Clozapine administration and the risk of drug-related pure red cell aplasia: a novel case report.

LETTERS TO THE EDITORS

Quetiapine in Postpartum Psychosis To the Editors: ostpartum psychosis (PP) is a rare psychiatric disorder with a prevalence of 1 to 2 per 1000 deliveries1 characterized by delusion, hallucinations, bizarre behavior, depression, mania, and mood liability that usually presents within the first 2 weeks postpartum.2 Postpartum psychosis increases the risk for suicide3 and infanticide4; for these reasons, the prevention, early detection, and treatment of the disorder are necessary and important. The onset of PP is rapid.5 The majority of cases begin within 2 weeks, but the symptoms often appear as early as 2 to 3 days after delivery. The early symptoms include insomnia, rapid mood fluctuations, and obsessive concerns regarding the newborn, but the presentation rapidly metamorphoses into a clinical state characterized by delusions of paranoia and grandiosity, hallucinations, disorganized behavior, and catatonic features.5,6 Cognitive changes in the form of confusion, disorientation, and perplexity are quite common.7 Symptoms of manic or mixed episodes are particularly common in early onset cases and usually precede the appearance of psychotic features.8 A few case reports suggest that PP may be treated with lithium or other anticonvulsants and typical antipsychotics.9,10 Little is known about the efficacy of atypical antipsychotics in PP.11 Clozapine has been reported to be effective in 1 case report,11 and olanzapine has been demonstrated to prevent PP and postpartum mood episodes in women with bipolar disorder.12 For the first time, here we present 2 different cases of PP, with different psychopathological presentations, both successfully treated with quetiapine. F.F. was 34 years old at the time of her first pregnancy, suffering from bipolar disorder, type I. The disease was first diagnosed at the age of 27 years, and she was successfully treated and stabilized with valproate (1000 mg/d) and quetiapine (200 mg/d). With the agreement of her psychiatrist, she decided not to take any medication during the pregnancy. The pregnancy went well; in the third trimester, the patient showed light depressive symptoms, which were treated with supportive psychotherapy. Two days after a noncomplicated vaginal delivery, the patient came

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back home and started breastfeeding. On the third day, she developed severe insomnia, religious delusions, disorganized speech, and word salad. The symptoms prevented her from taking care of her daughter’s basic needs. Since the clinical situation abruptly worsened after 24 hours, the patient was hospitalized. Quetiapine (up to 300 mg daily) was immediately prescribed. Given the critical conditions, the obstetrician added bromocriptine (5 mg daily) for lactation suppression. Psychotic symptoms progressively disappeared after 7 days, and the patient was discharged after 10 days. Quetiapine (300 mg daily) was continued as prophylactic and maintenance therapy. The patient had a second and a third child, 3 and 5 years after the first birth, respectively. Quetiapine (sustained released tablets 300 mg/d) was administered immediately after the births of her second and third child. Both postpartum periods occurred without any psychiatric complications. A.G. was 37 years old at the time of her first delivery, with a history of fibromyalgia and dysthymia. One week after the delivery, she developed symptoms of postpartum depression with anxiety, insomnia, fatigue, restlessness, and emotional liability. The anxiety worsened after her 1-month-old daughter developed severe infant sleep apnea, requiring immediate hospitalization and resuscitation. Two months after the delivery, the patient consulted her general practitioner (GP), complaining of paranoid delusions, excessive concerns about the baby’s health, and depersonalization. The GP prescribed risperidone (2 mg) and desvenlafaxine (50 mg), with no significant improvement after 2 weeks of treatment. Because infanticide delusions (‘‘an external voice telling her to kill the baby’’) and disorganized behavior appeared, the GP asked the patient to consult a psychiatrist, who immediately hospitalized the patient, stopping the previous therapy and starting quetiapine (up to 300 mg/d). Psychotic symptoms disappeared after 7 to 10 days. The quetiapine regimen was maintained for 3 months and then progressively decreased; escitalopram (10 mg) plus mirtazapine (30 mg) were introduced to treat the residual depression and anxiety symptoms. The literature about the immediate treatment of postpartum psychosis is scant, mostly because of the rarity of this condition and the lack of double-blind studies due to ethical limitations. The only studies available are retrospective studies or case reports. These studies indicate that lithium Journal of Clinical Psychopharmacology

and typical antipsychotics can be a good treatment9,10,13; similarly, sublingual 17-Aestradiol (3Y6 times a day) with a goal to reach the serum level of 400 pmol/L has been reported to be efficacious in a pilot study.14 On the other hand, a few naturalistic and open-label studies have been published, concerning the prevention of PP. In particular, lithium, with or without antidepressants, seems to be effective in preventing PP.15,16 More recently, olanzapine alone or in combination with other drugs seems also to represent a preventive drug for PP.12 On the other hand, 17-A-estradiol17 has no effect on the prevention of PP in women with histories of bipolar or schizoaffective disorder; similarly, valproic acid is no more effective than monitoring without drugs for the prevention of postpartum episodes of bipolar disorder.18 This is the first case report on the use of quetiapine in PP for immediate treatment and prevention. Quetiapine is an atypical antipsychotic medication indicated for the treatment of schizophrenia, short-term manic episodes, and depression associated with bipolar disorders, with 5-HT2A and D2 antagonist properties and low D2 affinities compared with other atypical antipsychotics.19 Remarkably, quetiapine also exerts partial agonist activity at 5-HT1A receptors, and this property, along with its antagonist action at 5-HT2A receptors and >2 adrenoreceptors, is believed to be the neurobiological mechanism accounting for quetiapine’s clinical antidepressant properties.19 For this dual action, along with its unique receptorial affinity, quetiapine may represent a first-choice treatment of PP, a condition characterized by the coexistence of depressive and psychotic symptoms. It has also been hypothesized that sleep loss resulting from the interaction of various putative causal factors may be the final common pathway in the development of PP in susceptible women; consequently, the improvement of insomnia induced by quetiapine could alleviate the symptoms of PP.20 Remarkably, as the first patient suggests, quetiapine may be also used for the prevention of PP in patients experiencing bipolar disorder, a clinical condition with increased risk for PP.1 Even if, for ethical reasons, double-blind, placebo-controlled studies are not allowed in PP, more clinical retrospective studies will be needed to assess the atypical antipsychotic in this lifethreatening psychiatric condition.

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Volume 34, Number 6, December 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Journal of Clinical Psychopharmacology

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AUTHOR DISCLOSURE INFORMATION The present report did not receive any support from pharmaceutical companies. Dr Gobbi has been a speaker for Eli Lilly Canada and Merck Canada and has received grant/honoraria from GlaxoSmithKline, Merck & Co., AstraZeneca.

Gabriella Gobbi, MD, PhD Neurobiological Psychiatry Unit Department of Psychiatry McGill University Montreal, Quebec, Canada [email protected]

REFERENCES 1. Kendell R, Chalmers J, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry. 1987;150:662Y673. 2. Sit D, Rothschild AJ, Wisner KL. A review of postpartum psychosis. J Womens Health. 2006;15:352Y368. 3. Appleby L, Mortensen PB, Faragher EB. Suicide and other causes of mortality after post-partum psychiatric admission. Br J Psychiatry. 1998;173:209Y211. 4. Spinelli MG. Maternal infanticide associated with mental illness: prevention and promise of saved lives. Am J Psychiatry. 2004;161:1548Y1557. 5. Brockington IF, Hillier VF, Francis AF, et al. Definitions of mania: concordance and prediction of outcome. Am J Psychiatry. 1983;140:435Y439. 6. Dean C, Kendell RE. The symptomatology of puerperal illnesses. Br J Psychiatry. 1981;139:128Y133. 7. Wisner KL, Peindl K, Hanusa BH. Symptomatology of affective and psychotic illnesses related to childbearing. J Affect Disord. 1994;30:77Y87. 8. Protheroe C. Puerperal psychoses: a long-term study 1927Y1961. Br J Psychiatry. 1969;115:9Y30. 9. Doucet S, Jones I, Letourneau N, et al. Interventions for the prevention and treatment of postpartum psychosis: a systematic review. Arch Womens Ment Health. 2011;14:89Y98. 10. Sharma V. Treatment of postpartum psychosis: challenges and opportunities. Curr Drug Saf. 2008;3:76Y81. 11. Kornhuber J, Weller M. Postpartum psychosis and mastitis: a new indication for clozapine? Am J Psychiatry. 1991;148: 1751Y1752. 12. Sharma V, Smith A, Mazmanian D. Olanzapine in the prevention of postpartum psychosis and mood episodes in bipolar disorder. Bipolar Disord. 2006;8:400Y404.

* 2014 Lippincott Williams & Wilkins

13. Targum S, Davenport Y, Webster M. Postpartum mania in bipolar manic-depressive patients withdrawn from lithium carbonate. J Nerv Ment Dis. 1979;167:572Y574. 14. Ahokas A, Aito M, Rimon R. Positive treatment effect of estradiol in postpartum psychosis: a pilot study. J Clin Psychiatry. 2000;61:166Y169. 15. Austin MP. Puerperal affective psychosis: is there a case for lithium prophylaxis? Br J Psychiatry. 1992;161:692Y694. 16. Cohen LS, Sichel DA, Robertson LM, et al. Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry. 1995;152:1641Y1645. 17. Kumar C, McIvor RJ, Davies T, et al. Estrogen administration does not reduce the rate of recurrence of affective psychosis after childbirth. J Clin Psychiatry. 2003;64:112Y118. 18. Wisner KL, Hanusa BH, Piendl KS, et al. Prevention of postpartum episodes in women with bipolar disorder. Biol Psychiatry. 2004;56:592Y596. 19. Comai S, Tau M, Pavlovic Z, et al. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol. 2012;32:237Y260. 20. Sharma V, Mazmanian D. Sleep loss and postpartum psychosis. Bipolar Disord. 2003;5:98Y105.

Impact of Lithium Treatment on FGF-23 Serum Concentrations in Depressive Patients To the Editor: epression is a multifaceted disorder with diverse causes and has been associated with the risk to develop severe medical disorders.1 Indeed, depression increases the risk of cardiovascular disease by 1.5-fold to 2-fold, of stroke by 1.8-fold, of Alzheimer disease by 2.1-fold, of diabetes by 60%, and of cancer by 1.3-fold to 1.8fold.1 Fibroblast growth factors (FGFs) are best known for their regulatory roles in cell growth, differentiation, and morphogenesis in early stages of neural development and have been discussed as switch genes, biomarkers, and treatment targets for affective disorders recently.2,3 However, at least FGF23 has also been proposed as a cardiovascular risk marker,4 a central player of disordered mineral metabolism,5 and acts to

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Letters to the Editors

decrease phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels.5 A close, bidirectional relationship exists between depression and cardiovascular disease.1 Indeed, major depression is associated with an increased risk of coronary artery disease, myocardial infarction, congestive heart failure, and isolated systolic hypertension leading to increased mortality and morbidity in patients.1 Moreover, a strong relationship has been described between severe coronary and aortic calcifications, intima thickness, osteoporosis, and depressive disorders.1 Fibroblast growth factor 23 lowers serum levels of 1,25(OH)2D3, which in turn up-regulates renal and intestinal phosphate and calcium transport.6Y9 In mice, it was shown recently that lithium treatment up-regulates FGF-23 formation, an effect paralleled by substantial decrease of serum 1,25(OH)2D3 and phosphate concentrations.10 The present study explores the effect of lithium treatment on serum FGF-23, 1,25(OH)2D3, calcium, and phosphate concentrations in depressed patients. A total of 95 acute depressive patients (age 48 T 14 years) were recruited for this study. Inclusion criteria consist of unipolar depression, age older than 18 years, indication for antidepressant pharmacotherapy, insufficient response to an adequate antidepressant pretreatment and clinical indication for lithium augmentation, hamilton depression rating score greater than 12, and written informed consent. Diagnosis was confirmed on the basis of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Fibroblast growth factor 23 serum concentrations were measured first in medicated patients before lithium augmentation and then after 4 weeks of medication with lithium. Detailed clinical data of the patients have already been published.11 All patients reached a lithium serum level of more than 0.4 mmol/L. Serum FGF-23 concentrations were measured by enzyme-linked immunosorbent assay (Immutopics International, California; AVP EIA kit, Phoenix Europe, Karlsruhe, Germany). enzyme-linked immunosorbent assay kits were employed to determine serum concentrations of 1,25(OH)2D3 (IDS, Boldon, United Kingdom). Data are provided as mean T SEM; n represents the number of independent experiments. All data were tested for significance using unpaired Student t test. Only results with P G 0.05 were considered statistically significant. As illustrated in Figure 1, lithium treatment was followed by a marked increase of serum FGF-23 concentration. As shown in Figure 1, lithium treatment significantly decreased serum 1,25(OH)2D3 www.psychopharmacology.com


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FIGURE 1. Serum FGF-23 and 1,25(OH)2D3 levels/concentrations before and after lithium treatment. Arithmetic means T SEM (n = 95) of serum FGF-23 (A) and 1,25(OH)2D3 levels (B) before (white bars) and after (black bars) lithium treatment. **P G 0.01 indicates significant difference from respective value before treatment.

concentration. Lithium treatment significantly decreased serum phosphate concentrations (data not shown).

DISCUSSION The present observations reveal that lithium treatment results in a significant increase of serum FGF-23 concentration, a significant decrease of serum 1,25(OH)2D3 concentration, and a significant decrease of serum phosphate concentration. Neuroprotective and procognitive effects of lithium have been evidenced in both experimental research and in clinical studies using brain imaging, suggesting lithium to be effective in the prophylaxis of dementia and in neurodegenerative disorders, such as Huntington disease, Parkinson disease, and amyotrophic lateral sclerosis.12 However, the exact mechanism of lithium’s neuroprotective effect is largely unknown. Interestingly, lithium augmentation leads to a brain-derived neurotrophic factor increase,11 and lithium acts as a GSK3 A inhibitor.13 Fibroblast growth factor 2, IGF-1, and brain-derived neurotrophic factor can stimulate the magnitude of Akt activation.13 At least FGF-2 has been shown to promote the survival of hippocampal neurons significantly more effectively than the 2 other peptides.13 In line with our data, the neuroprotective effect of lithium might be at least partly mediated by an increase of FGF-23. Enhanced serum phosphate concentration predisposes to vascular calcification4Y9 and is considered a predictor of early mortality.4Y9 Along those lines, FGF-23 deficiency is followed by increase of serum phosphate, calcium, and 1,25(OH)2D3 concentrations with subsequent vascular calcification, decrease of bone density, and reduction of life-span.4Y9 Conversely, lowdose lithium uptake in tap water has been shown to promote longevity in humans.14 In

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conclusion, our observations might partly explain these findings as lithium might decrease phosphate concentrations, decrease vascular calcification, and thereby increase the life-span. At least in theory, the effect of lithium on FGF-23 serum levels may in part be due to polyuria and dehydration.15 Serum FGF23 levels are enhanced in gene-targeted mice lacking kinases involved in stimulation of renal tubular NaCl transport, and thus required for adequate renal salt and fluid reabsorption as well as hydration.15,16 The increase of FGF-23 serum concentration presumably accounts for the decrease of serum 1,25(OH)2D3 concentrations after lithium treatment, as FGF-23 down-regulates the renal 1> hydroxylase and thus the formation of 1,25(OH)2D3.6,8 1,25(OH)2D3 stimulates both renal and intestinal phosphate transport.17 Beyond its effect on 1,25(OH)2D3 formation, FGF23 inhibits renal tubular phosphate reabsorption more directly.6,8 The effect of FGF-23 on 1,25(OH)2D3 formation and renal tubular phosphate transport presumably accounts for the observed decrease of serum phosphate concentration. High serum phosphate concentrations foster vascular calcification and eventually lead to early appearance of age-related disorders and decrease of life-span.18,19 Fibroblast growth factor 23 is a powerful inhibitor of aging.19 Lack of FGF-23 leads to premature appearance of a wide variety of age-related disorders, such as osteopenia, osteoporosis, impaired angiogenesis, enhanced erythrocyte turnover, pulmonary emphysema, skin atrophy, infertility, hearing loss, neuron degeneration, Parkinson disease, cognitive impairment, neoplasms, and inflammation.19 In view of the present observations, lithium may counteract at least some of those disorders observed in FGF-23 deficiency. However, the observation of an increased bone mass after treatment with lithium

might underlie our observed effect of lithium on FGF-23 concentrations.20 However, our data are preliminary; as in this study, no placebo-treated group was observed, and the effects on FGF-23 and 1,25(OH)2D3 were rather small in magnitude. However, small effects might cause changes when medications are used chronically. In conclusion, lithium treatment might lead to an up-regulation of FGF-23 serum concentration, which in turn might result in decreased serum 1,25(OH)2D3 and phosphate concentrations. Antidepressant mechanisms that may underlie the observed effect of lithium on FGF-23 are the proper formation of synaptic connections in the cerebral cortex, the maturation and survival of catecholamine neurons, and neurogenesis.2 Our data are in line with an observed dysregulation of several FGF system transcripts in the frontal cortical regions of the brains of human subjects with major depressive disorder.21 Fibroblast growth factor is a growth factor essential for the proper formation of synaptic connections in the cerebral cortex, maturation and survival of catecholamine neurons, and neurogenesis.21,22 Moreover, a correlation between antidepressant treatments and FGF expression in the cerebral cortex and hippocampus has been observed.22,23 Our data are in line with previous observations showing that the FGF system might be altered in post-mortem brains of individuals with major depressive disorder22 and can be modulated by antidepressant treatment.22,23 Moreover, a change of the FGF system after acute social defeat has been observed, and FGF showed an antidepressant effect in rat.23 In this context, the stimulation of FGF via lithium might be linked to its known GSK3 A inhibitory action.1,10 In summary, the effects of lithium on FGF-23 serum levels may protect from vascular calcification and the appearance of age-related disorders. * 2014 Lippincott Williams & Wilkins



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ACKNOWLEDGMENT H. Fakhri, R. Ricken, and M. Adli share the first authorship. Supported by the Deutsche Forschungsgemeinschaft (LA 2694/1-2).

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. *Berlin Research Network of Depression: Christoph Richter, MD; Bruno Steinacher, MD, PhD; Tom Bschor, MD, PhD; Sebastian Erbe, MD; Albert Dieffenbacher, MD, PhD; Samuel Elstner, MD; Marcus Gastpar, MD, PhD; Brigitte SchulzRatei, MD, PhD; Hubertus Himmerich, MD, PhD; Joachim Zeiler, MD, PhD; Alexandra Lingesleben, MD; Andreas Heinz, MD, PhD; Ju¨rgen Gallinat, MD, PhD; Meryam Schouler-Ocak, MD, PhD; Gernot Deter, MD; Hartmut Dormhagen, MD; Rainer Hellweg, MD, PhD; Phillip Sterzer, MD, PhD; Andreas Stro¨hle, MD, PhD; Thomas Stamm, MD; Mazda Adli, MD, PhD; Roland Ricken, MD; Friedel M. Reischies, MD, PhD; Peter Bra¨unig, MD, PhD; Ramona Pietsch, MD; Iris Hauth, MD; Frank Godemann, MD, PhD; Peter Neu, MD, PhD. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercialNoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. Hajar Fakhri, MD Department of Physiology University of Tu¨bingen Tu¨bingen, Germany

Roland Ricken, MD Mazda Adli, MD, PhD Department of Psychiatry and Psychotherapy Charite´ University Medicine Berlin Campus Mitte Berlin, Germany

Abul Fajol, MD Department of Physiology University of Tu¨bingen Tu¨bingen, Germany

Marc Walter, MD, PhD University Psychiatric Clinics University of Basel Basel, Switzerland

Michael Fo¨ller, MD, PhD Berlin Research Network of Depression* Florian Lang, MD, PhD Department of Physiology University of Tu¨bingen Tu¨bingen, Germany * 2014 Lippincott Williams & Wilkins


Undine E. Lang, MD, PhD University Psychiatric Clinics University of Basel Basel, Switzerland [email protected]

Claudia Lange, MSc University Psychiatric Clinics University of Basel Basel, Switzerland

REFERENCES 1. Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31:761Y777. 2. Zhang X, Bao L, Yang L, et al. Roles of intracellular fibroblast growth factors in neural development and functions. Sci China Life Sci. 2012;55:1038Y1044.

neuronal survival in hippocampal cultures. Brain Res. 2007;1154:40Y49. 14. Zarse K, Terao T, Tian J, et al. Low-dose lithium uptake promotes longevity in humans and metazoans. Eur J Nutr. 2011;50:387Y389. 15. Sugawara M, Hashimoto K, Ota Z. Involvement of prostaglandin E2, cAMP, and vasopressin in lithium-induced polyuria. Am J Physiol. 1988;254:R863YR869. 16. Pathare G, Fo¨ller M, Michael D, et al. Enhanced FGF23 serum concentrations and phosphaturia in gene-targeted mice expressing WNK-resistant Spak. Kidney Blood Press Res. 2012;36:355Y364. 17. Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 on intestinal calcium and phosphate transport. J Lab Clin Med. 2002;139:279Y284.

3. Turner CA, Watson SJ, Akil H. The fibroblast growth factor family: neuromodulation of affective behavior. Neuron. 2012;76:160Y174.

18. Rodriguez M, Martinez-Moreno JM, Rodrı´guez-Otiz ME, et al. Vitamin D and Vascular Calcification in Chronic Kidney Disease. Kidney Blood Press Res. 2011;34:261Y268.

4. Heine GH, Seiler S, Fliser D. FGF-23: the rise of a novel cardiovascular risk marker in CKD. Nephrol Dial Transplant. 2012;27:3072Y3081.

19. Kuro-o M. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol. 2013;9:650Y660.

5. Komaba H, Fukagawa M. The role of FGF23 in CKDVwith or without Klotho. Nat Rev Nephrol. 2012;8:484Y490. 6. Gattineni J, Twombley K, Goetz R, et al. Regulation of serum 1,25(OH)2 Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol. 2011;301:F371YF377. 7. Inoue Y, Segawa H, Kaneko I, et al. Role of the vitamin D receptor in FGF23 action on phosphate metabolism. Biochem J. 2005;390:325Y331. 8. Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98:6500Y6505.

20. Zamani A, Omrani GR, Nasab MM. Lithium’s effect on bone mineral density. Bone. 2009;44(2):331Y334. 21. Evans SJ, Choudary PV, Neal CR, et al. Dysregulation of the fibroblast growth factor system in major depression. Proc Natl Acad Sci U S A. 2004;101:15506Y15511. 22. Bachis A, Mallei A, Cruz MI, et al. Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons. Neuropharmacol. 2008;55:1114Y1120. 23. Maragnoli ME, Fumagalli F, Gennarelli M, et al. Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain. Biol Psychiatry. 2004;55:1095Y1102.

9. Marsell R, Jonsson KB. The phosphate regulating hormone fibroblast growth factor-23. Acta Physiol (Oxf). 2010;200:97Y106.

Lamotrigine Reduces Affective Instability in Depressed Patients With Mixed Mood and Anxiety Disorders

10. Fakhri H, Pathare G, Fajol A, et al. Regulation of mineral metabolism by lithium. Pflugers Arch. 2014;466:467Y475. 11. Ricken R, Adli M, Lange C, et al. Brain-Derived Neurotrophic Factor serum concentrations in acute depressive patients increase during lithium augmentation of antidepressants. J Clin Psychopharmacol. 2013;33:806Y809. 12. Forlenza OV, de Paula VJ, Machado-Vieira R, et al. Does lithium prevent Alzheimer’s disease? Drugs Aging. 2012;29:335Y342. 13. Johnson-Farley NN, Patel K, Kim D, et al. Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and

To the Editors: here is a puzzling ambiguity about the efficacy of lamotrigine as a treatment of recurrent bipolar depression.1Y3 A summary of 5 short-term studies (mostly for depression in bipolar disorders) concluded that the results were statistically negative with a few exceptions on secondary measures.4 A subsequent meta-analysis

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of these studies did show a small but significant benefit for lamotrigine over placebo.3 The Systematic Treatment Enhancement Program for Bipolar Disorder study that incorporated patient choice into the randomization also found a numerical but nonsignificant benefit of lamotrigine.5 Clinical trials for a variety of depressive syndromes and positive findings on the Clinical Global Impression scale suggest that clinicians observe benefits that formal studies using traditional outcome scales do not show.1,2 A substantial proportion of patients with complaints of depression reported short-duration frequent mood fluctuations that are labeled affective instability (AI).6,7 We previously reported that patients treated with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs did improve on the Beck Depression Inventory (BDI)8 but not on AI.9 Lamotrigine seems to reduce affective lability1,10 in patients with borderline personality disorder. We therefore undertook an open-label uncontrolled study to assess whether lamotrigine would reduce AI in patients with mixed mood and anxiety disorders. The study was approved by the university research ethics board, and all participants gave signed informed consent. Consecutive male and female patients between the ages of 18 and 65 years with complaints of recurring and persistent depression were recruited from 2 practices in a center. We excluded people with histories of bipolar I disorder, substance abuse, severe active suicidal thoughts, medical comorbidity that might affect their mood, or substance abuse within the past 2 years. After the initial interview, the participants were offered infrequent follow-up visits for medication management and counseling about mood management. We used the Mini-International Neuropsychiatric Interview for diagnostic assessment.11 After the initial psychiatric interview, the research assistant handled the distribution and return of self-report questionnaires. At induction, time 1 (T1) questionnaires were distributed with a stamped return envelope. The participants were contacted after approximately 5 months and mailed identical time 2 (T2) questionnaires with a medication list to report their current medication. Within the first 2 weeks of starting lamotrigine (dose, 12.5 mg/d), the participants completed 3 assessments of mood. These were as follows1: twice daily visual analog scales (VAS) just after arising and just before bedtime for 7 consecutive days. The prompt was ‘‘in the last few hours I felt depressed’’; the anchors were ‘‘not at all’’ to ‘‘very much so.’’ We calculated the AI with

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the mean square successive difference (MSSD) statistic.7 The MSSD is a singlenumber summary that takes into account fluctuations in ratings that are adjacent in time. For each mood, we also calculated the mean VAS rating, which is a measure of overall level irrespective of time.2 The BDI-1A is a common 21-item self-report questionnaire.8 The retrospective time frame is 1 week. It shows high internal consistency and correlates on an average of 0.73 with the Hamilton Depression Rating Scale and 0.72 with clinical ratings.3,8 The Affective Lability Scale (ALS) is an 18-item self-report questionnaire used for measuring switches in mood.12 The 1-month test-retest reliability for the ALS was reported as 0.73 and the Cronbach > was 0.9.12 Wilcoxon signed rank tests for matched pairs were calculated to test whether the median difference in pretreatment and posttreatment scores was significantly different from 0. The tests were conducted at a significance level of 0.05. Forty participants returned the T1 questionnaires and 25 of these participants completed the T2 questionnaires (complete data). However, on medication review at T2, only 20 participants were actually taking lamotrigine. The data on these 20 participants were analyzed. The mean (SD) age was 44.7 (11.7) years and 13 participants were women. At induction into the study, 16 participants met the criteria for current or past major depression and 12 participants had histories of hypomania but had no current hypomania. All participants had complaints of recurring depressive episodes (duration, G2 weeks). In addition, at the time of the study, 7 participants had histories of panic disorder, 13 participants experienced generalized anxiety disorder, 4 participants had social anxiety disorder, and 3 participants had obsessive-compulsive disorder. At T2, the mean (SD) lamotrigine dose was 250 (79.3) mg. Seventeen participants also received an SSRI antidepressant, 14 participants were on atypical neuroleptics (usually low doses of quetiapine [12.5Y25 mg for sleep]), and 4 participants were on low doses of benzodiazepines.

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The mean (SD) duration of treatment was 236 (84.2) days. The changes in the measures are recorded in Table 1. There was a significant decrease in the depression MSSD (P = 0.01) and ALS (P G 0.01). There was no significant change in the BDI score or in the mean levels of VAS depression scores.

DISCUSSION The main finding is that the depression MSSD score and the ALS that are both measures of AI improved with lamotrigine treatment. There was a nonsignificant numerical reduction in the BDI score, which was consistent with the findings from previous studies.3 One man who did improve remarked that lamotrigine had made his depressive mood swings ‘‘less steep and deep.’’ The study is small and not controlled, and it needs to be replicated using experimental methods. The patients were treated with other drugs and instruction for mood management, and it is possible that the response was caused by treatments other than lamotrigine. The drugs were mainly low doses of SSRI antidepressants for anxiety and low doses of atypical neuroleptics (mainly quetiapine) for sleep. In a previous similar study, the SSRI antidepressants did not improve AI, but the BDI did improve.9 The evidence that SSRI antidepressants have a direct effect on AI is not strong,13 but it is possible that there is an indirect effect. Our study suggests the testable hypothesis that lamotrigine might have a primary effect on AI, but improvement in typical depressive syndromes as assessed by standard rating scales could occur with sufficient duration of treatment.1 This is a proof-of-principle study that demonstrates (a) that lamotrigine has a therapeutic effect on AI and (b) that it is feasible to measure AI in treatment outcome studies. The corollary is that the measures of AI should be included in studies of lamotrigine and other interventions for the maintenance of mood disorders.

TABLE 1. Psychometric and Self-Report Measures Measure Depressed AI MSSD depressed ALS Summary depression VAS mean depressed BDI

T1, Mean (SD) T2, Mean (SD) Z Statistic P of the Change 6.02 (4.50) 46.85 (11.1)

3.03 (3.04) 37.5 (9.96)

j2.46 j2.84

0.01 G0.01

58.39 (35.1) 25.6 (9.90)

54.11 (43.04) 20.95 (10.93)

j1.27 j1.69

0.20 0.09




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AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Funding for the study was provided by the Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Rudy C. Bowen, MD Department of Psychiatry University of Saskatchewan Saskatoon, Saskatchewan Canada [email protected]

Lloyd Balbuena, PhD Marilyn Baetz, MD, FRCP(C) Department of Psychiatry University of Saskatchewan Saskatoon, Saskatchewan Canada

10. Lieb K, Vo¨llm B, Ru¨cker G, et al. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry. 2010;196:4Y12. 11. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998; 59(suppl 20):22Y33. 12. Oliver M, Simons JS. The Affective Lability Scales: development of a short-form measure. Pers Individ Dif. 2004;37: 1279Y1288. 13. Parker G, Tully L, Olley A, et al. SSRIs as mood stabilizers for bipolar II disorder? A proof of concept study. J Affect Disord. 2006;92:205Y214.

REFERENCES 1. Zavodnick AD, Ali R. Lamotrigine in the treatment of unipolar depression with and without comorbidities: a literature review. Psychiatr Q. 2012;83:371Y383. 2. Vieta E, Valentı´ M. Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS Drugs. 2013;27:515Y529. 3. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4Y9. 4. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79Y88. 5. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210Y216. 6. Bowen R, Baetz M, Hawkes J, et al. Mood variability in anxiety disorders. J Affect Disord. 2006;91:165Y170. 7. Jahng S, Wood PK, Trull TJ. Analysis of affective instability in ecological momentary assessment: indices using successive difference and group comparison via multilevel modeling. Psychol Methods. 2008;13:354Y375. 8. Beck AT, Steer RA. Beck Depression Inventory (BDI). In: American Psychiatric Association, ed. Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Association; 2000:519Y523. 9. Bowen RC, Mahmood J, Milani A, et al. Treatment for depression and change in mood instability. J Affect Disord. 2011; 128:171Y174.


Naltrexone in Bipolar Disorder With Depression A Double-Blind, Placebo-Controlled Study To the Editors: oth agonists and antagonists at K-opioid receptors (MORs) and J-opioid receptors (KOR) affect mood in humans and animals.1 The endogenous substrates of MOR and KOR (endorphins and dynorphin, respectively) may modulate mood, in part, through effects on monoamine neurotransmitters, including dopamine.2 Notably, MOR and KOR have opposing effects on dopamine systems and mood: MOR agonism elevates mood, whereas KOR agonism lowers mood.3,4 Thus, unbalanced drive through MOR or KOR might dysregulate mood, and drugs that alter activity through KOR and MOR might restore normal mood. The most common opiate antagonist in clinical use is naltrexone, which has been tested and approved for the treatment of alcoholism. In humans, naltrexone is both a MOR antagonist and a KOR antagonist. Blockade of MOR mutes reward, whereas animal studies suggest that blockade of KOR elevates mood.5 The effects of combined blockade should depend on the state of endogenous stimulation of MOR and KOR in the individual receiving naltrexone. In patients with bipolar disorder, who have swings into depression and mania, naltrexone has been reported to have therapeutic effects on both alcohol abuse and mood.6 However, the effect on mood could be secondary to reduced alcohol use. We tested whether naltrexone might have beneficial effects, improving or stabilizing

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mood, in patients who have bipolar disorder alone without comorbid alcohol or other drug abuse. Outpatients, 18 to 65 years old, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (American Psychiatric Association, 2000) criteria for bipolar disorder, type I or II, were recruited for this 12-week, doubleblind, placebo-controlled study. The participants had to have current symptoms of depression, as indicated by a MontgomeryAsberg Depression Rating Scale (MADRS) score of 5 or higher, with no current dependence on substances other than caffeine and/or nicotine or a history of opiate abuse or dependency. The participants had to be on a stable medication regimen for at least 2 weeks before enrollment and were randomized to receive either naltrexone (n = 17) or matching placebo (n = 15) as an ‘‘add-on’’ to their existing medications. All procedures were approved by the McLean Hospital Institutional Review Board. All participants gave written consent to participate after the procedures, and possible side effects were explained to them. In accordance with accepted guidelines, naltrexone treatment was initiated slowly by starting dosing at 25 mg of naltrexone once daily for the first 3 days, then 25 mg twice daily for the next 4 days. From day 8 until the end of the study, the participants took 50 mg once daily. After a baseline evaluation, the participants had mood symptoms evaluated at weeks 1, 2, 3, 4, 6, 8, 10, and 12. Our objective was to compare variability and change in symptoms of depression and mania in persons with bipolar disorder and depression during treatment with naltrexone. The primary outcome measure was the MADRS7 score, and the secondary outcomes measures were Hamilton Depression (HAM-D)8 and Young Mania Rating Scale (YMRS)9 scores. The primary test of the effects of naltrexone was differences in within-subject variability in symptoms during treatment between naltrexone and placebo, and the secondary test was differences in changes in mean symptom ratings between naltrexone and placebo at the end of the treatment. All analyses used all available data from the participants with a baseline visit. To compare within-subject variability in MADRS, HAM-D, and YMRS ratings between naltrexone and placebo, 2 linear mixed-effects models were fit to all postbaseline symptom ratings for each instrument. All models had fixed effects of study time, treatment (naltrexone or placebo), and study time by treatment interaction, as well as random intercepts and www.psychopharmacology.com


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slopes, if a model containing both random intercepts and slopes was supported by the data. When fitting the first model, we assumed that the covariance of the random slopes and intercepts as well as the error variance were different between treatments. When fitting the second model, we still assumed that the covariance of random slopes and intercepts was different between the groups but assumed that the error variance was the same. A likelihood ratio test comparing the fit of these 2 models provided a test that the withinsubject variability (after accounting for individual differences in mean subject ratings and their change over time) differed between naltrexone and placebo. To compare changes in mean MADRS, HAM-D, and YMRS between the treatment groups, we used linear mixed-effects models similar to those used for comparing within-subject variability between the groups but including the baseline measurements and assuming a common intercept between the groups. For these models, we assumed the same covariance between groups for MADRS and HAM-D but not for YMRS because we had evidence from our variability models that the covariance for YMRS differed between the treatment groups. The addition of quadratic terms for time allowed us to test for evidence against our assumption that symptom ratings changed linearly over the course of the study. In post hoc analyses, to assess whether variance differences that we observed for YMRS could be caused by a small number of participants with influential observations or variance differences present before the start of the study, we (1) refit our variance models after removing the data from 2 participants with potentially influential observations (absolute value of studentized residuals, >3) and (2) refit our models to our intake and baseline measurements. The models were fit using the PROC MIXED routine from SAS. All statistical tests were conducted at the testwise 2sided > level of 0.05. Data from 16 participants on naltrexone and 14 participants on placebo, with a total of 180 postbaseline measurements, contributed to the analysis of postbaseline symptom variability. For MADRS and HAM-D, the models with random slopes and intercepts were fit to the data. For YMRS, the data only supported models with random intercepts. On the basis of these models, there were no significant differences between the naltrexone and placebo groups in within-subject variance of MADRS (W12 = 0.27, P = 0.60) or HAM-D (W12 = 2.02,

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P = 0.16) scores during the treatment. Within-subject variance of MADRS scores was estimated to be 39.8 points for naltrexone and 34.5 points for placebo, and within-subject variance of HAM-D scores was estimated to be 22.8 points for naltrexone and 32.7 points for placebo. Within-subject variability of YMRS scores during the treatment was significantly higher for naltrexone than for placebo (W12 = 28.60, P < 0.0001). The estimated within-subject variance was 18.7 points for naltrexone and 5.3 points for placebo. However, further inspection of this result revealed that it was driven by a few outlying observations. When the 2 participants with large studentized residuals (absolute value, Q3.0) were excluded from the data set, the variance estimate for naltrexone was no longer greater (4.8 points for naltrexone and 5.3 points for placebo; W12 = 0.12, P = 0.73). In addition, when the same statistical model was fit to YMRS measurements collected before the start of treatment, pretreatment variability was substantially higher for the naltrexone than placebo (17.8 points for naltrexone and 6.4 points for placebo; W12 = 3.52, P = 0.06). Data from 17 participants on naltrexone and 15 participants on placebo, with a total of 212 clinical measurements, contributed to the analysis of mean symptom ratings. Mean (SD) clinical ratings at baseline were 22.1 (6.5) for MADRS (range, 9Y34), 21.2 (9.1) for HAM-D, and 5.0 (4.6) for YMRS. There were no significant differences between the naltrexone and placebo groups in changes in mean symptom ratings during the treatment on MADRS (t20 = j0.29, P = 0.78), HAM-D (t19 = 0.11, P = 0.91), or YMRS (t149 = 0.58, P = 0.56). The estimated 12-week mean differences in decreases between naltrexone and placebo were j1.43 (95% confidence interval [CI], j11.85 to 8.99) for MADRS, 0.40 (95% CI, j7.35 to 8.15) for HAM-D, and 0.85 (95% CI, j2.05 to 3.75) for YMRS. These differences are small and not statistically significant. The estimated 12-week decreases in symptom ratings were 1.07 (95% CI, j6.59 to 8.73) for naltrexone and 2.50 (95% CI, j4.79 to 9.79) for placebo in MADRS, 2.88 (95% CI, j2.81 to 8.58) for naltrexone and 2.48 (95% CI, j2.75 to 7.71) for placebo in HAM-D, and 1.02 (95% CI, j1.65 to 3.69) for naltrexone and 0.17 (95% CI, j1.11 to 1.45) for placebo in YMRS. We observed no significant evidence of nonlinear changes in ratings during the treatment, so all results are from models assuming linear changes in ratings with time.

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DISCUSSION Our findings in the patients with bipolar disorder, in the absence of substance abuse, show no evidence that naltrexone elevates or stabilizes mood. We believe that this is the first placebo-controlled trial of naltrexone in patients with bipolar disorder without alcohol abuse. Past results from an open-label study of naltrexone in patients with comorbid bipolar disorder and alcohol abuse reported an improvement in both depressive and manic symptoms as well as alcohol use and craving.6 A larger, double-blind study by the same group saw no difference in mood symptoms and only a trend toward lower alcohol use and craving with naltrexone treatment.10 Any therapeutic effects of naltrexone on mood in these comorbid patients might have been secondary to reduced alcohol use. One previously published report recorded an instance in which naltrexone may have induced mania in a patient with bipolar disorder.11 Although we did see increased variability in manic symptoms in our group treated with naltrexone, this same group tended to have greater mood variability before the treatment. Therefore, we did not find compelling evidence that naltrexone was associated with induction of mania. Removing input through both MOR and KOR, through blockade using naltrexone, might destabilize mood, so careful monitoring of mood lability in those started on naltrexone, and especially those with an inherent mood disorder, would appear to be appropriate. This study was powered to detect a difference in MADRS score of 10 points or more, which was similar to effects observed in many antidepressant trials, which often define response as a 50% reduction or higher. However, our results cannot rule out modest to moderate naltrexone-associated changes in symptom ratings and variability. More studies would be needed to determine whether naltrexone might induce mania or mood instability in some patients. ACKNOWLEDGMENTS This work was supported by a grant from the Stanley Medical Research Institute (Murphy). AUTHOR DISCLOSURE INFORMATION Within the past 5 years, Dr Murphy has been an investigator in studies funded by Ono Pharmaceutical Company, Shire, Cenerex, Cardiokine and Sanofi, as well as National Alliance for Research on Schizophrenia and Depression. * 2014 Lippincott Williams & Wilkins



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Drs Cohen and Ravichandran as well as Ms Babb have no commercial supports or interests. Beth L. Murphy, MD, PhD Frazier Research Institute McLean Hospital Belmont, MA and Harvard Medical School Boston, MA [email protected]

Caitlin Ravichandran, PhD Harvard Medical School Boston, MA and Laboratory for Psychiatric Biostatistics McLean Hospital Belmont, MA

Suzann M. Babb, MS Bruce M. Cohen, MD, PhD Frazier Research Institute McLean Hospital Belmont, MA and Harvard Medical School Boston, MA

REFERENCES 1. Carlezon WA Jr, Be´guin C, Knoll AT, et al. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther. 2009;123:334Y343. 2. Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A. 1992;89:2046Y2050. 3. Barber A, Gottschlich R. Novel developments with selective, non-peptidic kappa-opioid receptor agonists. Expert Opin Investig Drugs. 1997;6:1351Y1368. 4. Carlezon WA Jr, Be´guin C, DiNieri JA, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther. 2006;316:440Y447. 5. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305:323Y330. 6. Brown ES, Beard L, Dobbs L, et al. Naltrexone in patients with bipolar disorder and alcohol dependence. Depress Anxiety. 2006;23:492Y495. 7. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382Y389. 8. Hamilton MA. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56Y62. 9. Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429Y435. 10. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with


bipolar disorder and alcohol dependence. Alcohol Clin Exp Res. 2009;33:1863Y1869. 11. Sullivan MA, Nunes EV. New-onset mania and psychosis following heroin detoxification and naltrexone maintenance. Am J Addict. 2005;14:486Y487.

Selective Serotonin Reuptake Inhibitors Exposure During Pregnancy and Neonatal Outcomes To the Editors: read with interest the article by Grzeskowiak et al1 about the effect of late-gestation exposure to selective serotonin reuptake inhibitors (SSRIs) on the neonatal outcomes. Their study design was a retrospective cohort study carried out by gathering information from 33,965 pregnant women and their neonates for a period of 8 years. The total number of women prescribed with SSRIs (group A), number of women having psychiatric illness but not prescribed with SSRIs (group B), and number of women having no psychiatric illness and not prescribed with SSRIs (group C) were 221, 1566, and 32,004, respectively. The odds ratios (95% confidence intervals) for preterm delivery, low birth weight, admission to hospital, and length of hospital stay longer than 3 days were significantly higher for the neonates of the women in group A as compared with that for the neonates of the women in group B, being 2.68 (1.83Y3.93), 2.26 (1.31Y3.91), 1.92 (1.39Y2.65), and 1.93 (1.11Y3.36), respectively. From these results, they concluded the existence of positive associations between SSRI exposure during pregnancy (late-gestation period) and several adverse lneonatal outcomes. I appreciate their study design in the way that the control group was set, a valid method to elucidate the net effect of SSRIs on adverse neonatal outcomes. Namely, they presented the odds ratios in group A or group B against group C for several neonatal outcomes. I think that their study limitation for the lack of information on the severity of the psychiatric illness of the pregnant women and the limitation of the representativeness of their study participants should be explored in a further study. Recently, Stephansson et al2 reported the effect of exposure to SSRIs on 3 types of mortalityVstillbirth, neonatal death, and postneonatal death. In their study, the exposure period to SSRIs was also considered in their subanalysis. As their main

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result, there was no significant association between SSRI exposure and the risk of stillbirth or infant mortality, except for the significant increase of the stillbirth rate by SSRI exposure from 3 months before the start of pregnancy until the first trimester. Although it would be somewhat difficult to directly compare these 2 studies, the discrepancies between the 2 studies in respect of the effect of SSRI exposure during pregnancy on the neonatal outcomes were clearly observed. Namely, Grzeskowiak et al1 clarified the subclinical effects of SSRI exposure on the neonatal outcomes, and Stephansson et al2 reported no clear effect of SSRI exposure on the mortality. I strongly recommend that Grzeskowiak et al1 should conduct a further study to check the clinical manifestations of the infants, including fatal outcomes. Such an additional survey may be expected to more clearly reveal the effect of SSRI exposure during pregnancy (lategestation period) on the infant life prognosis. AUTHOR DISCLOSURE INFORMATION The author declares no conflicts of interest. Tomoyuki Kawada, MD, PhD Department of Hygiene and Public Health Nippon Medical School Bunkyo-Ku, Tokyo, Japan [email protected]

REFERENCES 1. Grzeskowiak LE, Gilbert AL, Morrison JL. Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 2012;32:615Y621. 2. Stephansson O, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309:48Y54.

Reply to Dr Kawada Late-Gestation Selective Serotonin Reuptake Inhibitor Exposure and Perinatal Mortality Reply: e appreciate the interest by Dr Kawada1 in our study investigating neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors (SSRIs)2 and the call for additional analyses to examine clinical manifestations of the infants, in particular, fatal outcomes. Given the rarity of fatal outcomes, such as stillbirth (3.69 per 1000) and neonatal death

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(2.20 per 1000) as reported by Stephansson et al,3 our associated sample size was not sufficient to enable adequate statistical power to justify their investigation. We do, however, appreciate the significance of including data on infant mortality to more completely describe the effects of prenatal SSRI exposure on extreme clinical manifestations and the infant life prognosis. In accordance with this, we have included data on stillbirths and neonatal death later. Our original analysis included the investigation of neonatal outcomes among live-born singletons. After including data on infants previously excluded from the study (ie, fetal deaths), there was only 1 (0.61%; 6.1 per 1000 births) stillbirth in the group of women who received a dispensing for an SSRI, 14 (0.89%; 8.9 per 1000 births) stillbirths in the group of women who had a documented psychiatric illness but did not receive a dispensing for an SSRI, and 198 (0.45%; 4.5 per 1000 births) stillbirths in the group of women who did not have a psychiatric illness and did not receive a dispensing for an SSRI. With recognized limitations of sample size set aside, these differences were not statistically significant. From the available data, we can confirm that there were 2 (0.90%; 9.0 per 1000 births) neonatal deaths in the group of women who received a dispensing for an SSRI, 5 (0.3%; 3.2 per 1000 births) neonatal deaths in the group of women who had a documented psychiatric illness but did not receive a dispensing for an SSRI, and 96 (0.30%; 3.0 per 1000 births) neonatal deaths in the group of women who did not have a psychiatric illness and did not receive a dispensing for an SSRI. Again, with recognized limitations of sample size set aside, these differences were not statistically significant. Furthermore, no data were available to us in relation to the cause of death. Given the relatively small number of outcomes, we feel that these results should be interpreted with caution, making it difficult to draw accurate comparisons with previous studies, such as that published by Stephansson et al.3 An important note is that our overall rates of fatal outcomes in our cohort are higher than what was identified by Stephansson et al.3 This could be a manifestation of our cohort being derived from a single specialist tertiary level teaching hospital that is likely to attract high-risk pregnancies,2 as opposed to the populationbased approach undertaken by Stephansson et al.3 We also acknowledge the limitation of not having data available to assess the severity of underlying maternal illness. Further studies with adequate sample size are

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required to clarify these findings, and we look forward to this evolving literature. ACKNOWLEDGMENT Dr Morrison was supported by a Heart Foundation South Australian Cardiovascular Research Network Fellowship (CR10A4988). AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Luke E. Grzeskowiak, PhD, BPharm (Hons), GCertClinEpid The Robinson Institute The University of Adelaide Adelaide, South Australia, Australia [email protected]

Janna L. Morrison, PhD, BSc (Hons), MSc School of Pharmacy and Medical Sciences Sansom Institute for Health Research University of South Australia Adelaide, South Australia, Australia

REFERENCES 1. Kawada T. Selective serontonin reuptake inhibitors exposure during pregnancy and neonatal outcomes. J Clin Psychopharmacol. 2014;34. [Epub ahead of print]. 2. Grzeskowiak LE, Gilbert AL, Morrison JL. Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 2012;32:615Y621. 3. Stephansson O, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309:48Y54.

Sleep-Related Eating Disorder Associated With Mirtazapine To the Editors: leep-related eating disorder (SRED) is defined as recurrent episodes of involuntary eating and drinking during arousal from sleep with problematic consequences.1 Patients are partially or fully amnestic for this eating behavior. The pathophysiologic mechanism of SRED is uncertain but it has been suggested that it may be related to dopaminergic dysfunction. This theory is supported by the increased prevalence of SRED in restless legs syndrome (RLS).2 Several case reports have been reported in which SRED was associated with zolpidem use.3Y6 The authors present a case of a patient who showed binge eating behavior

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after sleep-onset due to mirtazapine treatment. The patient showed complete remission after mirtazapine treatment was discontinued. On the basis of a literature review, this is the first report of SRED linked to the use of mirtazapine.

CASE REPORT The subject in this case report is a 24-year-old woman who was brought to the psychiatric ward by her parents and was admitted with depressed mood and suicidal gestures (drug ingestion: zolpidem 50 mg). She reported that she had experienced depressed mood, volition loss, and sleep disturbance for several years and had treated her symptoms with fluoxetine (40 mg/d), trazodone (75 mg/d), and zolpidem (10 mg/d) at a local psychiatric clinic she had visited a year ago. Also, she intermittently experienced night binge eating after sleep-onset but could not remember her eating behavior the next morning. Her weight increased from 50 to 70 kg during a period of 6 months. Physical and neurological examinations and all laboratory tests were normal. There was also no evidence of RLS, periodic limb movement disorder (PLMD), and history of other prior parasomnias. Abnormal eating behavior could be associated with zolpidem and fluoxetine combination therapy. Therefore, we discontinued her all medications at intake and replaced them with mirtazapine (30 mg/d) and clonazepam (0.25 mg/d). Her depressive mood, suicidal ideation, and insomnia improved, and her night binge eating episodes disappeared. After 2 weeks of inpatient therapy, she was discharged from the hospital with markedly improved states. However, 2 weeks after discharge, she reported weight gain and night binge eating episodes (4 weeks of mirtazapine and clonazepam use). She usually received her medications around 11 P.M. and went directly to bed. Approximately 1 to 2 hours after sleep-onset, she arose and ate large amounts of food. She seemed to be awake and showed nervousness and irritability when family attempted to stop her behavior. But she could not remember her unusual eating behavior the next morning. Even after her mirtazapine dose was reduced to 15 mg/d, her abnormal eating behaviors continued. We finally discontinued mirtazapine, and the binge eating behavior disappeared.

DISCUSSION For a diagnosis of SRED, a patient must experience recurrent episodes of involuntary eating and drinking with problematic results. These involuntary eating and drinking episodes should include 1 or * 2014 Lippincott Williams & Wilkins



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more of the following: consumption of peculiar forms of food or toxic substances, insomnia related to sleep disruption with daytime fatigue or sleepiness, sleep-related injury, dangerous behaviors performed while in pursuit of food or while cooking food, morning anorexia, and adverse health consequences from recurrent binge eating of high-caloric foods.1 Because our patient exhibited recurrent episodes of binge and uncontrollable eating after arousal from sleep, she could not remember her abnormal eating behavior; her symptoms met the diagnostic criteria for SRED. Several drugs, such as zolpidem, triazolam, olanzapine, risperidone, and quetiapine related to SRED,3Y9 and topiramate, clonazepam, and dopaminergics showed therapeutic benefits through case reports and small uncontrolled studies.10Y12 Mirtazapine enhances serotonin release by blocking >-2 autoreceptors and heteroreceptors, selectively antagonizing the serotonin 5-HT2 and 5-HT3 receptors in the central and peripheral nervous system. Blockade of 5-HT2 and 5-HT3 receptors may produce antidepressant effects by relieving sleep disturbance or increasing appetite. Mirtazapine also has a potent antagonist effect on histamine 1 receptors, which may augment the sedative and appetite-increasing effects. The pathophysiology of SRED is still unclear. However, because SRED is prevalent in patients with RLS and PLMD, there is evidence that SRED may be related to dopaminergic dysfunction.2,10,13,14 Some investigators have reported that combined selective >-2 adrenoceptor antagonists and norepinephrine transporter inhibitors caused a marked and selective increase of extracellular dopamine in prefrontal cortex.15,16 However, second-generation antidepressants alone may cause RLS in 9% of patients, and mirtazapine induced or exacerbated RLS in 28% of patients.17 Moreover, recent reports showed an association of mirtazapine with PLMD-like symptoms.18 Although serotonin-mediated dopamine inhibition might be a mechanism,19 it is uncertain which mechanism of mirtazapine causes SRED. Here, we report the first case of mirtazapine-related SRED. The use of mirtazapine should, therefore, be considered a possible precipitating factor for developing SRED, and it will not necessarily have an immediate onset.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. * 2014 Lippincott Williams & Wilkins

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercialNoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. Jong-Hyun Jeong, MD, PhD Department of Psychiatry St Vincent’s Hospital College of Medicine The Catholic University of Korea Suwon, Korea

Won-Myong Bahk, MD, PhD Department of Psychiatry St Mary’s Hospital College of Medicine The Catholic University of Korea Seoul, Korea [email protected]

REFERENCES 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.


12. Kobayashi N, Yoshimura R, Takano M. Successful treatment with clonazepam and pramipexole of a patient with sleep-related eating disorder associated with restless legs syndrome: a case report. Case Rep Med. 2012;2012:893681. 13. Winkelman JW. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry. 1998;59:14Y19. 14. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep. 1991;14:419Y431. 15. Masana M, Bortolozzi A, Artigas F. Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. Int J Neuropsychopharmacol. 2011;14:53Y68. 16. Masana M, Castane A, Santana N, et al. Noradrenergic antidepressants increase cortical dopamine: potential use in augmentation strategies. Neuropharmacology. 2012;63:675Y684. 17. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res. 2008;43:70Y75.

2. Provini F, Antelmi E, Vignatelli L, et al. Association of restless legs syndrome with nocturnal eating: a case-control study. Mov Disord. 2009;24:871Y877.

18. Mattoo SK, Mahajan S, Sarkar S, et al. PLMD-like nocturnal movements with mirtazapine. Gen Hosp Psychiatry. 2013;35:576.e7Y576.e8.

3. Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med. 2002;3:323Y327.

19. Kugaya A, Seneca NM, Snyder PJ, et al. Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology. 2003; 28:413Y420.

4. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med. 2007;3:637Y638. 5. Dang A, Garg G, Rataboli PV. Zolpidem induced Nocturnal Sleep-Related Eating Disorder (NSRED) in a male patient. Int J Eat Disord. 2009;42:385Y386. 6. Yun CH, Ji KH. Zolpidem-induced sleep-related eating disorder. J Neurol Sci. 2010;288:200Y201. 7. Paquet V, Strul J, Servais L, et al. Sleep-related eating disorder induced by olanzapine. J Clin Psychiatry. 2002;63:597. 8. Tamanna S, Ullah MI, Pope CR, et al. Quetiapine-induced sleep-related eating disorder-like behavior: a case series. J Med Case Rep. 2012;6:380. 9. Lu ML, Shen WW. Sleep-related eating disorder induced by risperidone. J Clin Psychiatry. 2004;65:273Y274. 10. Schenck CH, Hurwitz TD, O’Connor KA, et al. Additional categories of sleep-related eating disorders and the current status of treatment. Sleep. 1993;16:457Y466. 11. Provini F, Albani F, Vetrugno R, et al. A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder. Eur J Neurol. 2005;12:432Y436.

Donepezil-Associated Mania in Two Patients Who Were Using Donepezil Without a Prescription To the Editors: ore than 40 years ago, it was postulated that excess acetylcholine was associated with depression and decreased acetylcholine was associated with mania.1 Although the prevailing notion that increased cholinergic status is associated with depression, to date, there are 7 case reports of mania related to the use of donepezil in subjects with dementia.2Y7 Donepezil is a reversible acetylcholinesterase inhibitor, which acts on the nervous system when used in the treatment of dementia of the Alzheimer type. We report the first 2 cases of mania associated with donepezil use in healthy men who took donepezil that was not originally prescribed for them.

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CASE REPORTS Patient 1, Mr B, is a 28-year-old white man. He is a full-time graduate student in the process of completing his thesis and lives with his parents and grandparents. He was brought to the emergency room (ER) by his mother for acute agitation. The patient’s mother states that neither her son nor any of their family members are known to have psychiatric disorders. The patient’s mother recounts that he started acting not quite like himself more than 2 weeks before his presentation at the ER. In the 7 days leading up to his admission, she noticed that her son was (1) sleeping only 1 to 2 hours per day, (2) talking faster and louder, (3) spending money on clothing and computer gadgets, (4) more irritable than usual, and (5) constantly talking about expanding the subject matter of his thesis to unrelated fields. The patient reports that, 2 weeks before admission, his energy levels suddenly/unexpectedly increased, and he experienced increased confidence about completing his graduate degree. The patient denied taking any prescribed medication. Initially, Mr B denied any drug use, and his urine drug screen was negative (for amphetamine, barbiturates, benzodiazepines, cocaine, tetrahydrocannabinol, methadone, methamphetamine, opiates, phencyclidine, and tricyclic antidepressants), but upon further inquiries as to elicit substance use, he admitted to having stolen his grandmother’s donepezil; she had been recently diagnosed with mild Alzheimer dementia. He had read on the Internet of students using donepezil to increase their cognitive abilities and had started taking it to facilitate the completion of his thesis. The patient stated that he started taking donepezil approximately 4 weeks before presenting to the ER. After 2 weeks at 5 mg, the patient increased the dose he was taking to 10 mg, after which he further increased the dose to 15 mg. The latter dosage was what he was taking upon presentation. He reported mild initial diarrhea but denied any other side effect. He reported that the medication had been quite helpful as he completed the remaining half of his thesis in less than 2 weeks, whereas it had taken him 6 months to complete the first half. On mental status examination, the patient’s psychomotor activity was markedly elevated, speech was pressured, mood was elated and labile at times, and thought process was positive for flight of ideas and occasional loosening of associations. Thought content was positive for grandiose ideation. The patient was alert and oriented, and his insight

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and judgment were impaired. A diagnosis of drug-induced mania was made while ruling out the possibility of a primary mood disorder; however, the concordance of donepezil use and the onset of manic symptoms strongly suggest a causal link. A full medical and neurological (computed tomography brain, electroencephalography) as well as toxicological (urine street-drug screen) and infectious disease (human immunodeficiency virus and syphilis [rapid plasma reagin]) workup was negative. The patient was kept in the emergency room for 5 days and was treated with risperidone of 0.5 mg po 2 times a day. His symptoms abated almost completely by the fourth day. He was seen as an outpatient every 2 to 3 weeks for 2 months and weaned off risperidone after 3 months of treatment. Patient 2, Mr K, is 64-year-old white man with no current or previous psychiatric diagnosis. The patient was brought to the emergency room after his wife called 911 because of his agitation and violent behavior. The patient’s wife stated that the patient had started sleeping less and had become increasingly hyperactive for the previous 2 weeks. She said this behavior shift was initially subtle but had increased quite rapidly during the few days before his presentation to the ER. This shift had begun with the patient sleeping very little at night and showing increased energy during the day. This then progressed to the patient being somewhat more irritable and short-tempered with his wife. In the previous few days, the patient had been spending money on items he could not afford and did not need. The morning before the patient was brought to emergency, the couple fought over the wife’s concerns for the patient’s spending. During that fight, the patient, who had never been a violent man, struck his wife. On examination, the patient was found to have increased psychomotor agitation, pressured speech, elated mood, labile affect, flight of ideas, and grandiose ideations. The patient was alert and oriented. Insight and judgment were impaired. The patient had no medical history except for bilateral knee osteoarthritis. He and his wife denied any family psychiatric history (including bipolar disorder or dementia). He had chronic knee pain due to osteoarthritis for which he took arthrotec (diclofenac/ misoprostol) 50 mg (2Y3 times daily). This was the only medication the patient was actively taking. The patient was assessed by internal medicine, neurology, and geriatrics before being seen by psychiatry. The medical investigation was completely negative. All clinical and paraclinical investigations including computed tomography scan and MRI, electroencephalography,

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human immunodeficiency virus, rapid plasma reagin, and urine drug screen were negative. Cognitive assessment was performed, and the patient achieved a perfect score on both the Folstein and Montreal Cognitive Assessment. Additional information was provided by the patient’s son who stated that the patient managed the household, finances, and cooking. The only new stressor for the patient was his wife’s recent diagnosis of mild Alzheimer dementia for which she was treated with donepezil. The son made the comment that, while she initially responded quite well to the medication, she then seemed to be doing poorly on it. When the treating team sorted out the medication the patient was taking, it became clear that since the most recent medication renewal (then 4 weeks before), the patient had been taking his wife’s donepezil, and his wife had been taking his nonsteroidal anti-inflammatory drugs. A diagnosis of drug-induced mania was made while ruling out the possibility of a primary late-onset mood disorder; however, the concordance of donepezil use and the onset of manic symptoms strongly suggest a causal link. The patient was admitted to the inpatient psychiatric unit for 4 days. He was treated with risperidone of 0.25 mg po 2 times a day. His symptoms abated almost completely by the second day. He was seen as an outpatient 2 months later and was weaned off risperidone.

DISCUSSION These 2 cases are, to our knowledge, the first reports describing donepezilassociated mania in otherwise healthy, nondemented, nonYmood-disordered men. Six of the 7 previous case reports of donepezil-associated mania involved patients with previous diagnoses of either depression or bipolar affective disorder, and all these cases involved patients with dementia. Moreover, a small study of 12 bipolar and cognitively impaired (mild) patients treated with donepezil, to investigate whether this medication would improve cognition, showed that 2 subjects developed frank mania 2 weeks into treatment.8 Our 2 cases are similar to all previously reported cases only in that the patients presented with elevated mood symptoms very rapidly after the initiation of donepezil (manic/hypomanic symptoms commenced within days of starting donepezil). These 2 cases challenge the prevailing notion that excess acetylcholine is associated with depression. It could be hypothesized that certain subjects with dementia and comorbid mood disorders may have altered neurobiochemical sensitivities causing a seemingly paradoxical * 2014 Lippincott Williams & Wilkins



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reaction to increased levels of acetylcholine associated with donepezil. In fact, long-term use of donepezil has been found to be effective in attenuating depressive symptoms in cognitively impaired patients9,10 but not in noncognitively impaired patients.11 However, the heightened affective effect of donepezil has been observed in healthy young adults. Pompeia and colleagues12 published the results of a doubleblind, crossover study of 15 young male participants treated with donepezil to study the acute mood effects of this medication. These subjects were considered to have unaltered monoamine and acetylcholine neurotransmitter pathways. The study showed a moderate increase in the feelings of ‘‘strong’’ in the ‘‘strong-feeble’’ of the Visual Analogue Mood Scale. This mood impact of donepezil was first described by the same group when investigating the cognitive impact of donepezil in the treatment for young healthy adults.13 Given the prevailing notion that acetylcholine is associated with depression, it was thought that this agent might be an interesting adjunct in the treatment of mania in patients with bipolar disorder. Two double-blind, placebo-controlled studies investigated the impact of donepezil as an adjunct in the treatment of mania. The first, by Evins and colleagues,14 shows that donepezil is not an effective adjunctive treatment to commonly used mood stabilizers (lithium or valproic acid) for refractory manic patients. In fact, the patients in the treatment arm remain manic at 6 weeks, whereas those treated only with lithium improved significantly. The second study, by Chen and colleagues,15 also shows that donepezil is not an effective adjunctive treatment of mania. On the basis of the observations above, it would seem that the prevailing belief of increased cholinergic tone is not as straightforward and clear as once thought. Donepezil’s impact on not only the acetylcholine pathway but also the serotonergic, dopaminergic, and adrenergic pathways needs further investigation and comparison in healthy young adults, cognitively intact older adults, and older adults with dementia. We were unable to find such studies in humans; however, 2 studies in rats have shown that acute administration of donepezil is associated with increased dopamine levels in the cortex and hippocampus of the treated rodents.16,17 Heightened dopamine has been associated with manic-like behaviors in mouse models of bipolar disorder.18 Functional imaging experiments might be helpful in elucidating by which mechanism donepezil interacts with the monoamine signaling pathways. * 2014 Lippincott Williams & Wilkins

AUTHOR DISCLOSURE INFORMATION Leon Tourian has no financial interests to declare. Howard Margolese was a consultant to Bristol-Myers Squibb, Janssen, Novartis, Lundbeck, Sunovian, and Otsuka; received grants from Bristol-Myers Squibb, Janssen, Envivo, and Roche (in the past, received grants from Pfizer, Eli Lilly, and Amgen); and conducted paid lectures for Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Lundbeck, Sunovian, and Otsuka. Serge Gauthier was a consultant to TauRx, Servier, and Sanofi; received grants from Pfizer; and conducted paid lectures for Ever, Novartis, and Merck. Leon Tourian Jr, MD, MSc, FRCPC Clinical Pharmacology and Toxicology Program McGill University Montreal, Quebec, Canada [email protected]

Howard C. Margolese, MD, MSc, FRCPC Clinical Pharmacology and Toxicology Program McGill University Montreal, Quebec, Canada and Clinical Psychopharmacology and Therapeutics Unit McGill University Health Centre Montreal, Quebec, Canada

Serge Gauthier, MD, FRCPC Clinical Psychopharmacology and Therapeutics Unit McGill University Health Centre Montreal, Quebec, Canada and McGill Center for Studies on Aging Verdun, Quebec, Canada

REFERENCES 1. Janowsky DS, El-Yousef MK, Davis JM, et al. A cholinergic-adrenergic hypothesis of mania and depression. Lancet. 1972;2(7778):632Y635. 2. Benazzi F. Mania associated with donepezil. Int J Geriatr Psychiatry. 1998;13(11):814Y815. 3. Benazzi F. Mania associated with donepezil. J Psychiatry Neurosci. 1999;24(5):468Y469. 4. Benazzi F, Rossi E. Mania and donepezil. Can J Psychiatry. 1999;44(5):506Y507. 5. Collins C, Copeland B, Croucher M. Bipolar affective disorder, type II, apparently precipitated by donepezil. Int Psychogeriatr. 2011;23(3):503Y504. 6. Rao V, Ovitt L, Robbins B. Donepezil induced hypomania. J Neuropsychiatry Clin Neurosci. 2008;20(1):107. 7. Wicklund S, Wright M. Donepezil-induced mania. J Neuropsychiatry Clin Neurosci. 2012;24(3):E27. 8. Gildengers AG, Butters MA, Chisholm D, et al. A 12-week open-label pilot study of donepezil for cognitive functioning and instrumental activities of daily living in late-life bipolar disorder. Int J Geriatr Psychiatry. 2008;23(7):693Y698.


9. Gauthier S, Feldman H, Hecker J, et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr. 2002;14(4):389Y404. 10. Burt T. Donepezil and related cholinesterase inhibitors as mood and behavioral controlling agents. Curr Psychiatry Rep. 2000;2(6):473Y478. 11. Reynolds CF III, Butters MA, Lopez O, et al. Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry. 2011;68(1):51Y60. 12. Pompeia S, Gouveia JR, Galduroz JC. Acute mood effect of donepezil in young, healthy volunteers. Hum Psychopharmacol. 2013;28(3):263Y269. 13. Zaninotto AL, Bueno OF, Pradella-Hallinan M, et al. Acute cognitive effects of donepezil in young, healthy volunteers. Hum Psychopharmacol. 2009;24(6):453Y464. 14. Eden Evins A, Demopulos C, Nierenberg A, et al. A double-blind, placebo-controlled trial of adjunctive donepezil in treatment-resistant mania. Bipolar Disord. 2006;8(1):75Y80. 15. Chen J, Lu Z, Zhang M, et al. A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania. Neuropsychiatr Dis Treat. 2013;9:839Y845. 16. Liang YQ, Tang XC. Comparative studies of huperzine A, donepezil, and rivastigmine on brain acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats. Acta Pharmacol Sin. 2006;27(9): 1127Y1136. 17. Shearman E, Rossi S, Szasz B, et al. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study. Brain Res Bull. 2006;69(2):204Y213. 18. van Enkhuizen J, Geyer MA, Halberstadt AL, et al. Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder. J Affect Disord. 2014;155:247Y254.

Predictors of Response to Adjunctive Osmotic-Release Methylphenidate or Placebo in Patients With Major Depressive Disorder Effects of Apathy/Anhedonia and Fatigue To the Editors: ajor depressive disorder (MDD) is a complex illness that involves an array

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of integrated neurobiological systems and heterogeneous clinical profiles. This provides a potential explanation for the disappointing rates of response with firstline antidepressants.1 Furthermore, reliable clinical (eg, symptoms and demographics) or biological (eg, genetic polymorphisms) predictors of depression outcome have yet to play a role in improving treatment response. To enhance antidepressant response, pharmacotherapy augmentation is a common strategy2 that aims to target specific neurochemical pathways underlying certain symptoms.3 In particular, treatments that target dopaminergic networks are frequently used because they have been found to modulate core depressive symptoms including anhedonia, poor concentration and motivation, fatigue, as well as psychomotor retardation. Dopaminergic drugs such as methylphenidate, dextroamphetamine, and modafinil have been shown to benefit patients with MDD.4Y6 Whereas response prediction to monotherapy has been evaluated, response to augmentation therapies has not been as rigorously tested to date. With respect to monotherapy, not achieving early improvement (20% improvement on a depression scale by 2 weeks) strongly predicts nonresponse.7 From a statistical perspective, predicting response (defined as 50% decrease in depression score) based on ‘‘early improvement’’ using the same measure that defines response may be problematic for several reasons. First, a measure will naturally correlate with outcomes on that same measure, thereby inflating the predictive value of early improvement. Second, in the context of augmentation therapies that are prescribed to treat specific residual symptoms, a general depression symptom scale may not adequately capture the targeted impact of augmentation therapy. In a 5-week placebo-controlled trial of osmotic-release oral system (OROS) methylphenidate as an adjunctive therapy for selective serotonin reuptake inhibitor nonresponse,8 we demonstrated that OROS did not separate from placebo on the basis of the MontgomeryAsberg Depression Rating Scale (MADRS).9 We therefore conducted a secondary analysis to test the post hoc hypothesis that baseline or early changes in apathy or anhedonia as well as fatigue would predict response to OROS methylphenidate and predict whether a patient was receiving active drug or placebo. The original trial methods, design, and rationale have been detailed previously.8 Briefly, this was a multisite, flexible-dose, randomized, placebo-controlled study to evaluate the efficacy of adjunctive OROS methylphenidate (18Y54 mg) for 5 weeks in patients with MDD who demonstrated

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an inadequate antidepressant response (N= 144). Study visits occurred at baseline, 5 days, 14 days, 21 days, 28 days, and 35 days. Osmotic-release oral system methylphenidate was used in this study8 to address the limitations (sample size and inclusion criteria) of a previous trial.10 Patients with MDD aged 18 to 65 years who met the criteria for a current major depressive episode with a minimum severity of 20 on the MADRS were recruited. The inclusion criteria were the following: failure of at least 1 but no more than 3 adequate antidepressant trials for the current depressive episode, on a stable antidepressant for 4 weeks before study entry, as well as no psychiatric comorbidities other than generalized anxiety disorder and social phobia. For the present intent-to-treat analysis, the 2-week percentage change in the Apathy Evaluation Scale (AES)11 predicting 5-week response (MADRS change, Q50%) was the primary outcome. Secondary variables were the AES 2-week percentage change prediction of remission (MADRS, e10), the Multidimensional Assessment of Fatigue (MAF),12 and the MADRS 2-week percentage change prediction of response and remission. Baseline prediction of response and remission was also evaluated. Logistic regressions were used to predict response and remission within the drug-only and placebo-only group as well as the drug group versus placebo group. These analyses were repeated using a machine learning method known as the classification and regression tree algorithm,13 included in the Statistical Package for the Social Sciences 17.0 software package (SPSS, 2008). This involves searching through a set of features (eg, percentage change scores of the aforementioned scales from baseline to 2 weeks). The algorithm looks for the combination of features that best splits patients into groups (responders/nonresponders) by attempting to find a cutoff value that maximizes the correct number of patients in each group. The algorithm continues until everyone is classified. The result is decision trees that allow for complex statistical inference including cutoff scores for features. A total of 144 patients were included in this analysis (OROS, n = 72; placebo, n = 72). There were no baseline differences among the responders and nonresponders within the drug group or placebo group or between the drug group and placebo group. Response and remission rates for OROS and placebo did not differ significantly (38.9% and 27.8% vs 41.7% and 25.0%, respectively). Overall, the OROS group demonstrated greater changes on the AES compared with the placebo group by 5 weeks.

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Furthermore, in the OROS group, the responders had greater 2-week percentage change on the MADRS, AES, and MAF compared with the nonresponders. In the placebo group, differences between the responders and the nonresponders occurred only with the MADRS 2-week percentage change. After 2 weeks of treatment, the greatest contributors to the MADRS percentage change from baseline were apparent sadness (r = 0.64; P G 0.001), reported sadness (r = 0.60; P G 0.001), concentration (r = 0.62; P G 0.001), lassitude (r = 0.68; P G 0.001), inability to feel (r = 0.67; P G 0.001), and suicidal thoughts (r = 0.411; P G 0.001). Compared with the placebo group, the OROS group had significantly greater change in lassitude from baseline to week 2 (t = j3.152; P = 0.002) on the MADRS, although overall change in depression at end point was not different between the groups. Baseline MADRS, AES, or MAF total scores did not predict response or remission in the methylphenidate group or placebo group. Both the AES and MAF 2-week percentage change predicted response and remission in the drug group (response model accuracy: 68.2% and 72.2%, P = 0.005, respectively; remission model accuracy: 69.7% and 75.8%, P G 0.05, respectively) but not in the placebo group. However, the MADRS at 2-week percentage change predicted response and remission to both OROS and placebo (active drug model accuracy: 77.6% and 86.6%, P G 0.001, respectively). On the basis of the decision trees, the MADRS 2-week percentage change was the strongest predictor of response (Fig. 1A). However, in this 1-tiered model a MADRS improvement cutoff of 35% instead of the conventional 20% predicted nonresponders with 83.3% accuracy and responders with 74.1% accuracy; remission was predicted with 94.7% accuracy and nonremission with 68.4% accuracy, with a cutoff for improvement of 48.5%. However, when the conventional 20% improvement cutoff was forced into the model, 60% of responders, 77.8% of nonresponders, 57.9% of remitters, and 89.5% of nonremitters were correctly classified. When the MADRS was removed from the model, the AES 2-week percentage change (at a cutoff of 6.4% improvement), along with the MAF 2-week percentage change (at a cutoff of 23.7% improvement), predicted response with 96.7% accuracy and nonresponse with 55.6% accuracy (Fig. 1B). For the remitters, a 2-tiered model where the 2-week percentage change on the AES (at a cutoff of 11% improvement) and MAF (at a cutoff of 6.2% improvement) * 2014 Lippincott Williams & Wilkins



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FIGURE 1. Decision tree for predicting response to methylphenidate using AES, MAF, and MADRS total scores (A) and only AES and MAF total scores (B). NResp indicates nonresponder; Resp, responder.

predicted remission and nonremission with 92.1% and 52.6% accuracy, respectively. For placebo, the most robust predictor was the MADRS 2-week percentage change combined with the MAF 2-week percentage change. This model predicted nonresponse with 78.6% accuracy and response with 60% accuracy. The AES did not predict response or remission to placebo. No predictive model was found for the remitters to placebo. The MADRS percentage change at 2 weeks was not able to distinguish between active drug and placebo. In contrast, the AES predicted the placebo group with 70.4% accuracy and the active drug group with 42.4% accuracy (P = 0.013) and the MAF predicted placebo with 71.8% accuracy and active drug with 53% accuracy (P = 0.022).

DISCUSSION We have demonstrated that the best predictor of response to adjunctive OROS methylphenidate was the early change in apathy. Furthermore, only the early AES change was able to predict drug group versus placebo group assignment. Clinically, this has utility for optimizing treatment strategy * 2014 Lippincott Williams & Wilkins

because it could cut down on overmedicating patients who are unlikely to respond. To date, clinical biomarkers of outcome have not been useful for antidepressant monotherapy, which may be caused by a lack of linking mechanism of action to outcome assessment. Although the mainstay of antidepressant monotherapy is to primarily affect serotonin and/or norepinephrine, augmentation strategies that target dopamine are often used to treat specific or residual symptoms.14 Therefore, linking outcome measures to putative drug mechanism of action is particularly relevant to augmentation strategies. Because dopamine has been linked to specific symptoms such as anhedonia, psychomotor retardation, as well as poor concentration and energy,15,16 dopaminergic agents provide a unique avenue to evaluate clinical markers of response on the basis of their anticipated effects on these symptoms. Osmotic-release oral system methylphenidate is approved for use in attentiondeficit/hyperactivity disorder and used off-label for adjunctive use in depression. Trials of methylphenidate in depression have yielded equivocal results on depression scores, whereas positive effects on apathy,

fatigue, and concentration are consistently reported.4,8 This suggests that the inconsistent findings may be partially caused by the focus on global measures of depression improvement. Therefore, when assessing the benefit of augmentation agents, it may be more pertinent to assess their effect on specific residual symptom clusters rather than on global improvement. Among the clinical biomarkers of monotherapy response, early improvement seems to be the most robust predictor in clinical practice. Current guidelines recommend switching treatment if at least 20% improvement is not seen by week 2 of treatment with a monotherapy.17 To our knowledge, the utility of this cutoff has not been explored with respect to augmentation strategies before the present study. However, we showed that 20% improvement was not a good predictive model for the following reasons: (1) it produced limited predictive value in a more descriptive mathematical model than logistic regression; (2) the correlation of improvement with outcome may be inflated; and (3) it did not distinguish between response to drug or placebo. To highlight the second point, the predictive value of early improvement may www.psychopharmacology.com


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be inflated by erroneously treating 2 time points (eg, baseline and end point) as independent. Early improvement and response criteria by definition are dependent on baseline scores. Therefore, early improvement will naturally correlate with response. In addition, the test-retest reliability of a well-designed scale should be high; for the Hamilton Depression Rating Scale, which was used to produce the 20% improvement cutoff,7 the test-retest reliability can be as high as 0.98.18 Given that there is a large proportion of patients who do not respond or remit in clinical trials,19,20 a large percentage of patients whose scores remain unchanged are contributing to the predictive correlation. This idea is further borne out by the finding that early improvement is more predictive of nonresponse. Finally, the 20% improvement criterion did not predict whether a patient was in the placebo group or drug group, whereas changes in apathy and fatigue did. This is relevant to clinical practice where it would be helpful to distinguish placebo responders early in the course of treatment and determine whether treatment with a new drug is, in fact, working. In conclusion, early changes in apathy and fatigue predicted response to OROS methylphenidate in patients with depression. It is proposed that assessment of symptoms that are expected to change with adjunctive treatment on the basis of mechanism of action may be more relevant in determining drug benefit than the ability to reduce global depression scores. ACKNOWLEDGMENTS The authors thank Anne Marie Quinn of Janssen-Ortho, Inc, for proofreading the article. The work for the analysis and preparation of this article did not receive funding support. However, the initial RCT from which the data were extracted was funded by Janssen-Ortho Inc. AUTHOR DISCLOSURE INFORMATION S.J.R. has received research travel support from Eli Lilly Canada and St Jude Medical. J.G. has received research travel support and fellowship from Eli Lilly Canada. A.V.R. is on speaker/advisory boards or has received research funds from the following: AstraZeneca, Canadian Network for Mood and Anxiety Treatments, Cephalon, Eli Lilly, Janssen-Ortho, Lundbeck, Pfizer, Roche, and Servier. S.H.K. has received grant/research support from the following: Bristol-Myers Squibb, Clera, Inc, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, and St Jude Medical. He is a consultant to AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,

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Eli Lilly, Lundbeck, Pfizer, Servier, and St Jude Medical. This analysis was carried out with support from the Ontario Brain Institute. Sakina J. Rizvi, HBSc Departments of Pharmaceutical Sciences and Neuroscience University of Toronto and Department of Psychiatry University Health Network Ontario, Canada

Joseph Geraci, PhD Department of Psychiatry University Health Network and Department of Pathology and Molecular Medicine Queen’s University Ontario, Canada

Arun Ravindran, MD Department of Psychiatry Centre for Addiction and Mental Health and Department of Psychiatry University of Toronto Ontario, Canada

Sidney H. Kennedy, MD, FRCPC Department of Psychiatry University Health Network and Department of Psychiatry University of Toronto Ontario, Canada [email protected]

REFERENCES 1. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9:449Y459. 2. Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010;67:26Y36. 3. Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69(suppl E1):4Y7. 4. Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev. 2008;16(2):CD006722. 5. Goss AJ, Kaser M, Costafreda SG, et al. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013;74(11):1101Y1107. 6. Patkar AA, Pae CU. Atypical antipsychotic augmentation strategies in the context of guideline-based care for the treatment of major depressive disorder. CNS Drugs. 2013;27(suppl 1):S29YS37. 7. Szegedi A, Jansen WT, van Willigenburg AP, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in

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patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70:344Y353. 8. Ravindran AV, Kennedy SH, O’Donovan MC, et al. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69:87Y94. 9. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382Y389. 10. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26:653Y656. 11. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991;38:143Y162. 12. Bormann J, Shively M, Smith TL, et al. Measurement of fatigue in HIV-positive adults: reliability and validity of the Global Fatigue Index. J Assoc Nurses AIDS Care. 2001;12:75Y83. 13. Chou PA. Optimal partitioning for classification and regression trees. IEEE Trans Pattern Anal Mach Intell. 1991;13:340Y354. 14. Papakostas GI. Dopaminergic-based pharmacotherapies for depression. Eur Neuropsychopharmacol. 2006;16:391Y402. 15. Meyer JH, McNeely HE, Sagrati S, et al. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry. 2006;163:1594Y1602. 16. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64:327Y337. 17. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009;117(suppl 1):S26YS43. 18. Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol. 2008;22:843Y848. 19. Thase ME, Nierenberg AA, Vrijland P, et al. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int Clin Psychopharmacol. 2010;25:189Y198.




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20. Trajkovi( G, Star*evi( V, Latas M, et al. Reliability of the Hamilton Rating Scale for Depression: a meta-analysis over a period of 49 years. Psychiatry Res. 2011;189:1Y9.

Possible Association of Syndrome of Inappropriate Secretion of Antidiuretic Hormone With St John’s Wort Use To the Editors: n Western society, there is currently a widespread interest in and general appeal for the use of herbal remedies in the treatment of depression. St John’s wort (SJW) is one such product. It has long been used for its antidepressant effects, and its efficacy has been confirmed in many clinical studies and reviewed in meta-analyses.1 Rates of adverse events are thought to be considerably lower with SJW when compared with synthetic antidepressants,2 making this herbal compound an appealing alternative for patients experiencing depression. Here, we account the first case report of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with the use of SJW.3

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CASE REPORT Mr C is a 67-year-old man who was brought to the emergency room after being found wandering outdoors. The patient had no medical history, was a nonsmoker, did not consume alcohol or illicit drugs, and had no known allergies. The patient’s psychiatric history was positive for depression. The patient attempted to use synthetic psychotropic agents but, because of their adverse effect profile, discontinued these. The patient reported that, in the previous 3 months, he had experienced poor sleep and a concomitant increase in depressive symptoms (poor appetite, difficulty concentrating, and reduced energy). Medication history revealed the use of a daily multivitamin or multimineral supplement and SJW (St John wort ingredients, 300-mg tablets), which the patient began in 2008 with sporadic use until approximately the previous 3 months when his depressive symptoms returned. Six weeks before admission, he began ingesting SJW 600 mg daily, then 900 mg daily for 4 weeks, followed by 600 mg daily for 4 weeks to the time of admission. The patient denied any of the common adverse effects associated with SJW. A physical examination revealed a well-nourished, pleasant man with normal * 2014 Lippincott Williams & Wilkins

vital signs. The patient was deemed euvolemic without edema. His blood pressure was normal (140/80), with no postural fall. Physical examination revealed no abnormalities. A negative result of computed tomographic scan of the patient’s head and chest ruled out possible central nervous system disturbances (stroke, hemorrhage, etc) and pulmonary malignancies, respectively. His blood workup result was otherwise normal, with normal results of thyroid function tests and serum cortisol. On mental status examination, the patient was poorly groomed and wearing a hospital gown. The patient’s speech was somewhat monotone. The patient stated that he was ‘‘sad.’’ Affect was constricted. The patient denied suicidal ideation or intention as well as any delusions. A cognitive screen, the Montreal Cognitive Assessment, score of 30/30 was obtained at the time of interview. Insight and judgment were judged as fair. Serum and urine laboratory results on admission are demonstrated in Table 1. On the basis of these laboratory findings and a negative medical workup, a working hypothesis of SIADH was given.4,5 The patient was held in the emergency department overnight. Proper follow-up ensured a gradual reestablishment of his serum sodium levels. No general medical condition was identified during the course of follow-up that could explain the development of SIADH in this patient. The patient returned to the same hospital’s emergency department 3 weeks after discharge because of an additional exacerbation of his underlying depression. At that time, the patient denied the use of SJW, his sodium levels had normalized (135 mEq/L), and urine studies were also within normal limits.

DISCUSSION To our knowledge, this is the first case report in which the use of SJW possibly induced hyponatremia through SIADH. Medical conditions generally6 associated


with SIADH were ruled out at the initial evaluation and during the follow-up of our patient, and cessation of SJW was associated with a normalization of his sodium homeostasis. The patient was not taking any other medication that could have caused hyponatremia. To demonstrate a more direct or definitive causation of SIADH by SJW, we would have had to take the unethical path of monitoring his sodium levels after rechallenging this patient with SJW. Antidepressant-related hyponatremia by way of SIADH has been reported for all classes of antidepressants such as tricyclic antidepressants,7 selective serotonin reuptake inhibitors,5 serotonin-norepinephrine reuptake inhibitors,8 and monoamine oxidase inhibitor.9 Syndrome of inappropriate secretion of antidiuretic hormone associated with psychotropic medications is related to increased hypothalamic production of antidiuretic hormone. The exact mechanism by which antidepressants cause increased antidiuretic hormone secretion has not been clearly elucidated. In most cases, hyponatremia occurs within the first 30 days after the onset of therapy.10 Moreover, previous hyponatremia, older age, and the concomitant use of diuretics are the most significant risk factors associated with the development of hyponatremia associated with antidepressants. St John’s wort is a flowering plant that contains several pharmacologically active products such as hypericin and hyperforin, which have the potential for psychogenic altering capacities. The exact antidepressant and biological mechanism of SJW has yet to be clearly elucidated. However, it is generally thought that hyperforin is mainly responsible for inhibiting the reuptake of serotonin.11Y13 The exact mechanism by which hyperforin increases serotonin levels remains unknown, but many hypotheses have been proposed.14Y16 These studies demonstrate, however, that hyperforin does not increase serotonin by the exact same mechanism as do antidepressants.

TABLE 1. Laboratory Results Blood and Urine Laboratory Tests Serum Na+, mEq/L Serum K+, mEq/L Serum osmolality, mOsm/kg Serum Cr, Kmol/L Serum urea, mmol/L TSH concentration, mU/L Urine Na+, mEq/L Urine K+, mEq/L Urine osmolality, mOsm/kg

Patient’s Results

Reference Range

122 4.2 255 79 3.0 4.11 67 64.9 524

136Y145 3.5Y5 275Y290 60Y110 8Y20 0.4Y5 20Y40 25Y125 2C and >2A noradrenergic receptors.1,10 It blocks the 5HT7 receptor and acts as a partial agonist of the 5HT1A receptor.1,11 Lurasidone has little, if any, affinity for histamine H1 and acetylcholine M1 receptors.10 The adverse events associated with lurasidone treatment are similar to those seen with the other atypical antipsychotic agents. Commonly seen adverse effects include akathisia, agitation, Parkinsonism, anxiety, somnolence, and dystonia.6 As with other antipsychotic agents, there

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are rare reports of leukopenia or neutropenia. The lurasidone clinical trials found it effective for both positive and negative symptoms of schizophrenia and that the most common adverse events were movement abnormalities, akathisia, nausea, and drowsiness.9 A later study by Citrome et al10 examined more than 400 patients who were treated with lurasidone for 12 months. The lurasidone doses ranged from 40 mg to 120 mg daily. In this study, the most frequent adverse effects were nausea (16.7%), insomnia (15.8%), and sedation (14.6%).10 Studies have found that there is no significant QTc prolongation associated with lurasidone use.5 In fact, 1 study found that high-dose lurasidone (up to 600 mg daily) was associated with minimal QTc interval increases of between 4.4 and 6.4 milliseconds.5 Overall, the authors felt that lurasidone was ‘‘safe and well tolerated’’ with minimal effect on prolactin levels, weight, or metabolic variables.10 Lurasidone has been classified as pregnancy category B by the FDA.1 It has been recommended that mothers do not breast feed while taking lurasidone.1 There are minimal data regarding overdose on lurasidone. In fact, a literature search was unable to find any case reports of overdose in the literature to date. The only mention of lurasidone overdose was the brief description of a single case in the package insert.12 That patient ingested an estimated 560 mg of lurasidone and recovered without sequelae. We now report the case of a 31-year-old man who overdosed on a large amount of lurasidone in an attempt to commit suicide.

CASE REPORT The patient was a 31-year-old man with a history of schizophrenia who was brought to the emergency department 90 minutes after an intentional overdose on seventeen 80-mg lurasidone tablets and five 1-mg clonazepam tablets in an attempt to end his life. The ingestion occurred immediately after lunch and was witnessed by his caregiver. His caregiver was able to confirm the number of pills ingested. His history was negative for tobacco, alcohol, or illicit drug use. His medical history was significant for hypertension and obesity as well as negative for any respiratory or endocrine disorder. Twenty-two days before this overdose, the patient weighed 131.8 kg and had a body mass index of 39.4. The patient’s medication regimen consisted of lurasidone (160 mg nightly), trazodone (150 mg nightly), and clonazepam (1 mg every 8 hours as needed). Upon presentation to the emergency department, the patient was noted to be cooperative, alert, and oriented in all * 2014 Lippincott Williams & Wilkins



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TABLE 1. Definitions of Inducers and Inhibitors From the United States FDA Term

Definition

Strong inducer Moderate inducer Strong inhibitor

Moderate inhibitor

A medication that causes an 80% decrease or higher in the AUC of the concurrently used medication A medication that causes a 50% to 80% decrease in the AUC of the concurrently used medication A medication that causes a 5-fold increase or higher in AUC or greater than 80% decrease in CL of the concurrently used medication A medication that causes a 2- or higher but less than 5-fold increase in AUC or 50% to 80% decrease in CL of the concurrently used medication


patient ingested 1360 mg of lurasidone, along with 5 mg of clonazepam with minimal medical difficulties. One interesting finding was the transient increase in the patient’s TSH level that was discovered the day after the overdose. It will be important to continue in reviewing cases of lurasidone overdose over time to compare their outcomes. It would also be useful to monitor TSH levels in those patients who have overdosed on lurasidone to ascertain whether there is a true relationship between lurasidone overdose and TSH elevation.

AUC indicates area underneath the curve; CL, drug clearance.

spheres. He was in no acute distress and was breathing easily. His temperature was 36.4 -C, his blood pressure was 140/87, and he had a pulse of 85 beats per minute. A complete blood count, a complete metabolic profile, and urinalysis were all within normal limits. Amylase, lipase, troponin, creatine kinase-MB, and creatine kinase were all within normal limits. Urine drug screen was positive only for benzodiazepines. Of note, the patient’s thyrotropin (TSH) was elevated at 6.100 mIU/L from a documented 4.015 mIU/L 3 weeks prior. Free T3 and free T4 were both within normal limits at 2.60 pg/mL and 1.15 ng/dL, respectively. Electrocardiogram displayed normal sinus rhythm with a rate of 91 beats per minute and a QTc of 452 milliseconds. There was no recent electrocardiogram available for comparison. The finding of neurologic examination was normal, except for mild oral-buccal dyskinesia that was also noted on prior outpatient documentation. The patient was admitted to the medical intensive care unit (ICU) for observation and administration of fluids. No other medical treatment was required in the ICU. His hypertension resolved within 12 hours of the ingestion. He was transferred to the inpatient psychiatric unit, and his physical condition remained stable. While on the inpatient psychiatric unit, lurasidone was restarted. However, shortly afterward, the lurasidone was discontinued at the patient’s request and he was switched to ziprasidone. The patient’s hypertension resolved quickly, and he was subsequently discharged home. A repeat TSH drawn 17 days after the discharge was found to be within normal limits at 3.053 mIU/L.

DISCUSSION This is a report on a 31-year-old man with schizophrenia who overdosed on lurasidone (1360 mg) and clonazepam (5 mg) in a suicide attempt. His medical * 2014 Lippincott Williams & Wilkins

history was significant for obesity and hypertension, but there was no history of any endocrine dysfunction. There was also a negative history of substance abuse. The amount of lurasidone ingested was 8.5 times the maximum recommended dose and was equal to 10.32 mg/kg of body weight. The patient’s overdose took place shortly after lunch, so the presence of food in his stomach could have increased his absorption of the lurasidone. The patient initially presented with mild hypertension and an elevated TSH (6.100 mIU/L), but there were no other physical examination or laboratory findings. The patient recovered without any significant medical sequelae, and his TSH level had normalized when checked more than 3 weeks after the overdose. There is 1 documented case of lurasidone overdose (560 mg) in a patient who recovered without any medical issues. Our case had essentially the same outcome. The overdose (1360 mg) resulted in only mild hypertension and a single laboratory test abnormality (elevated TSH). It is difficult to determine whether the elevation of TSH was an isolated incident or whether it was related to the overdose because there is no literature linking lurasidone therapy with thyroid dysfunction. In addition, as with other antipsychotic agents, lurasidone may decrease seizure threshold. In our patient’s case, concurrent ingestion of clonazepam may have played a protective role in the prevention of seizure activity. Our patient had no long-term problems due to his lurasidone overdose. In fact, other than receiving fluids in the ICU, he required no other treatment for the ingestion. Thus, in our patient’s case, the overdose of lurasidone was not life threatening. In conclusion, this is the largest single ingestion of lurasidone reported in the literature to date. To the best of our knowledge, it is also the first detailed case report described in the literature. The

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Gabor P. Molnar, DO Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL

Laura C. Grimsich, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL

Glenn Catalano, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL [email protected]

Maria C. Catalano, DO Ambulatory Care Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL

REFERENCES 1. Cruz MP. Lurasidone HCl (Latuda), an oral, once-daily atypical antipsychotic agent for the treatment of patients with schizophrenia. Proc Natl Acad Sci U S A. 2011;36: 489Y492. 2. Belmaker RH. Lurasidone and bipolar disorder. Am J Psychiatry. 2014;171: 131Y133. 3. Citrome L. Lurasidone in schizophrenia: new information about dosage and place in therapy. Adv Ther. 2012;29:815Y825.



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4. Preskorn S, Ereshefsky L, Chiu YY, et al. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open-label, crossover studies. Hum Psychopharmacol. 2013;28:495Y505. 5. Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs. 2009;18:1715Y1726. 6. Hussar DA. New drugs 2012 part I. Nursing. 2012;42:38Y45. 7. Kane JM. Lurasidone: a clinical overview. J Clin Psychiatry. 2011;72(suppl 1):24Y28. 8. Drug development and drug interactions: table of substrates, inhibitors and inducers [US Food and Drug Administration Web site]. September 16, 2011. Available at: http://www.fda.gov/drugs/ developmentapprovalprocess/ developmentresources/druginteractionslabeling/ ucm093664.htm#classInhibit. Accessed June 16, 2014. 9. Hopkins CR. ACS chemical neuroscience molecule spotlight on Latuda (lurasidone; SM-13,496). ACS Chem Neurosci. 2011;2:58Y59. 10. Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month double blind, active controlled study. Int Clin Psychopharmacol. 2012;27:165Y176. 11. Stahl SM. Stahl’s Essential Psychopharmacology: the Prescriber’s Guide. 4th ed. New York, NY: Cambridge University Press; 2011. 12. Physicians’ Desk Reference. 67th ed. Montvale, NJ: Thomson PDR; 2013.

Adding to Antidepressant Augmentation To the Editors: iterally, the term augmentation refers to the act of enlarging, increasing something. In psychopharmacology, this term is widely used to designate therapeutic strategies that aim at maximizing the efficacy of a monotherapy by adding a second drug. The accepted definition of antidepressant augmentation, validated by international guidelines,1 assumes that augmentation of antidepressants involves adding a second drug, other than an antidepressant, to the treatment regimen when no response or only partial response has been achieved, with the goal of enhancing treatment. Although enhancing the effectiveness of one another, the adding of an antidepressant to an ongoing antidepressant treatment is designated by the neutral generalist terms: association or combination. To test this definition against the literature, we performed a computerized

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literature search (National Library of Medicine/Medline) using the following words: ‘‘augmentation’’ and ‘‘antidepressant.’’ Articles included were both in English and non-English and up to January 2014. Abstracts of all retrieved occurrences were carefully read by F.M., F.H., and O.D. The corresponding publications were extracted and scrutinized when necessary. Articles retained had to deal with antidepressant combination strategies in treating depression as well as psychotic or anxiety disorders in humans. We ensured that the use of the term augmentation was not related to a translation error of nonEnglish articles. A total of 1388 occurrences were retrieved, and 531 were excluded as nonrelevant. In 768 publications, the use of the term augmentation was in accordance with the current definition. In 91 studies, the term augmentation was used to designate the combination of 2 antidepressants. The added antidepressant was bupropion in 32 articles, a tricyclic antidepressant in 21 articles, mirtazapine in 16 articles, an selective serotonin reuptake inhibitor (SSRI) in 8 articles, each of mianserin, agomelatine, and trazodone, as well as an monoamine oxidase inhibitor in 3 articles. Augmentation of an SSRI with nortriptyline was reported in 1 article. Although widely accepted as the definition of combining an antidepressant to another drug that is not an antidepressant, the concept of augmentation is used, in some cases, to designate the association of 2 antidepressants. The ‘‘augmenting’’ agent either adds a different mechanism of action (pharmacodynamic augmentation) or affects plasma concentration of the ongoing treatment by modifying its metabolism (pharmacokinetic augmentation). When added to an SSRI, bupropion augmentation is mainly pharmacodynamic because bupropion adds to serotonin reuptake inhibition, norepinephrine reuptake inhibition, and dopamine reuptake inhibition. Even for SSRIs, we could hardly omit that these drugs actually display different mechanisms of action. Fluoxetine is not only a serotonin reuptake inhibitor but also a potent 5-HT2C antagonist.2 Besides serotonin reuptake inhibition properties, paroxetine has mild anticholinergic (M1 receptor antagonism) and weak norepinephrine reuptake inhibition actions.2 Theoretically, adding fluoxetine to paroxetine enhances its antidepressant effectiveness by adding new pharmacodynamics mechanisms. Thus, paroxetine and fluoxetine combination should, theoretically, be considered as an augmentation strategy. With a view toward the development of a new antidepressant with innovating

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mechanism of action and for the sake of clarity, we suggest that the term augmentation should be used whenever the combination of 2 antidepressants results in the enhancement of pharmacodynamic or pharmacokinetic action of the ongoing treatment. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Fayc¸al Mouaffak, MD, PhD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France [email protected]

Franz Hozer, MD Olivia Delomel, MD Patrick Hardy, MD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France

REFERENCES 1. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies Biological Psychiatry Task Force on Treatment Guidelines for Unipolar Depressive D. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3(1):5Y43. 2. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge, England: Cambridge University Press; 2013.

Atomoxetine-Associated Akathisia A Case Report To the Editors: tomoxetine is the first nonstimulant drug approved by the Food and Drug Administration for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in patients older than 6 years.1 It works by blocking the presynaptic norepinephrine transporter, which leads to increased norepinephrine levels in the presynaptic gap.2 Common adverse effects of atomoxetine include nausea, vomiting, constipation, loss of appetite, weight loss, stomach pain, dizziness, headache, irritability, aggression, fatigue, and somnolence.3,4 In this

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report, we present an 8-year-old boy who developed akathisia after treatment with atomoxetine.

CASE An 8-year-old male patient was brought to our clinic by his mother with complaints of hyperactivity, difficulty in paying attention during school lectures, short attention span, forgetfulness, and impatience. The patient’s history revealed that these symptoms were present since the age of 3 or 4 years. Following his schoolteacher’s recommendations, the family applied to a child psychiatry clinic, where the patient began treatment with long-acting, extended-release methylphenidate (18 mg/d). However, because of the adverse effects, including loss of appetite, weight loss, and insomnia, the treatment was discontinued after approximately 2 months. Because his symptoms persisted, the family applied to our clinic. A review of the patient’s medical history and family medical history was unremarkable. On psychiatric evaluation, increased psychomotor activity, distractibility, short attention span, and impulsiveness were evident. No other psychiatric symptoms were observed. No pathological findings were found during his physical and neurological evaluations. During the diagnostic workup, an experienced child psychiatrist administered the ‘‘Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime’’; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Disruptive Behavior Disorders Rating Scale (parents/teacher); the Teacher’s Report Form; and the Child Behavior Checklist tests to the patient. After the evaluation, the patient was diagnosed with combined-type ADHD in accordance with the criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We intended to begin the treatment with short-acting or long-acting, extended-release methylphenidate; however, the family did not consent out of concern for adverse effects experienced during a previous episode. Therefore, we began the treatment with atomoxetine instead. First, atomoxetine was administered at 10 mg/d, on the basis of the patient’s weight (22 kg) (approximately 0.45 mg/kg per day). After 2 weeks, the dose was increased to 25 mg/d (approximately 1.13 mg/kg per day). The patient returned to our clinic within 2 days after the atomoxetine dose was increased with symptoms of inner sense of restlessness, difficulty in staying still, and having the urge to move. During initial evaluation, the symptoms were noted to have appeared instantly (within 2 days of the dose increase) * 2014 Lippincott Williams & Wilkins

and no other drug (other than atomoxetine) or substance use was detected. No pathological evidence was found during his physical examination, and his routine blood cell count and biochemical tests were normal. The patient scored 7 of 9 on the Barnes Akathisia Scale,5 and therefore, we believed that he had atomoxetine-associated akathisia. The atomoxetine treatment was terminated, and within 3 days, the patient’s symptoms disappeared. The patient then scored 1 of 9 on the Barnes Akathisia Scale. The patient had a score of 6 on the Naranjo Adverse Drug Reaction Probability Scale, which indicated a ‘‘probable’’ relationship between akathisia and atomoxetine therapy.6 The patient then began treatment with short-acting methylphenidate at a starting dose of 15 mg/kg, which was increased to 30 mg/kg after 1 week with his family’s consent. No adverse effects were noted, except for moderate loss of appetite.

DISCUSSION Akathisia is characterized by objective observable movements that include rocking from foot to foot while standing, pacing, fidgeting, swinging legs, lifting feet as if marching in place, crossing and uncrossing the legs when sitting, as well as difficulty in staying or sitting still. These movements are often accompanied by subjective symptoms such as irritability, inner sense of restlessness, dysphoria, and anxiety.7 We determined that our patient had akathisia because the symptoms of increased inner sense of restlessness, having difficulty in staying still, and having the urge to move appeared within 2 days after the dose of atomoxetine was increased. Although akathisia is most often seen as an adverse effect of typical antipsychotic treatment, it can also be associated with atypical antipsychotics, some antidepressants, antiemetics, and some calcium channel blockers.8 Our patient was only using atomoxetine during the course of treatment, and there was no history of any other drug or substance use before the treatment. To our knowledge, there is only 1 other reported case of atomoxetine-associated akathisia.9 The pathophysiology of drug-associated akathisia is not well understood. However, it is believed to be caused by decreased dopaminergic activity in the mesocorticolimbic pathway projecting toward the limbic system and prefrontal cortex from the ventral tegmental area (VTA). This decrease in dopaminergic activity causes the tonic inhibitory effects on motor functions to disappear.10Y12 In animal models, the disruption of the VTA (containing the bodies of dopaminergic neurons in the mesocortical


and mesolimbic pathways) resulted in an increase in involuntary motor activity.13,14 Serotonin and norepinephrine have been reported to cause akathisia by indirectly suppressing dopaminergic activity in the VTA.15,16 These data were further supported by reports that the A-blocker propranolol, which is frequently used in akathisia treatment, increased the dopaminergic activity in the mesocortical pathway.16 Atomoxetine exerts its effect by blocking the presynaptic norepinephrine transporter, thereby increasing the norepinephrine levels in the synaptic gap.2 Previous reports in the literature describe that akathisia is associated with compounds such as atomoxetine, which are known to inhibit the norepinephrine transporter, thereby increasing norepinephrine at the synaptic gap. Both venlafaxine and duloxetine have similar effects.17Y19 Atomoxetine-associated akathisia may be explained by this increase in norepinephrine in the synaptic gap.9 Recent proposals have suggested that akathisia may result from efforts to compensate for decreased dopaminergic activity in the nucleus accumbens, part of the mesolimbic pathway. This decrease results in a compensatory increase of adrenergic input from the locus coeruleus to the shell portion of the nucleus accumbens. As a result, stimulation of the shell portion of the nucleus accumbens through A-adrenoceptors produces the typical urge to display senseless, curious, purposeless, or stereotyped behaviors and is accompanied by dysphoric feelings.20 Herein, we described a patient with ADHD and atomoxetine-associated akathisia. Complaints such as inner sense of restlessness and difficulty in staying still, which may appear during ADHD treatment, could be misinterpreted as an increase in the severity of the ADHD symptoms. If this is the case, increasing the drug dose may worsen the akathisia symptoms. Therefore, it is important to evaluate the possible adverse effects of drugs when the symptoms become more severe in patients with ADHD. After evaluating these symptoms, physicians should consider the possibility of atomoxetine-associated akathisia because it may enhance disease management and help patients adapt to the treatment. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Kemal Utku Yazici, MD Department of Child and Adolescent Psychiatry Faculty of Medicine Firat University Elazig, Turkey [email protected]; [email protected] www.psychopharmacology.com


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Ipek Percinel, MD Department of Child and Adolescent Psychiatry Osmaniye State Hospital Osmaniye, Turkey

REFERENCES 1. Daughton JM, Kratochvil CJ. Review of ADHD pharmacotherapies: advantages, disadvantages, and clinical pearls. J Am Acad Child Adolesc Psychiatry. 2009;48:240Y248. 2. Barton J. Atomoxetine: a new pharmacotherapeutic approach in the management of attention deficit/hyperactivity disorder. Arch Dis Child. 2005;90 (suppl 1):i26Yi29. 3. Spencer T, Heiligenstein JH, Biederman J, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63:1140Y1147. 4. Eli Lilly and Company. Strattera\ (atomoxetine hydrochloride) Prescribing Information. Available at: http://pi.lilly.com/us/ strattera-pi.pdf. Accessed February 22, 2014. 5. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672Y676. 6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 7. Janicak PG, Beedle D. Medication-induced movement disorders. In: Sadock BJ, Sadock VA, Pedro R, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:2996Y3004. 8. Nelson DE. AkathisiaVa brief review. Scott Med J. 2001;46:133Y134. 9. Baweja R, Petrovic-Dovat L. A case of severe akathisia with atomoxetine. J Child Adolesc Psychopharmacol. 2013;23:426Y427. 10. Marsden CD, Jenner P. The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med. 1980;10:55Y72. 11. Koliscak LP, Makela EH. Selective serotonin reuptake inhibitor-induced akathisia. J Am Pharm Assoc (2003). 2009;49:e28Ye36. 12. Kumar R, Sachdev PS. Akathisia and second-generation antipsychotic drugs. Curr Opin Psychiatry. 2009;22:293Y299. 13. LeMoal M, Stinus L, Galey D. Radiofrequency lesion of the ventral mesencephalic tegmentum: neurological and behavioral considerations. Exp Neurol. 1976;50:521Y535. 14. Tassin JP, Stinus L, Simon H, et al. Relationship between the locomotor hyperactivity induced by A10 lesions and the destruction of the fronto-cortical dopaminergic innervation in the rat. Brain Res. 1978;141:267Y281. 15. Lipinski JF Jr, Mallya G, Zimmerman P, et al. Fluoxetine-induced akathisia: clinical and

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theoretical implications. J Clin Psychiatry. 1989;50:339Y342. 16. Lane RM. SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol. 1998;12:192Y214. 17. George M, Campbell JJ 3rd. Venlafaxine causing akathisia: a case report. J Neuropsychiatry Clin Neurosci. 2012;24:E3YE4. 18. Lai CH. Venlafaxine-related akathisia side-effects and management in a depressed patient. Psychiatry Clin Neurosci. 2013;67:127Y128. 19. Izci F, Zincir SB, Acar G, et al. Duloxetine and venlafaxine Nnduced akathisia: two case reports. BCP. 2013;23:357Y360. 20. Stahl SM, Lonnen AJ. The mechanism of drug-induced akathsia. CNS Spectr. 2011;16:7Y10.

Glutamatergic Dysfunction in Skin-Picking Disorder Treatment of a Pediatric Patient With N-Acetylcysteine To the Editors: kin-picking disorder (SPD) is characterized by repetitive and compulsive picking behaviors that result in skin lesions.1 Cognitive behavioral therapy and psychopharmacological agents (ie, selective serotonin reuptake inhibitors, mood stabilizers, typical/atypical antipsychotics, and naltrexone) are generally used to treat SPD, but there is no standardized treatment protocol.1Y3 N-Acetylcysteine (NAC) is an antioxidant that modulates glutamate (glu) transmission in the brain.4 N-Acetylcysteine is an effective treatment for patients with obsessive-compulsive disorder (OCD), as glutamatergic dysfunction is known to play a significant role in its pathophysiology.5Y7 Because of this, NAC has been increasingly prescribed to patients with SPD.8,9 In this case report, we discuss the clinical course of a 12-year-old female patient diagnosed with SPD that was treated with NAC.

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CASE REPORT A 12-year-old girl presented to our clinic with symptoms of marked distress, and she had been picking the skin on her face, arms, and legs for nearly 4 years. At first, she began picking the skin on her forehead and cheeks with her fingernails when experiencing stress. At that time, her parents considered this behavior a ‘‘bad

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habit.’’ However, although the patient’s parents repeatedly reminded her to stop picking her skin, her behaviors persisted. One year after the onset of symptoms, the wounds on the patient’s face began to increase and scar. Due to the growing concerns of her family, they applied to a dermatological clinic, which found no dermatological pathology. Then, they applied to another clinic, where the child was monitored by a child and adolescent psychiatrist. After a failed attempt at habit reversal therapy, for the next 4 years, the patient was given fluoxetine (40 mg/d), sertraline (200 mg/d), olanzapine (20 mg/d), aripiprazole (20 mg/d), and valproic acid (2000 mg/d) at the maximum tolerated dose for at least 10 to 12 weeks at a time in single or combined form. However, the patient’s symptoms did not regress, and she decided to stop the treatment. The patient believed that she could overcome the problem on her own, and that she did not need a physician. However, she presented to our clinic 6 months later with aggressive skin picking, which caused bleeding on her face, legs, and arms. The patient’s medical and family history did not show any obvious characteristics. There were multiple skin wounds of various sizes and at different stages of healing on her face, arms, and legs. A physical examination did not reveal any acute source of bleeding. However, we observed wounds that were crusted, which indicated prior mild bleeding. The patient reported that she was moderately depressed, and her affect was consistent with her mood. Her perception, thought process, and thought content were all within normal limits. However, during the last 6 months, her skin-picking behaviors progressed, she became increasingly socially isolated, her peer relationships deteriorated, and her academic performance further declined. No substance use was detected. The patient was referred to dermatology for a re-evaluation to determine any possible organic etiologies of her skin condition, but none were found. After ruling out psychiatric disorders characterized by repetitive and stereotyped behaviors, the patient was diagnosed with SPD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. She scored a 5 on the Clinical Global Impression-Severity (CGI-S) scale, which classified her as ‘‘Markedly Ill.’’ Because her previous medical treatments were unsuccessful, we decided to start her on 600 mg/d NAC. During the duration of her NAC treatment, she did not take any other medications. After 2 weeks of treatment, she had fewer compulsions to pick her skin, but when she did feel compelled to pick, she could not stop herself from * 2014 Lippincott Williams & Wilkins



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picking. No significant changes were detected upon physical examination, and her CGI-Improvement (CGI-I) scale score was 3, which denotes ‘‘Minimally Improved.’’ We then increased her daily dose of NAC to 1200 mg. After 4 weeks, her skin-picking impulses and behaviors decreased dramatically. Moreover, physical examination revealed that the lesions on her body improved significantly (CGI-I: 2, which denotes ‘‘Much Improved’’). We observed no adverse effects from the NAC treatment. Because her adherence to the treatment was good, her daily dose of NAC was further increased to 1800 mg. Four weeks after this dose increase, no new lesions were identified, and her old lesions were healing well. Her skin-picking behaviors were completely abrogated, and the compulsion to pick occurred rarely. When she did have the desire to pick, she managed to withstand it. Her stress levels and her social relationships improved and have stabilized, even during follow-up (CGI-I: 1, which denotes ‘‘Very Much Improved,’’ and CGI-S: 2, which denotes ‘‘Borderline Mentally Ill’’).

DISCUSSION In this case report, we discuss the clinical management of a 12-year-old female patient diagnosed with SPD according to the criteria of DSM-V. The patient significantly improved after the initiation of the NAC treatment. The DSM-V classifies SPD as one of the obsessive-compulsive and related disorders; and in recent years, NAC has become more widely used in its treatment. N-Acetylcysteine is an antioxidant that modulates glu transmission in the brain by exerting its effects on the nucleus accumbens and by acting as a substrate of the cystine/glu antiporter. The cystine/glu antiporter is localized at the plasma membrane of glial cells and regulates extracellular glu levels by bidirectional transport. In the human body, NAC metabolism causes cysteine to rapidly oxidize into cystine, which is then transported into glial cells via the cystine/glu antiporter as glu is excreted into the extracellular space. The increased levels of extracellular glu activate the metabotropic glu receptors (mGluR2/3) in the presynaptic neuron plasma membrane. These mGluR2/3 receptors act as autoreceptors, which are modulated by the increased concentrations of glu in the synaptic space. Because NAC modulates glu levels, reward-seeking repetitive behaviors regulated by the nucleus accumbens may be reduced.4,8,10,11 Preclinical trials have shown that the modulation of extracellular glu concentrations affects the nucleus accumbens, and prevents compulsive behaviors and cravings.12 * 2014 Lippincott Williams & Wilkins

N-Acetylcysteine is widely used in the treatment of OCD, trichotillomania (TTM), nail biting (NB), and SPD, which are all disorders that exist within the OCD spectrum.4 A double-blinded, randomized, and placebo-controlled study conducted on adult patients with TTM revealed that NAC was significantly superior to placebo.13 In addition, adult case reports in the literature show that NAC is an effective treatment for TTM, NB, and SPD.8,14Y16 However, conflicting results have been reported regarding the effectiveness of NAC in children and adolescents. NAcetylcysteine was reported to be an effective treatment for an 8-year-old patient with autism and NB behaviors.17 A double-blinded, randomized, and placebocontrolled study conducted on 6- to 18-year-old patients with NB found that NAC was superior to placebo, especially in the short-term. However, over time, NAC was found to be no more effective than placebo.18 An open-label study conducted in 35 patients between 5 and 39 years old, of which 25 were between 5 and 18 years old, demonstrated that SPD significantly improved with NAC treatment.9 Another double-blinded, randomized, and placebo-controlled study performed on 8- to 17-year-old patients with TTM revealed that results with NAC and placebo did not significantly differ.19 The patient with SPD in this case report first developed symptoms 4 years prior, and these symptoms progressively worsened during the 6 months before her presentation to our clinic. By the time we saw her, her social and academic functioning was greatly compromised due to her psychiatric condition. A careful assessment of her medication history revealed that she did not respond to selective serotonin reuptake inhibitors, atypical antipsychotics, and mood stabilizers, which suggests that the neurobiological basis of SPD may not involve the monoamine and dopamine secondary messenger systems, although this needs to be verified by further studies. Glutamatergic dysfunction has been demonstrated to play a role in the pathogenesis of OCD5 and may also contribute to the pathogenesis of SPD. The patient in this case report had not been using any psychoactive medications at the time of application to our hospital, and her SPD improved completely after 10 weeks of NAC treatment (600Y1800 mg/d). To our knowledge, this is the first case report of a pediatric SPD patient without other medical or psychiatric comorbidities that successfully responded to NAC treatment. No adverse effects were observed during treatment, and because NAC was effective and safe for this


patient, we believe that NAC has the potential to be safely prescribed to children. However, we only recommend this after further multicenter, randomized, and placebo-controlled studies with large sample sizes have verified the effectiveness of NAC for treating pediatric patients diagnosed with SPD. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Ipek Percinel, MD Department of Child and Adolescent Psychiatry Osmaniye State Hospital Osmaniye, Turkey [email protected]

Kemal Utku Yazici, MD Department of Child and Adolescent Psychiatry Firat University Faculty of Medicine Elazig, Turkey

REFERENCES 1. Arnold LM, Auchenbach MB, McElroy SL. Psychogenic excoriation. Clinical features, proposed diagnostic criteria, epidemiology and approaches to treatment. CNS Drugs. 2001;15:351Y359. 2. Siev J, Reese HE, Timpano K, et al. Assessment and treatment of pathological skin picking. In: Grant JE, Potenza MN, eds. The Oxford Handbook of Impulse Control Disorders. New York, NY: Oxford University Press; 2012;360Y374. 3. Grant JE, Odlaug BL, Chamberlain SR, et al. Skin picking disorder. Am J Psychiatry. 2012;169:1143Y1149. 4. Berk M, Malhi GS, Gray LJ, et al. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013;34:167Y177. 5. Kariuki-Nyuthe C, Gomez-Mancilla B, Stein DJ. Obsessive compulsive disorder and the glutamatergic system. Curr Opin Psychiatry. 2014;27:32Y37. 6. Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006;184: 254Y256. 7. Afshar H, Roohafza H, Mohammad-Beigi H, et al. N-acetylcysteine add-on treatment in refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2012;32:797Y803. 8. Odlaug BL, Grant JE. N-acetyl cysteine in the treatment of grooming disorders. J Clin Psychopharmacol. 2007;27:227Y229. 9. Miller JL, Angulo M. An open-label pilot study of N-acetylcysteine for skin-picking in



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Prader-Willi syndrome. Am J Med Genet A. 2014;164:421Y424. 10. Baker DA, Xi ZX, Shen H, et al. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci. 2002;22:9134Y9141. 11. Xi ZX, Baker DA, Shen H, et al. Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther. 2002;300:162Y171. 12. Baker DA, McFarland K, Lake RW, et al. N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci. 2003;1003:349Y351. 13. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator,

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in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009;66:756Y763. 14. Berk M, Jeavons S, Dean OM, et al. Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting. CNS Spectr. 2009;14:357Y360. 15. Rodrigues-Barata AR, Tosti A, Rodrı´guez-Pichardo A, et al. N-acetylcysteine in the treatment of trichotillomania. Int J Trichology. 2012;4:176Y178. 16. Silva-Netto R, Jesus G, Nogueira M, et al. N-acetylcysteine in the treatment of skin-picking disorder. Rev Bras Psiquiatr. 2014;36:101.

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17. Ghanizadeh A, Derakhshan N. N-acetylcysteine for treatment of autism, a case report. J Res Med Sci. 2012;17:985Y987. 18. Ghanizadeh A, Derakhshan N, Berk M. N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial. Antiinflamm Antiallergy Agents Med Chem. 2013;12:223Y228. 19. Bloch MH, Panza KE, Grant JE, et al. N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013;52:231Y240.



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