yoshida et al. 2004 [66] n=96; MDD; milnacipran No association Choi et al. 2005 [102] n=71; MDD; citalopram Better response with G allele HTR6 (C267T) Wu et al. 2001 [108] n=34; MDD; various ADs No association Lee et al. 2005 [109] n=91; MDD; various ADs Better response In C/T heterozygotes

ADs: antidepressant drugs; BP: bipolar disorder; MDD: major depressive disorder.

SERT (17q11.1-q12) [49]. Heils and colleagues identified a Serotonergic action is terminated primarily via uptake of polymorphism (5-HTTLPR) in the transcriptional control region 5-HT from the synaptic cleft by a specific transporter on the of SLC6A4 – a 44-base pair (bp) insertion/deletion involving presynaptic neuron. This transporter, SERT, appears to be the two units in a sequence of 16 repeat elements – that could site of action of many antidepressant drugs. Moreover, it is affect SERT expression [50]. Indeed, the long (L) 5-HTTLPR known to mediate the behavioral and toxic effects of cocaine allele has twice the SERT expression in the basal state than the and amphetamines. These findings are consistent with a major short (S) form. A growing body of evidence links 5-HTTLPR role for SERT in mood regulation, and make it an ideal genotypes to a variety of psychiatric disorders with affective candidate for pharmacogenetic studies. Human SERT is encoded symptomatology (e.g. depression, bipolar disorder, anxiety by a single gene (SLC6A4) localized to chromosome 17 disorders, eating disorders, substance abuse) and pathological

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Table 2. Monoamine genes and antidepressant response. Polymorphism Author Study design Results COMT (Val-Met) Szegedi et al. 2005 [40] n=102; MDD; mirtazapine Better response with Val allele or paroxetine (mirtazapine group) Arias et al. 2006 [41] n=346; MDD; SSRIs Worse response with Met/Met genotype (citalopram group) MAOA (VNTR) Cusin et al. 2002 [47] n=443; BP + MDD; fluvoxamine No association or paroxetine Yoshida et al. 2002 [25] n=54; MDD; fluvoxamine No association Yu et al. 2005 [48] n=230; MDD; fluoxetine Better response with three-repeat variant (female group) Norepinephrine Yoshida et al. 2004 [66] n=96; MDD; milnacipran Better response with T allele transporter (SLC6A2) (SLC6A2 T-182C). Slower onset of response with A/A genotype (SLC6A2 G1287A) Kim et al. 2006 [80] n=105; MDD; nortriptyline SLC6A2 G1287A significant association Dopamine Kirchheiner et al. 2006 [89] n=190; MDD; various ADs Faster response with ten-repeat transporter (DAT) variant (DAT1 VNTR) Norepinephrine Zill et al. 2003 [114] n=259; MDD; various ADs C/C genotype marginal association receptor (ADRB1) with faster and better response Dopamine receptors Serretti et al. 1999 [122] n=124; BP; total sleep deprivation No association (DRD4) (DRD2–DRD4) Serretti et al. 2001 [118] n=364; MDD + BP; fluvoxamine No association (DRD2-DRD4) or paroxetine Benedetti et al. 2003 [119] n=124; BP; total sleep deprivation No association (DRD2-DRD3) Garriock et al. 2006 [123] n=97; MDD; various ADs Significant effect of DRD4 exon 3 VNTR GNB3 (C825)T Zill et al. 2000 [128] n=88; MDD + BP; various ADs Better response with T/T genotype Joyce et al. 2003 [60] n=169; MDD; fluoxetine Worse response to nortriptyline or nortriptyline with T allele (aged <25 years group) Serretti et al. 2003 [129] n=490; MDD+BP; fluvoxamine Better response with T/T genotype or paroxetine Lee et al. 2004 [130] n=106; MDD; various ADs Severe depression and better response with T allele Hong et al. 2006 [27] n=224; MDD; fluoxetine No association

ADs: antidepressant drugs; BP: bipolar disorder; MDD: major depressive disorder; SSRIs: selective serotonin reuptake inhibitors.

behaviors, and personality traits related to anxiety, impulsivity, [63,64], or no effect of 5-HTTLPR genotypes [65,66]. and stress [51]. Since 1998, the 5-HTTLPR polymorphism has Compared with Western populations, L allele carriers are much been investigated as a marker of AD response in approximately less frequent among Asian populations. This increases the 20 studies (Table 3) [52,53]. In Caucasian samples, a consistent likelihood of random fluctuations in smaller samples; therefore, trend has emerged towards either a better response to SSRI further study with larger sample sizes is needed. drugs in 5-HTTLPR* L allele carriers [54–59] or a worse Recently, two functional variants were reported in the response in S/S homozygotes [60,61]. Conversely, Asian 5-HTTLPR L allele. 5-HTTLPR is now viewed as a triallelic studies have produced conflicting results, with some reporting locus with a subtype of the L allele (LG) and the S allele a better response in L/L homozygotes [27,62], others a more having comparable levels of SERT expression, while the favorable outcome in patients carrying at least one S allele other L subtype (LA) has higher SERT expression [67].

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The two lower expressing LG and S alleles could predict a action of antidepressants [82]. The dopamine transporter worse AD response compared with the higher expressing (DAT) is the primary determinant of extracellular dopamine LA allele. So far, these differences have been missed by concentrations and maintains the balance between dopamine pharmacogenetic studies that used a biallelic 5-HTTLPR homeostasis and function [83]. Greater DAT availability was genotype classification. consistently reported in the basal ganglia of depressed patients In bipolar disorder, the S allele of the 5-HTTLPR [84,85]. The clinical implications of this finding are not clear; polymorphism may predispose to AD-induced mania however, it has been speculated that an increase in dopamine [68,69], although negative studies have also been uptake at a presynaptic level could result in depletion of published [70,71]. Over the last few years, new postsynaptic dopamine, and has been related to some polymorphisms within the SLC6A4 gene have attracted features of depressive syndrome such as psychomotor interest as predictors of AD response, although their retardation and anhedonia [86]. Genetic variants that affect interactions with the 5-HTTLPR genotypes are yet to be DAT expression could therefore confer susceptibility to fully understood. Ogilvie and colleagues identified a depression and influence AD response. The gene for the 17-bp VNTR polymorphism within intron 2 (STin2) that dopamine transporter (SLC6A3), located on chromosome was related to susceptibility to major depression [72,73]. 5p15.3 [87], has a 40-bp VNTR polymorphism in exon 15 STin2, like the 5-HTTLPR polymorphism, can influence that influences DAT expression [88]. A recent study suggests SLC6A4 transcription [74], and the two polymorphisms that the 10-repeat variant, which has been related to may have a synergistic effect [75]. STin2 also affected AD increased gene transcription, may also predict a faster onset of response in a large Korean sample [63], but this finding AD response. Of note, this effect was reported with different was not replicated by subsequent studies [27,76]. classes of medications, including SSRIs (Table 2) [89]. More recently, a SNP (Rs25531) located just upstream of 5-HTTLPR revealed a significant influence on AD Serotonin receptors response and, intriguingly, a moderation effect on 5-HTTLPR The 5-HT1A receptors are located on serotonin cell bodies alleles [77,78]. in the midbrain dorsal raphe nucleus, and activation of these autoreceptors inhibits the firing of 5-HT neurons and Norepinephrine transporter diminishes the release of this neurotransmitter in the Many of the antidepressants used to treat major depressive prefrontal cortex. Several AD compounds desensitize disorder are antagonists at the human norepinephrine raphe 5-HT1A autoreceptors, resulting in enhanced 5-HT transporter (NET). Recent study revealed that using either a neurotransmission [90]. Agents that block 5-HT1A combination of medications that inhibit the NET and SERT, autoreceptors (e.g. pindolol) may accelerate the onset of or a single medication that inhibits both transporters, may AD action [91]. Conversely, compared with post mortem represent a more effective treatment for severe or brains from non-depressed individuals, brains from refractory depression than a single selective antagonist depressed suicide victims display elevated 5-HT1A density in [79]. As NET is likely to moderate the clinical effects of the raphe nuclei (autoreceptors) but not at post-synaptic ADs, functional variants of the NET gene (SLC6A2) could sites, which may lead to decreased serotonergic activity affect AD response (Table 2). In a study of 96 Japanese [92]. Human 5-HT1A gene (HTR1A) transcription is patients with major depression who were treated with modulated by a common C–1019G SNP in its upstream milnacipran (a dual serotonin/norepinephrine reuptake regulatory region. It has been suggested that the G allele inhibitor; SNRI) for 6 weeks [77], significant associations derepresses 5-HT1A autoreceptor expression to reduce were reported between two SLC6A2 polymorphisms and serotonergic neurotransmission. This mechanism would treatment response: the T-128C (the T allele predicting a explain the association of the G allele with depression better response) and G1287A polymorphisms (slower onset and suicide [93]. This allele may also counteract the of response in A/A genotype carriers) [66]. The G1287A therapeutic effect of antidepressant drugs by increasing polymorphism was also associated with AD response in a inhibitory 5-HT1A autoreceptors, as indicated by three recent Korean study [80]. Such findings require further independent Western studies [61,94,95]. Similarly, two replication, particularly in Western samples. Asian studies reported a better response to fluoxetine

in 5-HT1A C/C homozygotes [27,96]. A different Dopamine transporter polymorphism, Gly272Asp, was investigated in Japanese Evidence from study of laboratory animals and humans outpatients with a major depressive disorder who were support the involvement of the dopamine system in the treated with fluvoxamine [97]. Asp allele carriers showed a pathophysiology of depression [81], and in the therapeutic more marked reduction in depressive symptomatology

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compared with Gly/Gly homozygotes. This finding was not response to “noradrenergic” antidepressant agents (Table 2) confirmed by subsequent studies (Table 1) [96]. [114]; however, the finding was only marginally significant and

The activation of 5-HT2A receptors in the medial requires further study. prefrontal cortex and anterior cingulate cortex is thought to mediate the hallucinogenic properties of LSD, whereas in Dopamine receptors the amygdala, 5-HT2A receptor activation is a component of The results of animal studies have prompted investigators to antidepressant response. 5-HT2A receptors may mediate consider sensitization of the dopamine receptor D2 (DRD2) in some of the AD effects seen in experimental animal models the mesolimbic dopamine system, a final common pathway in of depression [98], and the antidepressant drug nefazodone antidepressant action [115]. It has been reported that D2 was found to (partially) exert its therapeutic effect via antagonists diminish the therapeutic effect of SSRIs in

5-HT2A receptor antagonism [99]. Three SNPs in the depressed patients [116]. In spite of this large body of gene for the 5-HT2A receptor (HTR2A), located on evidence supporting the involvement of DRD2 in depression chromosome 13q14 q21 [100], have been implicated in AD treatment, a functional polymorphism in the DRD2 gene, response (Table 1): which causes an amino acid change from serine to cysteine at codon 311 (DRD2 Ser311Cys) [117], showed no significant • HTR2A T102C – A preliminary positive association [101] influence on antidepressant response in two independent

was not confirmed by subsequent studies [27,47]. Italian studies (Table 3) [118,119]. DRD4 has considerable

• HTR2A G–1438A – One study reported a greater clinical homology to DRD2. It modulates the activity of nigrostriatal improvement in patients carrying the G allele [102], dopamine neurons and has been implicated in both normal in contrast with previous negative studies [66,103]. coordinated and drug-stimulated motor behaviors [120]. • HTR2A C1420T – One study showed a marginal DRD4, located on chromosome 11p15.5, is one of the most association of the T/T genotype with a worse response variable human genes known, and this diversity is the result of to SSRI treatment [47]. length and SNP variation in a 48-bp VNTR in exon 3 (DRD4 exon3 VNTR) [121] that encodes the third intracellular loop of

5-HT6 receptor is a G-protein-coupled receptor that this dopamine receptor. Variant alleles containing from two stimulates adenylyl cyclase. In the rat, it shows high (2R) to 11 (11R) repeats are found, with the resulting proteins affinity for ADs such as mianserin and clomipramine [104]. having 32–176 amino acids at this position. The frequency of

5-HT6 receptor antagonists seem to improve retention these alleles varies widely, the four-fold repeat (D4.4) being performance in experimental animals, and this finding most frequent. Prior studies have reported no association of implicates a role for 5-HT6 in cognition enhancement this polymorphism with antidepressant response [118,122]; [105,106]. A silent polymorphism within the first exon of however, in a recent work, DRD4 exon 3 variants revealed a the 5-HT6 gene (HTR6 T267C) could affect AD response significant modulation effect on various antidepressant drugs [107]. Although a first study involving few patients with (Table 2) [123]. major depression did not find an influence of this polymorphism [108], a larger study found greater efficacy G-protein β3 subunit of AD treatment in C/T genotype carriers compared with G-proteins are key components of intracellular signal other genotypes (Table 1) [109]. transduction in all cells of the body, including neurons. Inactive G-proteins are trimers coupled with receptors on the cell β α 1 adrenoceptors membrane. The active form is a GTP-bound monomer These receptors serve as important regulators of central resulting from the dissociation of a βγ dimer [124]. Chronic nervous system-mediated behavior and several neural treatment with fluoxetine attenuated GTP binding to the γ functions, including mood, memory, neuroendocrine control, subunit in the dorsal raphe nucleus of rats, thus inducing β and stimulation of autonomic function, and are involved in the desensitization of 5-HT1A receptors [125]. There are three mediation of AD effects [110]. This may also explain why subunit subtypes. The gene encoding the β3 subunit (GNB3), beta-blocker medications are associated with side effects located on chromosome 12p13 [126], includes 11 exons and such as depression and lethargy [111]. A SNP in the 10 introns. A polymorphism in GNB3 exon 10, GNB3 C825T, β 1 adrenoceptor gene (ADRB1), located on chromosome has been found to modulate signal transduction and ion 10q24-q26 [112], consisting of a G/C transversion at position transport activity [127]. The T variant was found to predict a 1165 (ADRB1 G1165C) was shown to alter the receptor– better AD response in four independent studies [60,128–130]. G-protein interaction, with functional consequences on signal Hong and colleagues reported the only negative study, and transduction [113]. This polymorphism could affect the this used an Asian sample (Table 2) [27].

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Table 3. Serotonin transporter gene polymorphism (5-HTTLPR) and antidepressant response. Authors Study design Positive association with response Ethnicity Smeraldi et al. 1998 [54] n=99; BP + MDD; fluvoxamine l allele p=0.017 Caucasian Zanardi et al. 2000 [55] n=64; BP + MDD; paroxetine l allele (s allele slower) p<0.001 Caucasian Pollock et al. 2000 [57] n=95; late-life MDD; paroxetine l allele (s allele slower) p=0.028 Caucasian Kim et al. 2000 [63] n=120; MDD/Korean; fluoxetine s allele p=0.007 Asian or paroxetine Zanardi et al. 2001 [56] n=155; BP + MDD; fluvoxamine l allele p=0.029 Caucasian Arias et al. 2005 [61] n=102; MDD; citalopram l allele (s allele more no remission) p=0.006 Caucasian Minov et al. 2001 [101] n=104; MDD; various ADs and ECT no association Caucasian Yoshida et al. 2002 [64] n=66; MDD/Japanese; fluvoxamine s allele Asian Yu et al. 2002 [62] n=121; MDD/Chinese; fluoxetine l allele p=0.013 Asian Joyce et al. 2003 [60] n=169; MDD; fluoxetine l allele (s/s genotype slower response Caucasian or nortriptyline in patients >25 years) Durham et al. 2004 [186] n=206; MDD geriatric; l allele (sertraline group) Mostly Caucasian sertraline or placebo Serretti et al. 2004 [177] n=221; MDD + BP; fluvoxamine l allele (s/s genotype poor response) Caucasian or paroxetine Lee et al. 2004 [187] n=128; MDD/Korean; various ADs l allele s/s genotype poor long-term Asian (13 years) prognosis Murphy et al. 2004 [59] n=122; MDD geriatric; paroxetine l allele p<0.05 Mostly Caucasian Murphy et al. 2004 [59] n=124; MDD geriatric; mirtazapine no association Mostly Caucasian Kraft et al. 2005 [77] n=96; MDD; fluoxetine l allele if rs25531 = A Mostly Caucasian s allele if rs25531 = G Kato et al. 2005 [188] n=81; MDD/Japanese; paroxetine l allele Asian or fluvoxamine Kim et al. 2006 [189] n=136; MDD; SSRIs s allele Asian Kim et al. 2006 [189] n=105; MDD; nortriptyline s allele Asian Hong et al. 2006 [27] n=224; MDD; fluoxetine l allele Asian

AD: antidepressant drug; BP: bipolar disorder; ECT: electroconvulsive therapy; MDD: major depressive disorder; SSRIs: selective serotonin reuptake inhibitors.

Other pharmacodynamic candidate genes been explored as moderators of antidepressant response. Hypothalamic–pituitary–adrenal axis and stress CRH receptor 1 (CRHR1) is a promising candidate since hormone system CRHR1 antagonists have consistently demonstrated A sustained overactivity of the hypothalamic–pituitary– antidepressant properties in experimental animals and adrenal (HPA) axis (basically, corticotropin-releasing humans [134]. Research on CRHR1 pharmacogenetics is at a hormone [CRH] hypersecretion) in response to stress has very early stage; however, a preliminary study identified been reported in some patients with major depression, three SNP markers of AD response in a sample of Mexican- especially in those who were abused as children [131]. Americans treated with desipramine or fluoxetine [135]. Corticosteroids can decrease the expression of post-synaptic The literature largely supports the hypothesis that the

5-HT1A receptors in the hippocampus [132]. Stress and function of the glucorticoid receptor (GR) is reduced in corticosteroid treatment both result in down-regulation of major depression, in the absence of clear evidence of brain-derived neurotrophic factor (BDNF), which has been decreased GR expression. The data also indicate that some suggested to cause atrophy in the hippocampus of antidepressants have direct effects on the GR, leading to depressed patients [133]. Following these lines of evidence, enhanced GR function and increased GR expression [136]. some genes coding for components of the HPA axis have Preliminary evidence that the GR gene (NR3CI) could affect

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AD response was collected, and a research group in Munich that Clock knockout mice have increased locomotor (Germany) reported the influence of the functional NR3CI sensitization to cocaine and increased drug reward polymorphism ER22/23EK and of SNPs within the gene dependence compared with wild-type animals [153]. This encoding the hsp90 co-chaperone FKBP5 (a part of the would suggest that the circadian-associated CLOCK mature GR heterocomplex that regulates GR sensitivity) protein is involved in regulating dopaminergic transmission [137]. This finding was not replicated by an independent in the brain’s reward circuit, which is altered in depressive group of researchers; however, they did demonstrate the disorders. A polymorphism in the 3’ flanking region of influence of another NR3CI polymorphism [138]. the CLOCK gene, a T to C substitution at position 3111 (CLOCK T3111C) is known to affect mRNA stability Angiotensin-converting enzyme–substance P system and half-life [154]. In healthy subjects, the C allele was NK1 receptors are the endogenous receptors for substance P, associated with significantly higher “eveningness”, a delay and NK1 receptor antagonists have shown antidepressant in preferred timing for activity or sleep [155]. In patients activity in some animal models [139,140]. Although the with mood disorders, the same C variant was coupled clinical efficacy of NK1 antagonists has not been definitively with higher recurrence rates in bipolar patients [155], demonstrated in patients with major depression [141,142], increased lifetime sleep disturbances [156], and persistence and animal data are hardly applicable to humans because of of insomnia during antidepressant treatment [157]. the differences between species in NK1 receptors, there is increasing evidence that substance P genes can influence AD Pro-inflammatory cytokines treatment. In the central nervous system, substance P is Animal studies on so-called “sickness behavior” [158], colocalized with the angiotensin-converting enzyme (ACE), which resembles human depression in terms of symptoms which is thought to participate in its degradation. An intronic such as anorexia, sleep disturbance, and suppression of insertion (I)/deletion (D) polymorphism in ACE has a exploratory behavior, and human studies of depression dramatic impact on substance P levels and may affect [159], both demonstrate increased production of pro- antidepressant activity. Indeed, the D allele, which inflammatory cytokines (interleukin-1 [IL-2], IL-6, tumor determines higher ACE plasma levels [143], was recently necrosis factor-α) in depression. Antidepressant treatment is associated with higher substance P levels [144] and a faster known to stimulate anti-inflammatory cytokines [160]. Pro- response to antidepressant treatment [145], including inflammatory cytokines may cause hyperactivity of the HPA total sleep deprivation [146], particularly among women axis and a reduction in 5-HT levels, which ultimately result in [147]. Furthermore, this polymorphism would have a the onset of depression. Successful antidepressant therapy regulatory effect on the HPA axis in depressed patients, with was shown to restore a physiological interplay between D/D genotype carriers displaying the highest cortisol immune and neuroendocrine systems [161]. A research response in the dexamethasone/CRH test administered at group in Taiwan released a preliminary report on a biallelic admission [148]. More recently, another component of the polymorphism in the promoter region (position -511) of the ACE–substance P system, the angiotensin II receptor gene IL-1 beta gene, which was associated with depression (ATI), was included among outcome predictors in major severity and fluoxetine therapeutic response [162]. Further depression [149]. study is warranted given the emerging role of cytokines in antidepressant drug activity Endogenous CLOCK system Alterations in biological rhythms are often reported in BDNF mood disorders. Melancholic depression has typical Decreased levels of neurotrophic factors have been circadian fluctuations, with morning worsening of mood consistently reported in depressed patients, among whom and improvement during the evening, which have been they could contribute to the atrophy of certain brain associated with outcome [150]. Sleep manipulations regions including the hippocampus and prefrontal cortex such as sleep deprivation can have a positive effect on [133]. Recent data suggest that antidepressant drugs the clinical status of depression [151]. In mammals, increase the synthesis and signaling of BDNF, and BDNF circadian rhythms are regulated by a circuitry consisting of signaling appears to be both sufficient and necessary for two cryptochrome genes (Cry1, Cry2), Arnt1, Circadian the antidepressant-induced behavioral effects [163]. BDNF Locomotor Output Cycles Kaput (Clock), casein kinase I secretion and intacellular trafficking are regulated by a epsilon genes (Csnk1e), and three period genes (Per1, functional polymorphism in the BDNF gene (chromosome Per2, Per3), all of which are expressed in the hypothalamic 11p13) resulting in a valine to methionine substitution in suprachiasmatic nuclei [152]. Recent studies demonstrate the 5’ pro-region (codon 66) of the human BDNF protein

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[164]. This polymorphism has been investigated as a The gene encoding P-glycoprotein – formerly known as moderator of antidepressant response with inconsistent MDR1, now ABCB1 – is localized to chromosome 16. An results [165,166]. However, due to the importance of intronic ABCB1 polymorphism was found to be associated BDNF in depression neurobiology and antidepressant with remission in antidepressant treatment, but not with drug response, further research is needed plasma levels [175]; therefore, it is likely that ABCB1 variants Although a number of other systems potentially play a role influence antidepressant response by affecting the transport in mood disorders and the antidepressant response, it is of drugs across the blood–brain barrier via a mechanism that outside the scope of this review to report extensively on these does not involve modification of drug plasma concentration. as they have not yet been related to pharmacogenetic targets. Discussion Pharmacokinetic candidate genes In spite of the popular claim that pharmacogenetics Pharmacokinetics is the study of the bodily absorption, holds the promise of an individualized approach to distribution, metabolism, and excretion of drugs. psychopharmacology, important shortcomings have so far Pharmacokinetic factors affect the delivery of drugs to their hampered the use of research data in clinical practice: sites of action, thereby influencing therapeutic response. Psychotropic drugs are metabolized by cytochrome • Studies have mainly focused on SSRIs – the other S/NRIs P450 isoenzymes [167]. Moreover, their access to the brain (venlafaxine, duloxetine, escitalopram) have no studies is regulated by P-glycoprotein [168]. Cytochrome P450 and addressing response based on genes/receptors – and P-glycoprotein were therefore tested as candidates in the analyzed response in the short term (4–8 weeks), while pharmacogenetics of antidepressants several patients, particularly the elderly, respond later, typically after 10–12 weeks. Cytochrome P450 • Studies mainly included unipolar subjects. Bipolar The cytochrome P450 (CYP) superfamily consists of more depression was seldom investigated in spite of its than 50 isoenzymes (hem proteins) that catalyze the frequency – bipolar disorder is highly recurrent and many oxidation of many drugs and chemicals. In humans, seven episodes are depressive. Other depressive disorders (e.g. isoforms – CYP1A, CYP2A6, CYP2B6, CYP2C, CYP2D6, dysthymia) have also not been specifically addressed. CYP2E1, and CYP3A – account for approximately 70% of • In the study of AD response, outcome was classically a the liver cytochromes. CYP2D6 appears to be involved in decrease in terms of overall psychopathology; however, the metabolism of most antidepressants. So far, up to not all symptoms have the same course and some may 75 different alleles of CYP2D6 have been described, persist in partial responders. Interestingly, a growing >15 of these encode an inactive or no enzyme at all, while body of evidence suggests that single candidate genes others consist of gene duplications [169]. A direct correlation can have a limited impact on a few clusters of symptoms was reported between the number of functional CYP2D6 rather than on the global clinical picture of mood copies and plasma levels of some tricyclic antidepressant, disorders (e.g. the selective effect of 5-HTTLPR and such as nortryptyline [170]. In fact, it has been suggested CLOCK variants on antidepressant response [157,176]). that starting doses of nortriptyline might be sufficient to • Most genes have related inconsistently to treatment reach therapeutic plasma levels in subjects with no or only outcome. Those with a large number of positive studies one functional copy of CYP2D6, among whom higher doses have a small prediction power that limits their application might increase toxicity. High normal doses of the drug in clinical decision-making. would be required for patients with two to four copies. As with tricyclic antidepressants, CYP2D6 variants have been With the exception of CYP2D6 variants that were found shown to modify plasma concentrations of the SSRI to influence response to tricyclic antidepressants, the most paroxetine [171] and the 5-HT–norepinephrine reuptake compelling evidence so far of a pharmacogenetic effect has inhibitor venlafaxine [172]. Such metabolic effects have been collected for 5-HTTLPR. However, recent studies been related to increased toxicity of venlafaxine, while no demonstrate that this polymorphism, pooled with the TPH1, relationship has emerged between CYP2D6 and tolerability can only correctly ascertain AD treatment outcome in <10% and efficacy in patients receiving paroxetine [173]. of patients [13,177]. These classification results are not sufficient in clinical terms to achieve a reliable outcome P-glycoprotein prediction in depression. This ATP-binding transporter protein is expressed in the liver, Most of the studies published so far focused on one or kidney, and small capillaries of the blood–brain barrier [174]. another marker. An alternative approach consists of

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DEPRESSION: MIND AND BODY Vol 3 No 1 2006 31 CASE STUDY 3535 MarketStreet, Suite4005,Philadelphia,PA 19104,USA. Address forcorrespondence: JohnPO’Reardon, Director, VNSClinic, 40 andhisHamiltonDepression Ratingscalescore (24-item patient’s baselineBeckDepression Inventory (BDI)score was On activationoftheVNSdevice2-weekspost-surgery, the therapies, andimplantationwasperformedwithoutincident. the refractory nature ofhisdepression despitemultiple not haveaprimarythyroid disease. secondary tohisserumT3augmentation,butthepatient did thyroxine (T4=0.65;normalrange0.78–2.19),likely prostatic hypertrophy, osteoporosis, andlowserum effects. Hismedicalhistoryincludedelevated lipids,mild (ECT), butthesewere discontinuedduetoadversecognitive received acourseofsixbilateralelectroconvulsive treatments (supportive–expressive type)wasineffective. Thepatient were alsounsuccessfulandatrialofpsychotherapy lithium carbonate,lamotrigine,andtriiodothyronine (T3) adequate antidepressant response. Augmentation with desipramine, andtranylcypromine alsofailedtoproduce an retrial, andcitalopram,sertraline,venlafaxine, bupropion, remission. Furthertreatment attemptswithafluoxetine episode hadendured for12yearswithoutresponse or resistant course.Inthisregard, atpresentation hiscurrent 10 months,buthasotherwisefollowedahighlytreatment- remission aftertherapywithfluoxetine foraperiodof The patientexperiencedasingleperiodofdepression been receiving ongoingpsychiatrictreatment since1986. (MDD) andco-morbidgeneralizedanxietydisorder, whohas of recurrent, chronic, severe majordepressive disorder This isthecaseofa65-year-old malepatientwithahistory Depression: MindandBody VNS Clinic,DepartmentofPsychiatry, UniversityofPennsylvania,Philadelphia,PA, USA John PO’Reardon,KiranBBapatla,andUmairAktar Improve Efficacy Optimizing theDutyCycleto to Vagus NerveStimulation(VNS): Depression withaDelayedResponse A CaseStudyofRefractoryMajor 32 Vagus nervestimulation(VNS)wasrecommended dueto 2006; 3 (1):32–4. D EPRESSION : M N AND IND B 39 andaHAM-D without evidenceofanybenefit,asreflected byaBDIof pulse width/30-son/5-minoff time,10%dutycycle) standard VNSdosing(1.5mA/30Hzfrequency/500 µs provided inTable 1. doses neededtoproduce efficacious results withVNSis the rangeofdosingparametersandtypicalaverage on-time of30sandanoff-time of3min.Anoverview 1.75 mA,500µspulsewidth,30Hzfrequency, withan of aresponse, and,by12weeks,dosageparameterswere primary psychiatrist. assessment intheVNSclinicwhilecontinuingtovisithis help himsleep.Thepatientwasseenevery2–4weeksfor day, andtrazodone200–300mgeverydayatbedtimeto clonazepam 1mgtwicedaily, diazepam5mgthree timesa a psychotropic regimen ofsertraline200mg/day, implemented. Intensitysettings ofVNSwere reduced to in histhroat evenduringtheVNSoff-time. complaining of“constanthoarseness” anda“sore feeling” experiencing significant adverse effects from VNS, were declinedbythepatient.Thepatientwasnowalso Hospitalization andaretrial ofECTwere considered, but help control thefeelingsofagitationandanxiety. His diazepamwasincreased to10mgthree timesadayto anxiety, agitation,despair, hopelessness,and exhaustion. and hewasexperiencingprominent symptomsofsevere ineffective. Byweek20,thepatient’s BDIscore was46, intensity andanincrease instimuluson-timeto60swas version; HAM-D ODY By 12weeks,thepatientwasatupperlevelof VNS wastitratedaccording topatienttoleranceinsearch A changeintreatment strategy wastherefore Vol 3No12006 24 ) was33.Hecontinuedtoreceive 24 of 30.Furthertitrationto2mA A CASE STUDY OF REFRACTORY MAJOR DEPRESSION WITH A DELAYED RESPONSE TO VNS

Table 1. Vagus nerve stimulation pulse generator dosing dosing of VNS parameters [2]. In a section on parameters for patients with treatment-resistant depression. “Individualization of Treatment” from the US Food and Parameter Full range Typical values Drug Administration-approved Physician Manual (Section 8-D, page 45), it is recommended that the output current Output current 0–3.5 mA 1–2 mA be increased in 0.25 mA increments to a comfortable Signal frequency 1–30 Hz 30 Hz tolerance level, and the median values for stimulation Pulse width 130–1000 μs 500 μs parameters at 12 months from the pivotal study are Signal on-time 7–60 s 30 s provided. The median dosing parameters cited are: 1 mA current, 500 µs pulse width, 30 Hz frequency, 30 s on-time, Signal off-time 0.2–180 min 5 min and 5 min off-time. This corresponds to a duty cycle of 10% and no specific guidance is provided to the 1 mA, 130 µs pulse width, and 20 Hz frequency, and it psychiatrist on optimizing the duty cycle beyond that level. was decided to optimize the duty cycle of VNS instead. The VNS device is capable of providing a range of The standard or typical VNS settings, as indicated in acceptable duty cycles from 2% to a maximum of 49%. Table 1 and as reported in the VNS literature for treatment- Levels in excess of 50% are not recommended due to resistant depression (TRD) [1], correspond to a duty excessive demands on device battery life and concerns cycle of 10% (on-time relative to off-time expressed as a about potential injury to the vagus nerve. percentage; Table 2). In general, the first parameter to be optimized in VNS is By week 28, the patient’s duty cycle had been titrated to the current amplitude. However, as illustrated by this case, it 30%; other stimulation parameters were kept the same. may be difficult for many patients to tolerate a current Concurrently, his depression improved significantly with a intensity greater than 1.5 mA due to side effects of drop in BDI score to 19. At the 32-week follow-up visit to the pharyngeal discomfort or pain. An alternative strategy for

VNS clinic, the patient’s BDI score was 19 and his HAM-D24 increasing the total effective dose received by the patient is score was 13. At the most recent visit (week 38, or to increase the duty cycle, or on-time relative to off-time. 9 months post activation), the patient was maintaining his This might be comparable to increasing the total daily dose improvement (HAM-D24 14, BDI 24). The trajectory of of an antidepressant medication by means of several divided change in his ratings is illustrated in Figures 1 and 2. Both doses, such that no single dose caused unacceptable side patient and physician global rating of overall change effects for the patient. corresponded to responder status of “much improved” In the case of this patient, we cannot be certain it was compared with the patient’s baseline depression severity post the increase in duty cycle that caused him to respond to surgery for VNS device implantation. Diazepam usage could treatment. It is possible that simply a longer period of VNS also be reduced back to 5 mg three times a day. The patients’ treatment made the difference. It also cannot be ruled out most recent ratings represent a 57% improvement in HAM- that the addition of duloxetine at week 20 was the

D24 score and 40% improvement in BDI score, compared significant variable in therapeutic change, although this with his baseline scores post surgery. appears unlikely given the lack of previous response to As illustrated in Figure 1, the improvement in this venlafaxine, also a dual reuptake inhibitor, as well as to patient’s depression coincided with the change in dosing many other antidepressant medications. However, it is strategy from titration of current intensity to a three-fold possible that duloxetine and VNS had synergistic or additive increase in the duty cycle. At the time the duty cycle was benefits in combination. increased, sertraline was discontinued and at week 20, This case illustrates that the time taken to achieve a duloxetine, a serotonin-norepinephrine reuptake inhibitor significant therapeutic effect for TRD patients with any was started and subsequently maintained at a dosage of particular intervention may be much longer than for non-TRD 60 mg/day. cases. The pivotal acute VNS study that compared active with sham therapy failed to show a significant difference between Discussion the two treatment groups [3]; some 15% of patients This case illustrates that flexibility in dosing strategy is responded to treatment compared with 10% of those who important when treating severely ill TRD patients with a received placebo. However, at 1 year, a 30% response was VNS device. An appropriate antidepressant medication trial observed in all patients treated with active therapy, either in requires both an adequate dose and duration. The the blinded or open-label crossover phase. This response rate physicians’ manual for VNS provides only minimal was significantly higher than that seen in the comparison guidance for the psychiatrist with regard to optimizing the group (<15% response rate) who were studied under similar

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 33 JOHN P O’REARDON, KIRAN B BAPATLA, AND UMAIR AKTAR

Table 2. VNS duty cycles (% on-time) VNS duty cycles (% on-time) Off-time (min) 0.2 0.3 0.5 0.8 1.1 1.8 3 5 10 7 58 44 30 20 15 10 6 4 2 14 69 56 41 29 23 15 9 6 3 21 76 64 49 36 29 19 12 8 4 30 81 71 57 44 35 25 16 10 5 On-time (s) 60 89 82 71 59 51 38 27 18 10

VNS: Vagus nerve stimulation

Figure 1. Change in the patient’s BDI score. Figure 2. Change in the patient’s HAM-D24 Item score.

60 45 40 50 35 40 30 24 25 30 20 BDI score HAM-D 20 15 10 10 5 0 0 0 2 4 6 9 12 16 20 24 28 32 38 0 6 16203238 Time (weeks) Time (weeks)

BDI: Beck Depression Inventory. HAM-D24: Hamilton Depression Scale - 24 item score. conditions [4]. The efficacy of the treatment has been Disclosures questioned by some [5]; however, the gradual effect of VNS Dr. O’Reardon has received research support from and is a member of has frequently been seen in clinical care, and this case is a the Speakers Bureau of Cyberonics Inc., manufacturer of the VNS device. cogent example of the possible course of treatment response Drs Bapatla and Aktar have no relevant financial interests to disclose. and the current debate regarding efficacy. There is clearly a need for further long-term study of References 1. Rush AJ, Sackeim HA, Marangell LB et al. Effects of 12 months of vagus nerve stimulation effects of VNS. In cases where VNS therapy is given, it may in treatment-resistant depression: a naturalistic study. Biol Psychiatry 2005;58:355–63. also be necessary to attempt number of VNS dosing 2. Depression Physician’s Manual. VNS Therapy™ Pulse Model 102 Generator and VNS Therapy™ Pulse Duo Model Generator. Houston, Tex: Cyberonics, Inc; 2005:1–68. strategies before one is found that is effective for the 3. Rush AJ, Marangell LB, Sackeim HA et al. Vagus nerve stimulation for treatment-resistant individual patient. Optimization of the VNS duty cycle by depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005;58:347–54. 4 George MS, Rush AJ, Marangell LB et al. A one-year comparison of vagus nerve means of a more rapid on-off cycle rather than simply the stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry standard 30 s on-time, 5 min off-time, may yield important 2005;58:364–73. 5. Carlat D. Vagus nerve stimulation: is the evidence convincing? Carlat Report on benefits for some TRD patients. Psychiatric Treatment 2006;4:1–8.

34 DEPRESSION: MIND AND BODY Vol 3 No 1 2006 CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by Paul Ballas and Po Wang

EPIDEMIOLOGY Specifically, the authors suggested that “individualism- collectivism” could be a significant influence, with highly individualistic cultures predisposing to feelings of alienation. Depersonalization in psychiatric patients: The study was limited by the diagnostic procedures, a transcultural study small sample size, and heterogeneity across groups. Sierra M, Gomez J, Molina JJ et al. Depersonalization disorder could not be diagnosed as the J Nerv Ment Dis 2006;194:356–61. patients were hospitalized for other primary psychiatric disorders. Research has suggested that patients have difficulty The authors of this paper examined the prevalence of describing depersonalization; thus, it is possible that IQ, depersonalization disorder in a small number of patients linguistic ability, and educational level may have influenced admitted to psychiatric units in Colombia, Spain, and the rate of self-report in patients with depersonalization. 1. Hunter EC, Sierra M, David AS. The epidemiology of depersonalisation and derealisation. the UK, to determine whether psychiatric patients A systematic review. Soc Psychiatry Psychiatr Epidemiol 2004;39:9–18. from different cultures have different rates of depersonalization. Patients from Columbia had lower Address for reprints: M Sierra, Depersonalization Research Unit, Institute of Psychiatry, King’s College, De Crespigny Park, Denmark Hill, rates of depersonalization in all parameters of the London SE5 8AF, UK. Email: [email protected] Dissociative Experiences Scale (DES) and the Cambridge Depersonalization Scale, with the exception of the DES absorption subscale, suggesting that cultural factors The caregiving environments provided to are involved. children by depressed mothers with or without an antisocial history Despite research suggesting that the clinical presentation of Kim-Cohen J, Caspi A, Rutter M et al. depersonalization disorders has remained stable over the last Am J Psychiatry 2006;163:1009–18. century, the reported prevalence has ranged from 7–80% [1]. To investigate whether this variation reflects true differences The authors of this paper explored developmental between cultures, the authors measured the prevalence rates outcomes in children in caregiver environments who had of depersonalization disorder in 140 psychiatric inpatients depressed mothers with or without a history of antisocial from university teaching hospitals in Colombia (n=41), Spain behavior. Children with mothers who were both antisocial (n=68), and the UK (n=31). The Beck Anxiety Inventory and and depressed were found to have higher rates of conduct the Beck Depression Inventory were used to screen for anxiety disorder and antisocial behavior than children whose and depression, and two self-rating scales, the Dissociative mothers suffered depression alone. These children also had Experiences Scale (DES) and the Cambridge Depersonalization an increased risk of experiencing caregiving abuses. Scale, were utilized to assess for depersonalization. The DES is divided into three subscales: depersonalization/derealization, Previously published data by the same authors suggest that absorption, and amnesia. children with mothers who have both a history of antisocial The prevalence of anxiety and depression was not personality disorder (ASPD) symptoms and major depressive significantly different between the three sample groups; disorder (MDD) have high levels of antisocial behavior. In however, the patient sample from Columbia had significantly addition, research has shown that the majority of children less depersonalization according to all measures except for the with early-onset mental disorders have poor functioning DES absorption subscale. These findings showed that cultural when they become adults [1]. Maternal depression and factors may influence the prevalence of depersonalization. ASPD have been shown to influence psychopathology in

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children through maladaptive parenting, sociodemographic Do bullied children get ill, or do ill children factors, and the level of stress within the family [1]. The get bullied? A prospective cohort study authors of this descriptive study examined these on the relationship between bullying and healthy- psychosocial issues by assessing 1116 mothers, their related symptoms children, and their caregiving environment, for differences Fekkes M, Pijpers FI, Fredriks AM et al. in depressed mothers with or without a history of ASPD. Pediatrics 2006;117:1568–74. Participants came from 15 906 twin pairs born in Wales and England in 1994 and 1995 who had been included in Bullying and physical or psychological problems have a E-Risk (Environmental Risk Longitudinal Twin Study). reinforcing relationship; that is, bullying leads to physical Mothers were administered the Diagnostic Interview or psychological problems, and physical or psychological Schedule for MDD and were interviewed about their lifetime problems predispose to being bullied. history of ASPD symptoms. Four categories of maternal psychopathology were assigned: Unfortunately, bullying is a common experience in school- age children worldwide, with 8% (Germany) to 30% (Italy) • Comparison group – 572 mothers who had of children experiencing bullying at least once per week. no symptoms of either ASPD or MDD. Cross-sectional studies have found an association between • Depressed group – 165 mothers with symptoms of MDD somatic and psychological symptoms and victimization. but no symptoms of ASPD. A number of prospective studies have found that • Antisocial group – 217 mothers with symptoms of ASPD victimization leads to depression and anxiety. Fekkes symptoms but not symptoms of MDD. and colleagues undertook a study of 1597 Dutch children • Comorbid group – 152 mothers with symptoms of both (aged 9–11 years, 50% boys) who were given self-rated MDD and ASPD. questionnaires (measuring bullying/victimization, depression, anxiety, and physical symptoms) at the beginning and Information from mothers and teachers on the children’s end of the school year to test two hypotheses: behavioral problems at 5 and 7 years of age revealed that the children of mothers in the comorbid group had more antisocial • Does bullying have physical or psychological sequelae? behavior but comparable levels of internalizing behavior • Do physical or psychological problems increase the risk problems compared with the children of depressed mothers, of being bullied? and higher levels of both internalizing and antisocial problems compared with children of mothers in the antisocial group. Importantly, in examining the effects of bullying, The authors assessed the caregiving environment through students with baseline physical or psychological problems maternal reports and interviewer observations. More were not included in the analysis. Likewise, in examining the parenting stress was reported by mothers in the comorbid role of physical or psychological problems on bullying, group than by those in the other groups. Compared with students who were already being bullied were not included depressed mothers, mothers in the comorbid group exhibited in the analysis. greater negative parenting and were more than twice as Questionnaires were given to children from 18 Dutch likely to have children who had experienced physical elementary schools during the 1999–2000 academic year, maltreatment and separation from their families. and were completed at baseline and the end of the school Since there was no assessment for maternal bipolar year by a total of 1118 pupils. A total of 14.6% of children disorder or borderline personality disorder, their impact could were bullied at the start of the school year, rising to 17.2% not be determined, limiting the study findings. All offspring by the end. Bullying led to higher odds of developing in this study were twins, again limiting the ability to physical and psychological problems, including depression, extrapolate these findings to mothers of singletons. Based anxiety, “tension”, and bedwetting. Bullied girls were also at on their results, the authors concluded that clinicians treating risk for developing abdominal pain; however, this was not depressed mothers should be aware that a history of ASPD true for boys. Children with baseline depression, anxiety, or in mothers might increase the risk of psychiatric problems in poor appetite, but not headache, abdominal pain, or their children. bedwetting, had higher odds of being bullied. 1. Kim-Cohen J, Moffitt TE, Taylor A et al. Maternal depression and children’s antisocial Victimization and physical or psychological problems behavior: nature and nurture effects. Arch Gen Psychiatry 2005;62:172–81. were found to have a reinforcing relationship, and although Address for reprints: J Kim-Cohen, Institute of Psychiatry, P0 Box 80, this study did not statistically correct for multiple King’s College, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. Email: [email protected] comparisons, the results are consistent with other studies.

36 DEPRESSION: MIND AND BODY Vol 3 No 1 2006 EPIDEMIOLOGY

This relationship needs to be considered by the education measurements moved further away from the target range, professionals and healthcare practitioners who see these either greater or lesser, depression severity increased. This children so that the significant negative impact of bullying is study, if validated, may report an objective laboratory understood, and bullying is considered as a potential measurement of depression state severity, something that is exacerbating factor when psychosomatic problems arise. still lacking at the current time.

Address for reprints: M Fekkes, The Netherlands Organization of Applied Address for reprints: AJ Lewy, Sleep and Mood Disorders Laboratory, Scientific Research, Quality of Life, PO Box 2215, 2301 CE Leiden, Oregon Health and Science University, 3181 Southwest Sam Jackson The Netherlands. Email: [email protected] Park Road, Portland, OR 97239, USA. [email protected]

The circadian basis of winter depression Ten-year prospective follow-up study of the Lewy AJ, Lefler BJ, Emens JS et al. naturalistic course of dysthymic disorder and Proc Natl Acad Sci U S A 2006;103:7414–9. double depression Klein DN, Shankman SA, Rose S. Depression severity in seasonal affective disorder may Am J Psychiatry 2006;163:872–80. correlate with a biological measurement of circadian phase shifts, thus suggesting a potential biological and Dysthymic disorder patients with or without a concurrent objective measure of depression severity. major depressive episode have a continued chronic course of experiencing depressive symptoms. Recovery Seasonal affective disorder (SAD) is a course of illness rates are high and recovery can be sustained; however, of major depressive episodes in which the episodes occur relapse rates are also high. in a seasonal pattern, most often during winter months. SAD may be a subtype of affective disorders that supports Dysthymic disorder, characterized as mild-to-moderate a biological rhythm, and more specifically a circadian depressive symptoms occurring chronically, affects up to phase-shift hypothesis contribution to affective disorder 6% of community-dwelling individuals and 36% of pathophysiology. The circadian phase-shift hypothesis psychiatric outpatients; however, longitudinal studies for proposes that a mismatch of the sleep–wake cycle and the >2 years are lacking. Previously, Klein and colleagues have endogenous circadian pacemaker contributes to affective reported on the 5-year outcomes of patients with dysthymic disorders. More specifically, winter depression may be partly disorder, and here they report on the 10-year course of due to awakening at a time preceding a later-occurring illness in 97 adults (mean age at study entry 32.1 years, sunrise. Thus, early morning bright light may substitute 74.7% female) with early onset (mean age of onset for the late dawn and thus reset the wake and endogenous 20.7 years) dysthymic disorder, who were assessed at circadian pacemaker synchrony. Other SAD patients may be baseline, and 30, 60, 90, and 120 months. Forty-five age more susceptible to mismatch later in the day; that is, and gender-matched non-chronic depressive disorder the earlier sundown is phase advanced from the onset patients comprised the control group. Treatments were of sleep. These patients may therefore respond to evening monitored but not controlled during the follow-up period. light therapy. Patients with dysthymic disorder had fewer years of In this study, Lewy and colleagues proposed a education and higher rates of anxiety and personality physiological marker, phase angle difference (PAD), as a disorder compared with those with non-chronic depression, correlate to clinical depressive severity. PAD is the time from but did not differ in other ways, such as age of depression “dim light melatonin onset” (DLMO), a measurable time onset, marital status, or socioeconomic status. Approximately point based on plasma melatonin levels, to the mid-sleep 5–6% of each group experienced hypomania during the time (half way time point between sleep onset and sleep follow-up study, and were not included in further analyses. offset). PAD measurements were taken in 68 patients with An estimated 74% of patients with dysthymic disorder SAD, and correlated with depression severity, as measured recovered (≥2 consecutive months with ≤2 mild symptoms) by the SAD version of the Hamilton Depression Rating Scale, in a median 52 months. Most recoveries occurred in the first both before and after treatment with melatonin. 3 years. Of recovered dysthymic patients, an estimated 71% PAD measurements had a statistically significant inverse relapsed into a chronic depression (≥24 months with parabolic linear relationship with depression severity in ≤1 month of full remission or ≤2 months of partial remission) patients both before and after treatment. The parabolic a median of 65 months since recovery. Most relapses also linear relationship suggested minimum depression severity occurred during the first 3 years. Patients with dysthymic was found at specific PAD target ranges. As PAD disorder at baseline, with or without a concurrent major

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depressive episode, had similar courses of illness, including This study included patients of Caucasian race only, which similar but lower rates of improvement compared with non- therefore limits these results from being generalized to other chronic depression patients. Patients with chronic depression ethnic groups. Its application to the DSM-IV diagnoses was at baseline were 14 times more likely to have a chronic also potentially limited, as the definitions of generalized depression course compared with non-chronic depression anxiety disorder and panic disorder used were also broader patients. Likewise, non-chronic depression patients at than usual. The structural equation modeling of twins baseline were 12 times more likely to have a non-chronic makes a number of assumptions to estimate genetic and course, compared with the chronic depression group environmental contributions. One assumption of this model is at baseline. Thus, dysthymic disorder with or without a that dizygotic twins do not differ in the environments from concurrent major depressive episode is likely to be a different their twin more than monozygotic twins. If monozygotic twins disorder than major depressive disorder. This has important do have more similar environments, those environmental implications for genetic and neurobiological research. contributions will show up as genetic influences. Nevertheless, this large twin study suggests that neuroticism may be a probe Address for reprints: DN Klein, Department of Psychology, Stony Brook University, Stony Brook, NY 11794-2500, USA. for looking for genetic susceptibility factors shared by anxiety Email: [email protected] and depressive disorders.

Address for reprints: JM Hettema, Virginia Institute for Psychiatric and A population-based twin study of the relationship Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth between neuroticism and internalizing disorders University, PO Box 980126, Richmond, VA 23298-0126, USA. Hettema JM, Neale MC, Myers JM et al. Email: [email protected] Am J Psychiatry 2006;163:857–64. Severe fatigue in adolescents: Genetic factors that underlie neuroticism may also underlie a common phenomenon? the high comorbidity between, and common susceptibility ter Wolbeek M, van Doornen LJ, Kavelaars A et al. to, anxiety and depressive disorders. Pediatrics 2006;117:e1078–86.

The high rates of comorbidity between anxiety and This study assessed the prevalence of severe fatigue and the depressive disorders suggest commonalities in the underlying impact of specific lifestyle factors on fatigue in 3467 Dutch etiologies, including genetic and environmental factors. adolescents. Although fatigue was highly prevalent in both Neuroticism has also been demonstrated to co-occur genders, the rate was higher among female subjects. with these so-called “internalizing disorders”; thus, Fatigue was associated with several symptoms of psychiatric understanding neuroticism may be an important way of disorders, including depression and anxiety. understanding the comorbidity of anxiety and depressive disorders. Hettema and colleagues examined the genetic Chronic fatigue syndrome (CFS) is characterized by severe, and environmental factors shared by neuroticism and enduring fatigue along with symptoms that are not explained “internalizing disorders” through assessing lifetime major by other medical or psychiatric disorders, including non- depressive disorder, generalized anxiety disorder, panic refreshing sleep, cognitive disturbances, myalgia, and disorder, agoraphobia, social phobia, animal phobia, and headaches. The study authors examined the rate of severe situational phobia in 9270 twins (monozygotic pairs, fatigue, the impact of fatigue, and the incidence of anxiety, dizygotic pairs, and monozygotic singletons) enrolled in the depression, and other comorbid factors in adolescents with CFS. Virginia Adult Twin Study of Psychiatric and Substance Use In total, 3467 adolescents (1749 girls and 1718 boys) from six Disorders. Neuroticism was assessed using the validated Dutch secondary schools were enrolled. Of these subjects, two Eysenck Personality Questionnaire and genetic and girls and 11 boys were excluded due to unreliable answering environmental contributions were estimated based on tendencies. Assessments included the Checklist Individual a structural equation modeling of twins. Strength (CIS) questionnaire, the Beck Depression Inventory, Genetic factors associated with neuroticism accounted and the State–Trait Anxiety Inventory for Children. CFS-related for between one-third to a half of the genetic factors symptoms, including unrefreshing sleep, muscle and joint pain, underlying the comorbidity of anxiety and depressive concentration and memory problems, and headaches, were disorders. Other genetic factors, which were not associated assessed using a list adopted from the Centers for Disease with neuroticism, also contributed to the co-occurrence of Control and Prevention side symptoms criteria. these internalizing disorders; however, environmental factors Fatigue was common in both genders, but was more had a minimal role in this overlap. prevalent in girls than in boys. Girls in the study were more

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fatigued than boys. A total of 6.5% and 20.5% of boys and study of the offspring of depressed parents conducted by the girls, respectively, had clinically significant values on the CIS above authors, the mean subject age was 26 years; thus, some questionnaire (>40). Among these subjects, severe fatigue had not passed through the period of onset of several for ≥1 month was reported in 61.5% of boys and 80.0% of disorders, including major depressive disorder [1]. The goal of girls. Sports participation and sleep characteristics played a the current study was to evaluate the extent and continuity significant role in predicting symptoms of fatigue in both of risk of parental depression to offspring 20 years on. genders. In general, girls had more symptoms of CFS, Data were collected on 151 offspring of parents with or depression, and anxiety. without depression who had been screened for the authors’ There were no differences between genders with regard to original study and followed for approximately 20 years fatigue and comorbid symptoms. Fatigue in female adolescents (mean age 35 years). Depressed parents had moderate-to- was associated with medication use, older age, early severe depression, and non-depressed parents were selected menarche, and no additional job. Girls reported more fatigue- from the community after screening to exclude those with a related school absenteeism than non-fatigued girls, but this history of mental illness. Independent interviews were effect was not observed in boys. In both genders, fatigue conducted on subjects, their spouses, and their children. duration was associated with severity of anxiety and Clinical assessments and interviews were conducted at four depression, number of symptoms related to CFS, and severity occasions from either childhood or adolescence through of fatigue. adulthood. Each interviewer was blinded to the results of the The authors of this article suggest fatigue is very common previous assessments. Several screening instruments were among adolescents, particularly among girls, who are more utilized including the Global Assessment Scale and the Schedule susceptible to comorbid disorders and symptoms of fatigue for Affective Disorders and Schizophrenia-Lifetime Version. than boys. It is of note that despite the differences, no At the 20-year follow-up assessment, there were no gender-specific relationships between fatigue and anxiety, significant differences in most socioeconomic factors CFS-related symptoms, or depression were observed. between subjects in the two groups. Offspring of depressed Duration of fatigue was related to comorbid CFS-related parents were approximately three times more likely to suffer symptoms and other psychiatric complaints. The authors from anxiety or mood disorders, particularly phobia and suggest that severe fatigue occurring for long durations may major depressive disorder. The age of onset of depression increase the risk of adolescents developing CFS. was younger in subjects with depressed parents than in subjects in the control group, but this difference was not Address for reprints: CJ Heijnen, Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, statistically significant (p=0.13). The study also showed that KC03.063.0, PO Box 85090, 3508 AB Utrecht, The Netherlands. alcohol dependence was more than twice as likely and drug Email: [email protected] dependence was six times as likely in the offspring of depressed parents compared with subjects with non- Offspring of depressed parents: 20 years later depressed parents. Subjects with depressed parents had Weissman MM, Wickramaratne P, Nomura Y et al. lower overall functioning, and poorer functioning at work Am J Psychiatry 2006;163:1001–8. and in their extended families. With regard to medical illness, the offspring of depressed The authors of this paper examined the risk of several parents were more than twice as likely to have a physical health psychiatric and medical disorders in 151 offspring of problem, twice as likely to have a neuromuscular disorder, and depressed and non-depressed parents in a 20-year follow-up more than five times as likely to have a cardiovascular problem. study. Offspring of depressed parents were approximately This study offers evidence that individuals with depressed three times more likely to have substance dependence, parents are at a higher risk for several psychiatric and medical anxiety disorders, or major depression. Subjects also suffered problems. The study results are limited by the small number greater social impairment and higher rates of medical of subjects, which meant that analysis by specific disorder or disorders and mortality as they entered middle age. sex could not be accomplished; however, as the authors assert, to date this is the longest follow-up study of the Previously published research has shown that children of offspring of depressed individuals with comparison subjects. depressed parents have a 2–3-fold greater risk of developing 1. Weissman MM, Warner V, Wickramaratne P et al. Offspring of depressed parents. 10 years later. Arch Gen Psychiatry 1997;54:932–40. anxiety disorders and major depressive disorder; however, the longest follow-up study of high-risk offspring that could be Address for reprints: MM Weissman, Department of Psychiatry, identified by the study authors was 4 years, and no study had Columbia University, New York State Psychiatric Institute, Unit 24, 1051 Riverside Drive, New York, NY 10032, USA. followed these subjects into adulthood. In a 10-year follow-up Email: [email protected]

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CLINICAL PRACTICE Additionally, the olfactory system is intimately connected to the limbic and orbitofrontal cortices. Therefore, olfactory identification deficits in psychotic processes may have both Olfactory identification deficits in first-episode important clinical and research uses. psychosis may predict patients at risk for persistent Address for reprints: KP Good, AJLB, 4th Floor, 5909 Veteran’s negative and disorganized or cognitive symptoms Memorial Lane, Halifax, NS, B3H 2E2 Canada. Good KP, Whitehorn D, Rui Q et al. Email: [email protected] Am J Psychiatry 2006;163:932–3. Aripiprazole in the treatment of patients with Psychotic patients with a better capability to identify odors borderline personality disorder: a double-blind, at baseline showed a higher rate of remission of negative placebo-controlled study and disorganized/cognitive symptoms at 1-year follow-up. Nickel MK, Muehlbacher M, Nickel C. Am J Psychiatry 2006;163:833–8. An impaired ability to identify odors has been reported in psychotic disorder patients, and high-risk patients who Aripiprazole (15 mg/day) given for 8 weeks was well eventually developed a psychotic disorder have been found tolerated and showed superior efficacy compared with to have a poorer ability to identify odors. Good and placebo in decreasing depressive and anxiety symptoms colleagues sought to study the potential prognostic value of in patients with borderline personality disorder. olfactory identification ability in new-onset psychosis patients. Fifty-eight subjects (40 male, mean age 22.5 years) Borderline personality disorder is characterized by pervasive who met criteria for schizophrenia, schizoaffective disorder, patterns of instability of affect regulation and behavioral or psychosis not otherwise specified were rated using control/impulsivity. Patients with borderline personality the University of Pennsylvania Smell Identification Test disorder require multidimensional treatment, including and the Positive and Negative Syndrome Scale (PANSS) psychotherapeutic and pharmacological modalities. at baseline, and using the PANSS at 1-year follow-up. Impulsivity symptoms have pointed toward serotonergic The PANSS was modeled to five factors: positive, negative, dysfunction, and symptoms of affective instability have cognitive/disorganized, anxiety/depression, and excitement. suggested potential benefits from mood-stabilizing Symptom remission was defined as having no item greater medications. Aripiprazole is an atypical antipsychotic than mild severity in any of these factors. medication with dopamine receptor type 2 partial agonism, Patients with higher olfactory identification scores had serotonin 1A (5-HT1A) receptor partial agonism, and higher remission rates of negative and cognitive/disorganized 5-HT2A receptor antagonism. It is approved by the US symptoms. Patients with normal smelling ability were Food and Drug Administration for the treatment of more likely to remit from negative symptoms (80%) and schizophrenia and bipolar mania. Nickel and colleagues cognitive/disorganized symptoms (68%), compared with investigated the efficacy of aripiprazole, given at a fixed patients with impaired smelling ability (56% and 33% for dose of 15 mg/day for 8 weeks, compared with placebo, in negative and cognitive/disorganized symptoms, respectively). patients (83% female, mean age 22.1 and 21.2 years for The three other PANSS factors did not correlate with baseline treatment and placebo group, respectively) with DSM-IIIR- olfactory identification scores. defined borderline personality disorder. Patients with Predicting improvements in negative symptom and schizophrenia, current psychotherapy, or current suicidal cognitive function domains is particularly important, given ideation were excluded. that these are commonly more difficult to treat compared Psychopathology was assessed weekly by the Symptom with positive symptoms. Olfactory testing is easily Checklist (SCL-90-R), Hamilton Depression Rating Scale administered, with patients asked to identify 40 scratch-and- (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and sniff impregnated cards based on multiple-choice answers. State–Trait Anger Expression Inventory. After randomization, However, determining whether diagnosis (schizophrenia, the two treatment groups were found to be fairly well schizoaffective, or psychosis not otherwise specified) has an matched on demographic variables and psychopathological impact on the predictive utility of olfactory identification will severity. Aripiprazole (15 mg/day) was associated with require larger sample sizes. The olfactory system has significantly greater absolute decreases and rates of change significant advantages for the study of psychotic processes in depressive and anxiety symptoms after 8 weeks of as the system involves relatively few neuronal connections treatment. Global improvement, measured by the Global between peripheral receptors and central pathways. Severity Index, was also greater for aripiprazole-treated,

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patients compared with those receiving placebo. No serious antiglaucoma and antidepressant medications filled from adverse effects (including suicidal acts) were reported. 2001–2003. Subjects were only included if they filled six Response and remission data were not reported, nor or more consecutive prescriptions for antiglaucoma were rates of comorbidity with bipolar disorders. Bipolar medications at least once every 2 months (n=6597). Among disorder and borderline personality disorder commonly co- these subjects, depressed patients were identified as those occur, and have overlapping symptomatology. An important who filled four or more antidepressant prescriptions from potential limitation of the specificity of aripiprazole for 2001–2003 (n=810). borderline personality disorder in this study is that The results revealed that 12.2% (12.7% after age- aripiprazole has demonstrated efficacy in treating bipolar adjustment) of those treated with beta-blockers and acute mania. Without specifically separating out bipolar 12.7% of those not treated with beta-blockers received disorder diagnoses, it is unclear, based on the presented antidepressant medication. Gender, place of birth, and age analysis, whether aripiprazole was uniquely efficacious for of the patient had significant effects on the prevalence borderline personality disorder. Finally, the exclusion of of depression in multivariate logistic regression analysis. patients concurrently engaged in psychotherapy or with This evidence presented here suggests that there is no suicidal ideations seriously limits the ability to generalize association between topical beta-blockers and the prevalence these results. Nevertheless, aripiprazole appears to have of depression in glaucoma patients. This finding is limited as efficacy as a pharmacological therapy for some patients with the data was gathered from HMO-related pharmacies. Higher borderline personality disorder, a difficult to treat illness. income patients may not have used such pharmacies and lower income patients may not have been able to afford the Address for reprints: MK Nickel, Clinic for Psychosomatic Medicine, Inntalklinik, 84359 Simbach am Inn, Germany. pay for both antiglaucoma and antidepressant medications. Email: [email protected] Patients with mild depression may not have used medication and may have selected to use psychotherapy or go untreated. Topical beta-blockers are not associated with an Address for reprints: I Kaiserman, Department of Ophthalmology, increased risk of treatment for depression Barzilai Medical Center, 78306 Ashkelon, Israel. Kaiserman I, Kaiserman N, Elhayany A et al. Email: [email protected] Ophthalmology 2006;113:1077–80. Omega-3 treatment of childhood depression: This observational, retrospective, population-based a controlled, double-blind pilot study cohort study assessed the effects of topical beta-blocker Nemets H, Nemets B, Apter A et al. use on the prevalence of depression in patients with Am J Psychiatry 2006:163:1098–100. glaucoma. The rates of depression were affected by the gender, age, and birthplace of the patient, but topical This 16-week pilot study explored the efficacy of omega-3 beta-blocker prescriptions were not significantly related fatty acids in pediatric depression. Twenty children, aged to the prevalence of depression in any age group. 6–12 years, were randomized to receive either omega-3 fatty acids or placebo, and depression rating scale scores Topical beta-blockers are one of the most common classes of were recorded for ≥1 month. Subjects receiving omega-3 medication used to treat increased intraocular pressure fatty acids showed improvement on all scales in symptoms caused by glaucoma. Despite the fact that these medications of depression. These data suggest that omega-3 fatty are applied locally, they are partially absorbed into the acids may be beneficial for the treatment of depression systemic circulation. It has been suggested this partial in children. absorption causes certain side effects, such as bradyarrhythmias, asthma exacerbations, and depression. Based on a previous study in which omega-3 fatty acids Therefore, the authors of this study aimed to determine were shown to have some efficacy as an adjuvant treatment whether the use of topical beta-blockers correlated with the for depression in adults [1], these authors examined the prevalence of depression in patients with glaucoma. efficacy of omega-3 fatty acids in the pediatric population. The Central District of Clalit Health Services was the Children were recruited from two depression clinics in largest health maintenance organization in Israel at the time Israel, and randomized to receive placebo or omega-3 fatty data were gathered, with 317 469 subjects included in the acids (1000 mg/day). Subjects were assessed for symptoms database. All members utilized a central repository to report of depression utilizing the Children’s Depression Inventory prescriptions filled from community pharmacies. The (CDI), the Clinical Global Impression (CGI) scale, and the authors screened this database for all prescriptions for Children’s Depression Rating Scale (CDRS). Assessments

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were made at 2, 4, 8, 12, and 16 weeks. Of the 28 subjects brachial artery and blood level measurements of glucose, randomized, 20 completed ≥1 month of assessments, 10 in triglyceride, cholesterol, cortisol, urea, electrolytes, and full each experimental category. blood count were made. The 30 depressed subjects were The omega-3 group showed a significant reduction in randomized to receive either metyrapone or placebo, and CDI and CDRS depressive score; seven of the 10 subjects measurements were repeated after 6 h. Subjects were then in the omega-3 group had a reduction in CDRS score administered the Brief Anxiety Scale questionnaire for of >50%. The CDRS data revealed differences between assessment of symptoms of anxiety. groups at 8, 12, and 16 weeks (p=0.04, 0.03 and 0.03, The results revealed that depressed subjects had impaired respectively). The CGI data also revealed differences FMD compared with healthy subjects. At baseline there was between groups at 8, 12, and 16 weeks (p=0.0104, 0.003, no difference between the metyrapone and placebo groups and 0.002 respectively). No clinically significant adverse with respect to FMD measurements. Metyrapone reactions were reported. significantly reduced cortisol levels and significantly The results of the study indicate that omega-3 fatty acids improved FMD compared with placebo. There was no may have efficacy in treating major depressive disorder in significant correlation between FMD, cortisol levels, and children, although they are limited by the small sample size. scores on the Brief Anxiety Scale questionnaire. However, it In addition, there were fewer girls than boys in the study is possible that metyrapone administration may have (three girls in the placebo group, two in the omega-3 resulted in greater stimulation of flow rather than actually group), making it difficult to assess the effect of gender on improving endothelial dysfunction. the results. 1. Hemingway H, Marmot M. Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. 1. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication BMJ 1999;318:1460–7. treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477–9. 2. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med 2002;23:51–61. Address for reprints: RH Belmaker, Beer-Sheva Mental Health Center, 3. Rajagopalan S, Brook R, Rubenfire M et al. Abnormal brachial artery flow-mediated PO Box 4600, Beer-Sheva, Israel. Email: belmaker@ bgumail.bgu.ac.il vasodilation in young adults with major depression. Am J Cardiol 2001;88:196–8. 4. Broadley AJ, Korszun A, Jones CJ et al. Arterial endothelial function is impaired in treated depression. Heart 2002;88:521–3. Metyrapone improves endothelial dysfunction in Address for reprints: MP Frenneaux, Department of Cardiovascular patients with treated depression Medicine, The Medical School, University of Birmingham, Edgbaston, Broadley AJ, Korszun A, Abdelaal E et al. Birmingham, B15 2TT, UK. Email: [email protected] J Am Coll Cardiol 2006;48:170–5. The Can-SAD study: a randomized controlled trial The authors of this paper assessed the effects of the effectiveness of light therapy and fluoxetine of metyrapone, a cortisol inhibitor, on endothelial in patients with winter seasonal affective disorder dysfunction in patients being treated for recurrent major Lam RW, Levitt AJ, Levitan RD et al. depressive disorder in a double-blind, placebo-controlled, Am J Psychiatry 2006;163:805–12. randomized trial. Metyrapone significantly reduced plasma cortisol levels and improved endothelial function Early morning bright light therapy and fluoxetine therapy compared with those receiving placebo, thus supporting were found to be equally efficacious for major depressive the notion that the endothelial dysfunction observed in episodes with seasonal patterns. depression involves cortisol. Seasonal affective disorder (SAD) is described as major Evidence suggests that depression is a risk factor for the depressive episodes occurring in a repetitive seasonal development of coronary heart disease, even after controlling pattern, which may respond to light therapy. Several for other risk factors [1,2]. Furthermore, research has shown placebo-controlled trials have shown early morning bright that depressed patients have endothelial dysfunction [3,4]. It light exposure to be effective as a first-line treatment for has been suggested that this abnormality is due to alterations SAD. Antidepressants, in particular selective serotonin in the hypothalamic–pituitary–adrenal axis, resulting in reuptake inhibitors, have also shown efficacy for SAD, increased cortisol levels. Thus, the aim of this study was to though this is based on fewer controlled studies. In this assess the effects of metyrapone, a cortisol inhibitor, study, Lam and colleagues compared the efficacy of light on endothelial function in depressed patients. therapy and fluoxetine for treatment of SAD. The authors enrolled 36 healthy subjects and Ninety-six patients who had major depressive episodes 30 depressed patients. Endothelial function was assessed at with a seasonal (winter) pattern were randomly assigned to baseline by measuring flow-mediated dilation (FMD) in the receive treatment for 8 weeks with either:

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• Light therapy (early morning upon awakening between these medications in adolescents and children. The risks in 7–8 am, bright [10 000 lux] light plus placebo). older adults remain to be evaluated. Juurlink and colleagues • Fluoxetine 20 mg/day plus early morning, low examined coroner’s records from Ontario, Canada from the light treatment. years 1992–2000. A total of 1138 suicides in individuals aged ≥66 years, who could be matched to four control subjects for Both treatment groups had high rates (67% for both demographical, medical, and psychiatric characteristics and groups) of clinical response (>50% decrease in the 24-item utilization of psychiatric services, were identified for analysis.

Hamilton Depression Rating Scale score [HAM-D24]) and The risk of suicide after use of an antidepressant was moderate rates of clinical remission (50% and 54% for light calculated as an odds ratio. and fluoxetine treatment groups, respectively; score <9 on The mean age of suicide was 74.9 years, 78% were men, the HAM-D24). Response and remission rates were and 80% lived in urban centers. Only 13% had used any comparable, and the study was powered to detect medium psychiatric services in the year preceding the suicide, and effect sizes (0.6) with a power of 80%. Both treatments only 32% had used antidepressants in the 6 months prior to were well-tolerated; however, the fluoxetine treatment death. Very few (3.3%) had a history of a suicide attempt group had higher rates of agitation, sleep disturbance, and 3 years prior to death. The most common suicides were by palpitations. Although patients with bipolar disorder type 2 firearm (33%), hanging (28%), and poisoning (25%). (but not type 1) were allowed in the study, no emergent A total of 73 suicides occurred in individuals treated hypomanic episodes were noted. with SSRIs; the total number of patients in the Ontario This study suggests equivalent efficacy of light therapy healthcare system using SSRIs was 244 749. Therefore, and antidepressant therapy for major depressive episodes one in 3353 SSRI-treated patients committed suicide. with seasonal affective course of illness, and light therapy In comparison, one in 16 037 patients treated with an may have some superior tolerability. The strengths of this alternative antidepressant committed suicide. However, it study include the use of a standard 8-week treatment can be presumed that in both situations the risk of suicide is duration, which is comparable to antidepressant efficacy predominantly related to the contribution of depression, trials. Future studies may address whether combination rather than the use of the antidepressant. The risk of suicide therapy with bright light and an antidepressant is superior to after treatment with an SSRI was highest in the first month monotherapy with either treatment or antidepressant after commencing treatment, and five times greater than combinations, both in terms of efficacy and tolerability. the risk associated with using other antidepressants. The risk was lower for all antidepressants, and similar between SSRIs Address for reprints: RW Lam, Mood Disorders Centre, UBC Hospital, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. and other antidepressants, in subsequent months. Email: [email protected] Violent suicides were associated with early SSRI use, but non-violent suicides did not differ between SSRI and The risk of suicide with selective serotonin other antidepressants. reuptake inhibitors in the elderly Overall, this study has important implications in Juurlink DN, Mamdani MM, Kopp A et al. supporting the increased risk of suicide with early use Am J Psychiatry 2006;163:813–21. of SSRIs for the treatment of depression in older adults, clearly expanding the risk beyond adolescents and children. Selective serotonin reuptake inhibitor (SSRI) use in older Some have suggested that unrecognized bipolar disorder adults was associated with a increased risk of suicide, in children, who have not had the time to fully manifest in particular violent suicide, compared with other mania episodes, might account for this risk. This study’s antidepressants. This risk was greatest in the first month finding in older adults as well as the association with violent after treatment. Although the increased suicide risk suicides suggests other underlying factors. Although this risk specific to SSRI antidepressants is supported by this seems more real, future studies should identify which study, depression itself still carries a greater absolute risk patients are susceptible to SSRI-associated increased risk of suicide. Therefore, the goal should be to identify the of suicide. The overall rate of suicide in patients treated subset of patients who are at risk of committing suicide. with SSRIs was low (approximately three in 10 000), and treatment of depression is still likely the best way The potential association between selective serotonin to prevent suicide. reuptake inhibitors (SSRIs) and suicide is currently a Address for reprints: DN Juurlink, Institute for Clinical Evaluative contentious debate, with the US Food and Drug Sciences, G Wing 106, 2075 Bayview Avenue, Toronto, ON, Canada Administration warning of this potential risk when using M4N 3M5. Email: [email protected]

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Variation in the gene encoding the serotonin 2A has been implicated by prior neurobiological evidence receptor is associated with outcome of as important in major depression and antidepressant action. antidepressant treatment Address for reprints: FJ McMahon, Genetic Basis of Mood and Anxiety McMahon FJ, Buervenich S, Charney D et al. Disorders, National Institute of Mental Health, 35 Convent Drive, Am J Hum Genet 2006;78:804–14. Room 1A202, Bethesda, MD 20892-3719, USA. Email: [email protected]

In this study based on genotype screening of 1297 patients from the STAR*D (Sequenced Treatment Primary care patients’ involvement in decision- Alternatives for Depression) clinical trial, serotonin 2A making is associated with improvement receptor allelic variations are associated with response in depression or remission to citalopram. Clever SL, Ford DE, Rubenstein LV et al. Med Care 2006;44:398–405. Antidepressant medications have proved effective for relieving the suffering from major depressive disorder; In patients who reported an involvement in their healthcare however, up to one-third of patients do not respond to an decisions, treatment for depression was more in line with adequate trial of a single antidepressant. Clinical symptoms treatment guidelines and more likely to result in remission. and family history are only rough guides to medication choices. McMahon and colleagues examined the genotypes Major depression is associated with substantial morbidity and of 1297 patients with major depressive disorder in the mortality. Antidepressant medications and psychotherapy are STAR*D (Sequenced Treatment Alternatives for Depression) effective treatments, but not all patients receive adequate trial for 68 candidate genes with 768 single nucleotide- therapy. In particular, many patients who present for polymorphism (SNP) markers correlated to patient response treatment to their primary care providers may not take full to citalopram. advantage of available or recommended care. Clever and Candidate genes and SNP markers were chosen based colleagues sought to investigate whether patients’ on current literature. The total sample was divided into a involvement in their care decisions improved major larger “discovery sample” (859 samples) and smaller depression treatment outcomes. A total of 1706 patients “replication sample” (438 samples). The “discovery from the QID (Quality Improvement for Depression) project sample” identified potential genetic effects, based on a rated their involvement in making decisions about their significance level of 0.01, which had a 90% power to healthcare on a 5-point scale. Depression symptoms were detect an effect size of 16%. These potential alleles were rated every 6 months over 2 years by the Center for assessed at the next level of the replication sample, which Epidemiologic Studies – Depression (CES-D) scale. Care was had an 80% power to detect an effect size of 16%, and a rated on whether it met recommended treatment guidelines, significance level of 0.05. Response and remission that is a therapeutic dose of at least one antidepressant for assignments (phenotypic definitions) were made prior the entire 6 month follow-up and four or more counseling to genotyping. sessions with a mental health profession in a 6-month period. Twelve SNPs emerged from the hypothesis-generating Approximately three-quarters of patients were female, phase of the discovery sample. Only one SNP met 69% were aged ≤50 years and almost 50% were married. significance in both the discovery and replication samples. Over half (57%) had been educated beyond high school. A This SNP was the second intron (non-coding region) of the total of 53% received care for their depression that met with serotonin 2A receptor (5-HT2A), which supports the role of treatment guidelines. Only 38% of patients reported that 5-HT2A in antidepressant response or remission. Specifically, their primary care provider managed mental health issues at 80% of A allele homozygotes in this locus were responders, their most recent visit. Reports of greater patient involvement compared with 62.4% of G allele homozygotes. with healthcare decisions were associated with greater receipt The specific role of 5-HT2A in antidepressant response of guideline-concordant treatment for depression and was not clarified by this study, given that the identified locus a greater probability of depression resolving over 18 months. was in the non-coding gene region, and two known Patient involvement in decision-making has been functional SNPs in 5-HT2A were not found to be significant associated with improved health outcomes in other studies, by the analyses. Additionally, the significance level of 0.05 and patient satisfaction is clearly improved. This study did not for the replication sample did not account for the need for objectively observe whether patients were actually more multiple comparisons corrections for the 12 SNPs evaluated involved with decision making by their primary care providers, from the discovery sample. Nevertheless, the 5-HT2A gene but rather patient perceptions. It is possible that improved

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outcomes led patients to believe they were more involved OSAHS may contribute to the increased risk of coronary with their treatment decisions. Furthermore, techniques that events associated with depression in this population. providers used to improve patient participation and/or Patients with CHD were assessed for the presence of perception of participation were not assessed, and these could depression using the Depression Interview and Structured be used to more effectively train other providers and possibly Hamilton (DISH), which was used to diagnose patients with improve outcomes. Nevertheless, primary care patients’ major, minor, or no depression. Fifty-three subjects were involvement in decision-making was associated with improved classed as having major depression, 36 had minor depression, depression treatment outcomes. and 43 had no depression. Subjects were evaluated for OSAHS during a 2-night assessment in a sleep medicine Address for reprints: LA Cooper, Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 East Monument Street, Suite laboratory. The evaluation included polysomnography 2-500, Baltimore, MD 21287, USA. Email: [email protected] measurements of frequency and duration of apnea, desaturation index, and maximum oxygen desaturation level. COMORBIDITIES Results revealed that 69% of the minor depression patients, 66% of the major depression patients, and 77% of those with no depression had OSAHS. Subjects with major Depression and obstructive sleep apnea in patients depression had longer durations of apnea and hypopneas, with coronary heart disease more frequent apneic episodes, and more oxygen Carney RM, Howells WB, Freedland KE et al. desaturation than subjects with minor depression. The Psychosom Med 2006;68:443–8. frequencies of oxygen desaturation and apneic episodes were not significantly different between subjects with major In this study of 132 patients with coronary heart disease, depression and those without depression. Women with the authors examined whether obstructive sleep major depression had fewer obstructive episodes than those apnea/hypopnea syndrome is part of the mechanism by without depression, while men with major depression had which depression increases the risk of cardiac events in more obstructive episodes than non-depressed men. these individuals. No significant difference in the rate of The evidence from this study suggests that in subjects depression was found between subjects with or without with CHD, OSAHS was not more common in those with obstructive sleep apnea/hypopnea syndrome. depression. Apneic episodes tended to be more frequent and longer in patients with CHD who also had major depression. It has been reported that depression is a risk factor for cardiac Men with CHD and major depression tended to have more events in patients with coronary heart disease (CHD) [1]. frequent apneic episodes than men with CHD alone.

Obstructive sleep apnea/hypopnea syndrome (OSAHS) has 1. Licinio J, Wong M-L (Eds). Biology of depression: from novel insights to therapeutic also been shown to be a risk factor for cardiac events and can strategies. Vol. 2. Wiley UK. 2005:617–31. present with depression. Major depressive disorder and Address for reprints: RM Carney, Behavioral Medicine Center, OSAHS are commonly comorbid in people with CHD. The 4625 Lindell Blvd., Suite 420, St. Louis, MO 63108, USA. authors of this study therefore hypothesized that undiagnosed Email: [email protected]

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 45 MEETING REPORT or dopamineantagonistssuch asatypicalantipsychotics, these, adjunctivedopamine agonistssuchaspramipexole, Vieta (University ofBarcelona, Barcelona, Spain). Among studies, treatments are availableand were reviewed byEduard under- ornot-treat theirpatients.Despitethepaucity of However, theseconcernsshouldnotcause clinicianstoeither sometimes seenfollowingtreatment withthesedrugs. switch tomaniaandtheincreasing numberofillnessepisodes prescribe antidepressants tobipolarpatientsduetheriskof for thisunder-treatment includewarinessofmanycliniciansto for typicallyhalfoftheweeksinayear. Possibleexplanations symptoms forlongperiodsoftime;current estimatessuggest patients (bothtypeIandII)are symptomaticfordepressive California, SanDiego,CA,USA),whonotedthatbipolar depression wasunderlinedbyLewisJudd(Universityof in thecontextofbipolardisorder. Theprevalence ofbipolar to beaddressed. Amongtheseisthetreatment of depression are stillalarge numberoftreatment requirements thatremain Despite thecurrent availabilityofantidepressant drugs,there Bipolar depression in aspects ofdepression. Abstractshavebeenpublished a brieftext;therefore, thisreport willfocusontheclinical presented atthemeeting,theycannotallbecovered insuch large numberoffindingsfrom bothclinicalandbasicsciences data ofinterest tothejournalreader. However, duetothe promising newtechniques. interest, andtraditionalmethodswere evaluatedalongwith and posterpresentations. Treatment strategieswere ofmajor major topics,andfeatured inmore than300reports, oral, pharmacology (ECNP)congress. Depression wasoneofthe attended the19thEuropean CollegeofNeuropsycho- Approximately 8000participantsfrom around theglobe Institute ofPsychiatry, UniversityofBologna,Italy. Alessandro Serretti Paris, France,16–20September, 2006 Annual Congress Neuropsychopharmacology (ECNP) The 19thEuropean Collegeof 46 Eur Neuropsychopharmacol The present articlewilltrytosummarizethemostrelevant 2006 Sep;16:Suppl4. D EPRESSION : M N AND IND B augmentation therapies. attention shouldtherefore bepaidwhenprescribing dermatological sideeffects ifnottitratedproperly. Careful may leadtodependence,andlamotriginecancause pindolol canaffect bloodpressure, psychostimulants some caution–thyroid hormonemayaltercalciumbalance, be ofbenefit.However, all concomitanttherapiesrequire Fricchione Parise,MentalHealthCenter, Avellino, Italy)may modafinil, andlamotrigine(alsodiscussedbyViviana benzodiazepines, S-adenosyl-methionine,pyschostimulants, expression analyses(Jonathan Kerr, St.George’s Hospital genes isnotyetavailable.Current linesofinvestigationinclude despite decadesofinvestigation, adefinitelistofsusceptibility to presentation, recurrence, andtreatment response. However, of depression thatcanbeinfluencedbygenetics, from liability Hospital, Brussels,Belgium),whosummarizedthemanyfacets of depression washighlightedbyJulienMendlewicz(Erasme The importanceofgenesinbothclinicalandresponse aspects Genetics anddepression University ofMedicalSciences,Pozna folate, thyroid hormone(alsodiscussedbyDorota Lojko, should beconsidered intheseindividuals.Theadditionof School, Boston,MA,USA)suggestedthatadd-ontherapies to achievefullremission. JonathanAlpert(Harvard Medical in unipolardepression, where large numbersofpatientsfail for alongtime,isanongoingproblem. Thisisalsothecase patients mayrespond totreatment butremain symptomatic Subsyndromal symptomatology, where mooddisorder Subsyndromal symptomatology be through anindirect stabilizingeffect. efficacy, asconfirmedbyempiricalevidence,maypossibly drugs haveoppositemechanismsofaction;therefore, their received specificattentionatthismeeting. Curiously, these ODY Vol 3No12006 ń , Poland),pindolol, THE 19TH EUROPEAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY ANNUAL CONGRESS

Medical School, London, UK) and pharmacogenetics (Ursula treatment practice. Clinicians are often puzzled by the over- D’Souza, Institute of Psychiatry, London, UK). Dr D’Souza optimistic reports of success in the literature that do not reported results from the large ongoing collaborative European match everyday clinical experience, where only low numbers GENDEP (Genome-Based Therapeutic Drugs for Depression) of patients achieve remission and frequently relapse. Results study, in which expression analyses evidenced that certain from STAR*D reported a 30% remission rate with first-line genes, including those encoding the serotonin transporter treatment (in this case, citalopram). This figure is closer to the (5-HTT), P-glycoprotein 1a and 1b (ABCB1a and ABCB1b), one observed in regular clinical practice than those sometimes and FK-506 binding protein 5 (FKBP5), were differentially reported in research. Second-line treatment – a switch to expressed following antidepressant treatment. The effects were sertraline, bupropion, or venlafaxine, or augmentation with observed over varying periods of time and at different drug either buproprion or buspirone – similarly resulted in a 30% concentrations. Interestingly, two of these genes – 5-HTT and remission rate. These findings highlight the unmet need for FKBP5 – were also associated with antidepressant response in more effective and rapid treatments for depression. depressed patients. In fact, a presentation by the current author, Siegfried Kasper (Medical University of Vienna, Vienna, Alessandro Serretti (University of Bologna, Bologna, Italy) Austria) reviewed the efficacy of second-generation reported that a polymorphism in the gene coding for 5-HTT antipsychotics in psychotic or resistant depression. The was associated with antidepressant response in so large a pharmacodynamic rationale for this association is not known, number of independent samples that it can be considered a but could involve the 5-HT2c and/or the serotonin or definitive finding. This gene variant is one of the most studied in norepinephrine reuptake blocking properties of these the psychiatric genetic field and was associated with a number compounds. The few studies performed in this field indicate of other features presented at this meeting. Karen Sugden that the addition of an atypical antipsychotic, such as (Institute of Psychiatry) summarized the evidence for its risperidone or olanzapine, results in a significantly higher interaction with environmental factors and depression liability proportion of treatment responders. This was observed for and Andreas Reif (University of Würzburg, Würzburg, unipolar depression with psychotic features and bipolar Germany) confirmed this association in violent offenders. depression, as reported by Gary Sachs (Massachusetts General Andrea Sarosi (Semmelweis University, Budapest, Hungary) Hospital, Boston, MA, USA), Samuray Ozdemir (Istanbul focused on neuropsychological aspects, reporting 5-HTT to be a University, Istanbul, Turkey), Octavian Vasiliu (Military Central genetic susceptibility factor for impaired inhibitory cognitive Hospital, Bucharest, Romania), and many others. However, control and verbal working memory dysfunction in major further discussion revealed that a risk/benefit ratio should be depressive disorder. In accordance with the known associations considered for depressed patients due to the increased of this gene variant with drug abuse and dependence, José likelihood of development of long-term side effects, such as Trigo Diaz (Universitat Pompeu Fabra, Barcelona, Spain) tardive diskynesia. demonstrated its influence on 3,4-methylenedioxymeth- amphetamine rewarding in animals. Katia Giaquinto (University New treatments of Salerno, Salerno, Italy) confirmed the association of 5-HTT Data on agomelatine, a new melatonergic antidepressant with antidepressant drug efficacy in eating disorders and Daria that acts as an agonist at melatonin receptors, MT1 and

Gaysina (Institute of Biochemistry and Genetics, Ufa, Russian MT2, and has 5-HT2c antagonist properties, was presented Federation) documented the association of 5-HTT with by Stuart Montgomery (University of London, London, UK), depression in a study of Russian women. Sidney Kennedy (Toronto General Hospital, Toronto, ON, The impact of allelic variation within the 5-HTT gene Canada), and Michel Hamon (Universitaire Pitié Salpêtrière), supports the hypothesis of searching for a broad effect of among others. The drug has proved effective in patients gene variants across many classification boundaries, both in with depression and improved sleep without adversely patients and in normal controls. effecting sexual functioning. Nonetheless, discussion raised the need for further evidence of its efficacy compared with Treatment-resistant depression traditional antidepressants. Madhukar Trivedi (University of Texas Southwestern Medical An interesting proposal came from Peter Nyhuis (University Center, Dallas, TX, USA) presented one of the largest studies of Duisburg-Essen, Essen, Germany), who suggested use of the to date of non-psychotic depression. The STAR*D (Sequenced opiate agonist, buprenorphine, in treatment-resistant depressed Treatment Alternatives to Relieve Depression) study aimed to patients (0.8–2 mg/day). A good response was observed, but follow patients after sequential antidepressant treatments only among those patients with concomitant cortisol according to a fixed augmentation algorithm. The currently suppression. Nyhuis et al. therefore suggested that the response available data offer an interesting view of ‘real world’ to opiates may describe a special subtype of depressive

DEPRESSION: MIND AND BODY Vol 3 No 1 2006 47 ALESSANDRO SERRETTI

disorders, corresponding to a dysregulation of the endogenous deep brain stimulation (DBS) in obsessive compulsive opioid system and not of the monoaminergic system. disorder and major depression but again, further studies are needed before everyday clinical application is possible. Non-pharmacological treatments Finally, Adriana Pontiggia and Sara Dallaspezia (Scientific Non-pharmacological treatments for depression were an Institute San Raffaele, Milan, Italy) reported on total sleep important topic at the meeting. It is well known that brief deprivation as a non-pharmacological treatment that is courses of psychotherapy are effective in mild-to-moderate particularly useful in bipolar depression and when drugs are depression, and this has been further illustrated by a number contraindicated. However, the efficacy of this technique may be of reports (Javier Ballesteros [University of the Basque transient, and it is hoped genetic analysis will help to identify Country, Leioa, Spain], Magnus Hansson [Umeå University, patients who are more likely to show a prolonged response. Umeå, Sweden]). The usefulness of combined treatments for depression was debated and consensus converged Future directions on the need for combined pharmacological and non- The ECNP president, David Nutt (University of Bristol, pharmacological treatments. Bristol, UK), summarized the historical pathway that has lead Tom Bolwig (Copenhagen University Hospital, to the present antidepressant treatments, and described how Copenhagen, Denmark) presented data on electroconvulsive knowledge of the mechanism of action of antidepressants therapy, treatment that has been subject to severe public could allow for the development of more effective criticism during recent years but is an effective therapy for treatments in the future. Gene expression studies are of treatment-resistant depression. Moreover, as suggested by particular importance as they identify genes that are Doron Mazeh (Abarbanel Mental Health Center, Bat-Yam, preferentially expressed after antidepressant administration, Israel), it could be considered for maintenance therapy in providing insights into the drug’s mechanism of action. cases where adequate maintenance can not be achieved by It has been shown that chronic treatment with SSRIs more traditional means. promotes the expression of genes related to neural cell New treatments also receiving growing attention include survival and neurogenensis in addition to those relating to repetitive transcranial magnetic stimulation (TMS) and vagus the serotonin pathway (TPH1 and 2), and to the transport of nerve stimulation (VNS). Thomas Schläpfer (University Hospital thyroid hormone (Ki-Chung Paik [Dankook University Bonn, Bonn, Germany) reported on the efficacy of TMS, the College of Medicine, Cheon-An, Republic of Korea], application of a magnetic field to the patient’s head, in treating Gabriele Flugge [German Primate Center, Göttingen, depression. As discussed by Roumen Milev (Queen’s Germany]. The identification of genes related to University, Kingston, ON, Canada), its favorable side-effect neurogenesis and intracellular signal transduction cascades profile makes it a useful tool for treating elderly depressed that are preferentially expressed after antidepressant patients. Chris Baeken (AZ-VUB, Jette, Belgium) told of his treatment might explain the delayed actions of attempts to determine the exact profile of responders using antidepressants, and constitute potential new drug targets. positron emission tomography; however, this has not yet been Furthermore, through study of cortisol pathways in defined and further discussion raised concerns about the depression, Carmine Pariante (Institute of Psychiatry) effectiveness of TMS in severe cases of depression. reported that enhanced glucocorticoid receptor activation in Michael Trimble (Institute of Neurology, London, UK) the brain after treatment with antidepressants appears to reported on the efficacy of VNS, particularly the long-term precede the onset of therapeutic action, and is important in outcomes of treatment for depression. The mechanism of the antidepressant’s therapeutic effects. Owen Wolkowitz action of VNS is possibly exerted through an increase in the (UCSF, San Francisco, CA, USA) noted that it is of interest gene expression of brain-derived neurotrophic factor and that both cortisol agonists and antagonists can relieve basic fibroblast growth factor (as seen in the rat depression, although their routine use is not yet suggested. hippocampus; Paolo Follesa, University Cagliari, Cagliari, Studies of gene expression reveal possible mechanisms of Italy), and in many cases it normalizes some of the central action for antidepressants that range from influencing the nervous system parameters altered in depression (Clinton expression of genes involved in the serotonin pathway to a Kilts, Emory University School of Medicine, Atlanta, GA, cascade of events that activate genes in other systems, and USA). Caroline Frick (University Hospital Bonn) reminded us hence a delayed antidepressant effect. A more detailed that predictors for response to this therapy have not yet been knowledge of this area will take us one step closer to identified, and its routine use is not yet common practice. predicting antidepressant efficacy (based on the Bruno Aouizerate (Centre Hospitalier Charles Perrens, pharmacogenetic profile of the patient), identification of Bordeaux, France) reviewed the demonstrated efficacy of new drug targets, and, possibly, permanent gene therapy.

48 DEPRESSION: MIND AND BODY Vol 3 No 1 2006 DEPRESSION: MIND AND BODY

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