Effectiveness of Risperidone for The

LETTERS TO THE EDITORS

Effect of Tandospirone on and anxiolytic,12,13 was effective for en- occasionally reported anxiety, which be- hancing MMN and improving cognitive came more frequent and severe when she Mismatch Negativity and performance. began to take care of her nephew whose Cognitive Performance in mother had obtained a job. At this time, the patient was able to help the household Schizophrenia CASE REPORT of her brother’s family, which she lived A Case Report The patient is a 37-year-old woman with, but was not motivated enough to go meeting Diagnostic and Statistical Manual out by herself. For anxiolytic purpose, tan- To the Editors: of Mental Disorders, Fourth Edition crite- dospirone, 30 mg/d as initial dose, was isturbances of cognitive function, eval- ria for schizophrenia. She graduated from added, which was titrated to 60 mg/d (re- D uated by neurophysiological1Y3 and a mainstream high school and entered a commended maximum dose) during the psychological4 measures, have been shown university. At age 20, she experienced au- initial month, because of the insufficient to predict outcome in patients with schizo- ditory hallucinations, delusion of persecu- effect of the lower dose. The dose of olan- phrenia. Mismatch negativity (MMN) is an tion, and emotional instability and was zapine was unchanged. By 3 months after event-related potential (ERP) generated in admitted to a local psychiatric hospital im- the start of tandospirone, her anxiety symp- response to occasional variations of acoustic mediately after the police spotted her wan- toms almost disappeared, and remained so stimuli and is suggested to reflect preatten- dering around in the rain. After discharge, at 6 months. By this time, she gained moti- tive cognitive operations.5 Specifically, re- she gave up studying and took a part time vation to shop at a grocery store by herself duced MMN amplitudes in response to job, which did not last long because of and pursue her favorite hobbies (embroidery frequent-deviant stimuli have been associ- social withdrawal despite treatment with and others). ated with the pathophysiology of schizo- haloperidol (up to 6 mg/d) and sulpiride (up Electroencephalograms (EEG) were phrenia, including decreased gray matter to 150 mg/d). At age 35, she was rehospi- recorded before the start of tandospirone volumes of the prefrontal cortex and superior talized because of severe auditory halluci- and 3 and 6 months thereafter, according to temporal gyrus.6 nations, delusion of persecution, thought a regimen previously reported.14 Mismatch A limited number of studies report the disturbance, and stupor. Switching to mon- negativity, in response to frequency-deviant ability of dopamine,7 serotonin (5-HT),7Y11 otherapy with olanzapine at 20 mg/d was tones, was measured with an oddball para- 9 and N-methyl-D-aspartate acid (NMDA) effective in treating these symptoms, and digm. Auditory stimuli were delivered transmissions to modulate MMN in healthy the patient was discharged after a 3-month binaurally through headphones with inter- human subjects. Here, we report a case hospitalization. stimulus intervals of 0.5 second. Deviant of schizophrenia in which adjunctive use Although her general psychiatric tones of 1500 Hz were randomly presented of tandospirone, a 5-HT1A partial agonist conditions remained relatively well, she in a series of standard tones of 1000 Hz,

FIGURE 1. Effect of adjunctive use of tandospirone, a 5-HT1A partial agonist, on MMN in a patient with schizophrenia receiving olanzapine. Mismatch negativity amplitudes (indicated by an arrow) in response to frequent-deviant stimuli were increased both at 3 and 6 months after the addition of tandospirone. Inset: cognitive performance, as evaluated by the Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J) composite score, was improved at 6 months compared with baseline.

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors with the presentation probability of 0.1 for that the change in MMN waveforms pre- 4. Matsui M, Sumiyoshi T, Arai H, et al. the deviant tones. During the recordings, ceded the improvement of behavioral per- Cognitive functioning related to quality subjects were requested to watch anima- formance during treatment (Fig. 1). This of life in schizophrenia. Prog tion. All electrodes were referred to the divergence in time suggests that some of Neuropsychopharmacol Biol Psychiatry. average amplitude of ear electrodes (band- the electrophysiological signals reflecting 2008;32:280Y287. width, 0.16Y120Hz;notchfilter,60Hz). preattentive cognitive process may be able 5. Garrido MI, Kilner JM, Stephan KE, et al. Electrode impedance was less than 10 k6. to predict treatment efficacy in neuropsy- The mismatch negativity: a review of Data were collected with a sampling rate chological performance. underlying mechanisms. Clin Neurophysiol. Y of 500 Hz. Averaging of ERP waves and The effect of 5-HT1A agonism on 2009;120:453 463. related procedures were performed using MMN may be mediated by its influence on 6. Rasser PE, Schall U, Todd J, et al. Gray EPLYZER II software (Kissei Comtec, Co glutamatergic and, possibly, GABAergic matter deficits, mismatch negativity, and Ltd, Nagano, Japan). The epoch was 600 function. This assumption is based on ob- outcomes in schizophrenia. Schizophr Bull. milliseconds, including a 100- millisecond servations that blockade of NMDA recep- 2009 [Epub ahead of print]. 9,19 prestimulus baseline. Neuropsychological tors reduces MMN and that 8-OH-DPAT, 7. Leung S, Croft RJ, Guille V, et al. Acute assessment was conducted with the Brief a5-HT1A agonist, modulates cortical acti- dopamine and/or serotonin depletion does Assessment of Cognition in Schizophrenia- vity through 5-HT1A receptors located on not modulate mismatch negativity 15 Japanese version (BACS-J) at the elec- GABAergic interneurons and those on pyra- (MMN) in healthy human participants. 20 troencephalogram measurement. Alternate midal neurons. Further study is needed Psychopharmacology (Berl). 2010;208: forms, where appropriate, were used at re- to confirm the potential benefit of agents 233Y244. assessments. Written informed consent was acting on 5-HT receptors for improving 1A 8. Kahkonen S, Makinen V, Jaaskelainen IP, obtained for these clinical evaluations. MMN and other components of ERPs in et al. Serotonergic modulation of mismatch As shown in Figure 1, MMN ampli- people with schizophrenia. negativity. Psychiatry Res. 2005;138: tudes were increased as early as 3 months 61Y74. from the start of augmentation therapy with tandospirone and remained so at 6 months. 9. Heekeren K, Daumann J, Neukirch A, et al. AUTHOR DISCLOSURE Mismatch negativity generation in the The BACS-J composite scores (in Z-score) INFORMATION human 5HT2A agonist and NMDA at baseline, 3 months, and 6 months were This study was funded by grants-in- antagonist model of psychosis. j0.88, j0.95, and j0.32, respectively aid for Scientific Research from the Japan Psychopharmacology (Berl). 2008;199: (Fig. 1, inset), suggesting improved perfor- Society for the Promotion of Science and 77Y88. mance after a 6-month adjunctive treatment. grants-in-aid from the Ministry of Health, 10. Oranje B, Jensen K, Wienberg M, et al. Labour and Welfare, Japan. Divergent effects of increased serotonergic DISCUSSION The authors declare no further con- activity on psychophysiological flicts of interest. parameters of human attention. To our knowledge, these findings pro- Int J Neuropsychopharmacol. 2008;11: vide the first evidence for the ability of 453Y463. 5-HT1A partial agonists to improve MMN in subjects with schizophrenia. So far, only Yuko Higuchi, MD, PhD 11. Wienberg M, Glenthoj B, Jensen K, et al. a limited number of neurochemical mani- A single high dose of escitalopram increases Tomiki Sumiyoshi, MD, PhD mismatch negativity without affecting pulations have been reported to enhance Yasuhiro Kawasaki, MD, PhD processing negativity or P300 amplitude in MMN in healthy volunteers, for example, 10,11 Toru Ito, MD, PhD healthy volunteers. J Psychopharmacol. 5-HT reuptake inhibitors, tryptophan 2009. depletion,8 and nicotinic receptor stimula- Tomonori Seo, MD, PhD tion,5 whereas N-acetyl-cysteine, a glutathi- 12. Sumiyoshi T, Matsui M, Nohara S, et al. Michio Suzuki, MD, PhD Enhancement of cognitive performance in one precursor, has been shown to enhance Department of Neuropsychiatry schizophrenia by addition of tandospirone to MMN in patients with schizophrenia.16 University of Toyama Graduate School neuroleptic treatment. Am J Psychiatry. Whether increased or decreased serotonergic of Medicine and Pharmaceutical Sciences 2001;158:1722Y1725. tones enhance MMN amplitudes has been Toyama, Japan controversial,7,8,10,11 suggesting a role for [email protected] 13. Sumiyoshi T, Matsui M, Yamashita I, et al. specific 5-HT receptor subtypes, such as 5- Effect of adjunctive treatment with serotonin-1A agonist tandospirone on HT1A and 5-HT2A receptors, in the modulation of MMN. It is likely that the deficits memory functions in schizophrenia. REFEFENCES J Clin Psychopharmacol. 2000;20: in MMN before the start of tandospirone Y treatment were due to chronicity of the ill- 1. Baldeweg T, Klugman A, Gruzelier J, et al. 386 388. ness (917 years), rather than a possible in- Mismatch negativity potentials and cognitive 14. Sumiyoshi T, Higuchi Y, Itoh T, et al. fluence of olanzapine, for example, actions impairment in schizophrenia. Schizophr Res. Effect of perospirone on P300 2004;69:203Y217. electrophysiological activity and social on 5-HT2A receptors. The addition of tandospirone was 2. Light GA, Braff DL. Mismatch negativity cognition in schizophrenia: a associated with a favorable effect on be- deficits are associated with poor functioning three-dimensional analysis with sLORETA. Y havioral performance as evaluated by neu- in schizophrenia patients. Arch Gen Psychiatry Res. 2009;172:180 183. ropsychological assessments, consistent Psychiatry. 2005;62:127Y136. 15. Kaneda Y, Sumiyoshi T, Keefe R, et al. Brief assessment of cognition in with previous reports that 5-HT1A agonists, 3. Kawakubo Y, Kasai K. Support for an 12,13 17 for example, tandospirone, buspirone, association between mismatch negativity schizophrenia: validation of the Japanese and perospirone,14,18 ameliorated cognitive and social functioning in schizophrenia. Prog version. Psychiatry Clin Neurosci. Y deficits related to frontal lobe function in Neuropsychopharmacol Biol Psychiatry. 2007;61:602 609. subjects with schizophrenia. It is noteworthy 2006;30:1367Y1368. 16. Lavoie S, Murry MM, Deppen P, et al.

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Glutathione precursor, N-acetyl-cysteine, of remission. The combination of olanza- immobility or use of physical restraints. improves mismatch negativity in pine 10 mg, risperidone 2 mg, venlafaxine She had not used oral contraceptives. There schizophrenia patients. 225 mg, and nortriptyline 100 mg was was no mention of homocysteinemia or Neuropsychopharmacology. used in her case probably to limit the un- raised level of antiphospholipid antibod- 2008;33:2187Y2199. wanted adverse effects of each individual ies in the patient’s file. A previous cerebral 17. Sumiyoshi T, Park S, Jayathilake K, et al. drug and because the symptoms had also scanner had revealed no anomaly. Effect of buspirone, a serotonin1A partial been very severe, posing significant dan- agonist, on cognitive function in ger to her life. She nonetheless gained a schizophrenia: a randomized, double-blind, significant amount of weight, approxi- DISCUSSION placebo-controlled study. Schizophr Res. mately 70 lb, and had hyperprolactinemia There are a number of studies 2007;95:158Y168. with secondary amenorrhea. An electro- reporting an association between pulmo- 18. Araki T, Yamasue H, Sumiyoshi T, et al. cardiogram revealed a normal QTc at nary venous thromboemboli, sometimes 1 Perospirone in the treatment of 402 milliseconds. She was discharged fatal, and SGAs, in particular clozapine schizophrenia: effect on verbal memory 3 months after her initial admission. and olanzapine. Such vascular phenomena organization. Prog Neuropsychopharmacol During outpatient follow-up, olanza- have been described since the 1960s for Biol Psychiatry. 2006;30:204Y208. pine was reduced to 5 mg daily, and ris- first-generation antipsychotics (FGAs). It 19. Javitt DC, Steinschneider M, Schroeder CE, peridone was discontinued. The patient was later identified that SGAs pose a et al. Role of cortical N-methyl-D-aspartate remained functional and euthymic until greater risk than FGAs do and that lower- receptors in auditory sensory memory and 13 months after her last discharge. At the potency FGAs pose a greater risk than mismatch negativity generation: implications time of recurrence, a psychosocial stressor higher-potency FGAs do. Odds ratios vary for schizophrenia. Proc Natl Acad Sci U S A. and the fact that she had abandoned her from 2.39 for low-potency FGAs to 6.9 1996;93:11962Y11967. medication due to frustration with her for SGAs.2 Although no evident expla- 20. Llado-Pelfort L, Santana N, Artigas F, et al. weight gain were identified. She became nation exists for this association, many Postsynaptic 5-HT1A receptors are involved isolated, anhedonic, and refused to eat underlymechanisms have been proposed: in the excitatory action of 8-OH-DPAT on or drink. Risperidone was reintroduced at interference with 5-hydroxytryptamine 2 prefrontal cortex pyramidal neurons. Society 1 mg twice a day, and she was readmitted receptors on platelets, raised levels of anti- for Neuroscience (Chicago). 2009;748:2. to the inpatient ward. The mental exami- phospholipid antibodies, venous stasis ex- nation revealed a young woman with acerbated by sedation or physical restraints, moderate excess weight, significant psy- and hyperhomocysteinemia.3 Hyperpro- chomotor retardation, flat affect, perplex- lactinemia is also identified as a potential Hyperprolactinemia and ity, negation of her symptoms, minimal risk factor,4 with prolactin having recently Atypical Antipsychotic collaboration, and refusal of most vital been recognized as a potent platelet aggre- signs and all laboratory tests. She had a gation coactivator.5 No increased risk of Therapy in a Case of severe thought disorder and offered only thromboembolism has been shown in past Fatal Thromboembolism a few words that made it possible to iden- users of antipsychotics. Polypharmacy was tify suicidal thoughts and probable psy- hypothesized as a possible confounder, and chotic symptoms. some studies have found current use of an To the Editors: Olanzapine was ceased as the patient antidepressant as conferring greater risk had been obsessed with her weight gain, (odds ratio = 4.9).6 To our knowledge, no CASE REPORT and risperidone was increased to 1 mg increased risk of thrombolembolus is as- A 19-year-old woman presented with morning and 2 mg before bedtime. The sociated with venlafaxine or nortriptyline a first episode of flat affect, psychomotor next morning, the patient was sitting down specifically. retardation, auditory hallucinations, and and writing, to be found 7 minutes later In a study on the in vitro effects of delusions. She was of Antillean origin, lying on the floor, unconscious, superfi- antipsychotics on human platelet aggre- and she had no known medical problems cially breathing with low blood pressure. gation and plasma coagulation involving and no personal or family history of psy- The medical team arrived almost instantly, clozapine, olanzapine, risperidone, and chiatric disorders or substance abuse. A and she had no pulse, was not breathing, haloperidol,7 clozapine was the only drug diagnosis of psychosis not otherwise and had fixated mydriasis. Reanimation that increased platelet aggregation and specified was retained. She elected to be measures proved unsuccessful, and an hour adhesion. treated with a combination of second- later, the patient was pronounced dead. The There seem to be few studies or generation antipsychotics (SGAs), risper- last medications received were loxapine reports of thromboemboli on risperidone idone 5 mg and olanzapine 10 mg, to limit 25 mg + diphenhydramine 25 mg and ris- therapy. Borras et al8 reported a 25-year- detected adverse effects such as hyperpro- peridone 2 mg + nortriptyline 100 mg the old patient with no known risk factors for lactinemia and weight gain and was rapidly evening before. thromboembolism who developed pulmo- discharged. On the basis of the pathologist’s re- nary embolus thrice: once under olanza- She was readmitted 5 days later with port, the coroner concluded to massive pine therapy and twice under risperidone relapse of her symptoms. She refused to bilateral pulmonary emboli elucidating a therapy. Kamijo et al9 studied Japanese eat and became actively suicidal, com- link to the use of nortriptyline and risper- patients who experienced idiopathic pul- mitting repetitive and very serious at- idone. The autopsy identified tremendous monary thromboembolism and found that tempts. Symptoms of major depression overdosage of nortriptyline and venlafax- 44% of their sample (7 patients) had anti- became evident. Pharmacological treat- ine, but this was attributed to postmortem psychotic use, and in 2 cases, the antipsy- ment brought no clear benefits and per- redistribution. Risperidone was at an infra- chotic was risperidone. Interestingly, more mission of electroconvulsive therapy was therapeutic dosage. women than men were affected, and patients granted by the court. She required phar- It should be noted that there was no developed symptoms in the early morning. macological treatment for maintenance identified cause of venous stasis such as Risperidone was identified in 1 study as

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors doubling the risk of venous thromboembo- platelet aggregation and plasma coagulation. The 2 principal research questions lism among elder nursing-home residents.10 Clin Exp Pharmacol Physiol. 2007;34: addressed in this retrospective study are the In conclusion, it is reasonable to sus- 775Y780. following: Is risperidone effective as a pect that risperidone, as other SGAs, must 8. Borras L, Eytan A, de Timary P, et al. dedicated medication for combat night- be considered as plausibly increasing the Pulmonary thromboembolism associated mares? Is risperidone’seffectiveness related risk of thromboemboli, and careful evalu- with olanzapine and risperidone. J Emerg to the concurrent use of other psychiatric ation of risks versus benefits is further Med. 2008;35:159Y161. medications or to concurrent substance needed in cases where known risk factors 9. Kamijo Y, Soma K, Nagai T, et al. Acute abuse? The study is intended to identify for thromboemboli are already identified, massive pulmonary thromboembolism indications for future prospective studies. such as in our case, namely the patient’s associated with risperidone and In this retrospective study, approved significant weight gain, polypharmacy, conventional phenothiazines. Circ J. by the institutional review board, cases concomitant use of antidepressants and 2003;67:46Y48. from both the inpatient and outpatient low-potency FGAs, and, most notably, 10. Liperoti R, Pedone C, Lapane KL, et al. services were reviewed. The diagnosis of hyperprolactinemia. Further studies are Venous thromboembolism among elderly PTSD was based on the DSM-IV-TR crite- needed on the prothrombotic risk associated patients treated with atypical and ria. Demographic characteristics included with SGAs and the possible mechanisms first-generation antipsychotic agents. age, sex, race, and marital status. Multiple involved. Arch Intern Med. 2005;165:2677Y2682. patient profile characteristics, and prior or concurrent substance abuse and psychotropic medications were included in the AUTHOR DISCLOSURE study. INFORMATION Effectiveness of Risperidone Inclusion criteria for the study were The author declares no conflict of nightmares associated with combat-related interest. for the Treatment of PTSD, initiation of risperidone treatment There was no pharmaceutical or in- Nightmares in Veterans specifically noted to be for nightmare dustry support. suppression, and a follow-up visit with With Posttraumatic clinical notes that referenced the exact Stress Disorder treatment response. The follow-up notes Anne-Marie Rousseau, MD had to permit classification of risperidone Department of Psychiatry response as 1 of 3 possible outcomes: full Hoˆpital du Sacre´-Coeur de Montreál response with no recall of nightmares, Universite´ de Montreál, Montreal To the Editors: partial response with reduction in fre- Quebec, Canada ecurrent nightmares and sleep conti- quency and perceived intensity, and no [email protected] R nuity disruptions are the 2 major sleep response, with unchanged nightmare fre- disturbances included for posttraumatic quency or intensity. Sixty-five cases met stress disorder (PTSD) criteria in the all the inclusion criteria. Additional co- REFERENCES Diagnostic and Statistical Manual of morbid diagnoses included other anxiety 1. Hamanaka S, Kamijo Y, Nagai T, et al. Mental Disorders, Fourth Edition, Text disorders (15), substance disorders (61), Massive pulmonary thromboembolism Revision (DSM-IV-TR). Reports of sleep mood disorders (47), cognitive disorders demonstrated at necropsy in Japanese abnormalities among combat veterans (10), personality disorders (8), and adjust- psychiatric patients treated with neuroleptics with PTSD have ranged from 59% to ment disorders (4). The length of treat- including atypical antipsychotics. Circ J. 73%.1 Posttraumatic stress disorderY ment ranged from 1 month to 9.8 years Y 2004;68:850 852. related nightmares may exert a serious for veterans seen primarily in one clinic. 2. Jo¨nsson AK, Brudin L, Ahlner J, et al. impact on patients’ social, occupational, Risperidone dosing ranged from Antipsychotics associated with pulmonary and personal functioning (DSM-IV-TR). 0.5 to 4.0 mg a day. Prior and concurrent embolism in a Swedish medicolegal autopsy In a review of the pharmacological psychiatric medication groups (antide- series. Int Clin Psychopharmacol. 2008;23: treatment of nightmares and insomnia in pressants, anxiolytics, benzodiazepines, Y 263 268. PTSD, Van Liempt et al2 noted that there opioids, anticonvulsants, hypnotics, and 3. Landry P, Rousseau AM, Skalli L. Adverse are insufficient controlled studies to de- antipsychotics) were recorded as present effects of antipsychotics. In: Hertzman M, rive evidence-based guidelines. The liter- or absent. All atypical antipsychotics Adler L, eds. Chichester, UK: John Wiley ature on the treatment of nightmares with were discontinued before starting risperi- and Sons, Ltd; 2010:337Y380. atypical antipsychotics in PTSD is scarce done treatment, whereas the other psychi- 4. Hagg S, Jonsson AK, Spigset O. Risk of and inconclusive. Reports of one case atric medications were often begun before venous thromboembolism due to treated with quetiapine,3 5 cases with risperidone and continued throughout the antipsychotic drug therapy. Expert Opin olanzapine,4 and 4 of 5 cases with aripi- months of the veteran’s treatment with Drug Saf. 2009;8:537Y547. prazole5 document some success for aty- risperidone. 5. Urban A, Masopust J, Maly R, et al. picals in the treatment of PTSD sleep In the statistical analysis, continuous Prolactin as a factor for increased platelet disturbances. No reports were found using variables were expressed as mean T SD. aggregation. Neuroendocrinol Lett. 2007;28: clozapine and ziprasidone. Risperidone Categorical variables were expressed as 518Y523. has a modest literature support for treating numbers and percentages of totals. A 6. Parkin L, Skegg DC, Herbison GP, et al. PTSD symptoms including sleep dis- priori established clinically relevant inde- Y Psychotropic drugs and fatal pulmonary turbances with nightmares.6 10 However, pendent variables were compared across embolism. Pharmacoepidemiol Drug Saf. none of the risperidone literature has in- response categories by using W2 tests for 2003;12:647Y652. vestigated risperidone as a therapy spe- linear trend. P G 0.05 was considered 7. Axelsson S, Hagg S, Eriksson AC, et al. In cifically for the treatment of PTSD-related statistically significant. Statistical corre- vitro effects of antipsychotics on human combat nightmares. lations for patient groups with less than

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TABLE 1. Comparisons of Full, Partial, and No Risperidone Responses in Veterans With and Without Prior and/or Concurrent Use of Psychotropic Medications

No. Patients Who No. Patients Who Did Not Used Medications Use Medications No. Patients With Psychotropic Medications Full Partial No Total Full Partial No Total Missing Data P Antidepressants 18 16 8 42 10 10 2 22 1 0.514 Anticonvulsants 8 8 5 21 19 17 5 41 3 0.313 Anxiolytics 5 6 3 14 23 20 7 50 1 0.422 Hypnotics 11 7 3 21 17 19 7 42 2 0.445 Benzodiazepines 9 14 5 28 18 12 5 35 2 0.215 Opioid agonists 9 9 1 19 19 17 9 45 1 0.319 Prior atypical antipsychotic use 1 7 4 12 27 19 6 52 1 0.004* *Signiﬁcant P value.

10 cases were not considered meaningful idone, 33.3% responded fully and 57.1% The precise mechanism by which the indices for conclusions. Statistical anal- responded partially. Fifty percent of the risperidone might affect PTSD symptoms yses were performed using Stata statis- 32 veterans receiving 2.0 mg had com- is not clear. Risperidone has high anti- tical package version 10 (Stata Corp, plete cessation of nightmares, whereas serotonergic receptor antagonism and anti- College Station, Tex). 31.3% had a partial result. Of the patients dopaminergic activity (5-HT2A, 5-HT7,D2), Among the 65 veterans treated with on 3.0 mg (n = 3) or 4.0 mg (n = 1), 25.0% which theoretically play an important role risperidone for PTSD-related nightmares, experienced no nightmares, whereas in reducing anxiety and insomnia.11 In ad- 55 (84.6%) reported changes in nightmare 75.0% had partial responses. dition, risperidone’s >-1 adrenoreceptor patterns. Full nightmare cessation was Adverse effects in 11 cases included blockade may modulate trauma nightmares noted in 28 patients (43.1%), and partial hand tremor, headaches, nausea and vom- by decreasing light sleep and normalizing response was found in 27 patients (41.5%). iting, drowsiness, irritability, gastric irrita- rapid eye movement sleep.12,13 All full responders reported cessation of tion, generalized weakness, enuresis, urine The results of this study suggest that nightmare recall on the first night. Partial retention, and weight gain. In these cases, low-dose risperidone is effective in stop- responders reported a decrease in the fre- risperidone doses ranged from 0.5 to 2.0 mg ping the memory of nightmares or reduc- quency and intensity of nightmares on the administered over a period of 1 month to ing the frequency and intensity in combat first and following nights. Risperidone 5 years. Eight veterans with adverse effects veterans with PTSD. This effect seems response was consistent for the full and had responded fully and 3 responded par- to be independent of the prior and/or partial responders from the first week of tially. Adverse effects were reported to have concurrent use of other psychiatric medi- treatment. Two of the veterans who re- ceased after discontinuation of risperidone. cations and of the prior and/or concurrent ported complete cessation of nightmares There was no statistically significant use of illicit substances. Only prior ex- with risperidone at 2.0 mg/d had no other correlation between risperidone treatment posure to atypical antipsychotics seems to concurrent psychiatric medications. Lack in veterans with prior or concurrent al- reduce response to risperidone. Future of response to risperidone was noted in cohol abuse/dependence (n = 36) com- prospective studies are needed to further 10 veterans (15.4%). pared with veterans without such a history. investigate these results. The demographic profile revealed Similarly, no statistically significant cor- a predominately male (95.3%), white relations were found between risperidone AUTHOR DISCLOSURE (72.3%), and married (69.2%) population treatment response and abuse/dependence INFORMATION with a mean age of 57.4 years (range, of other substances (cocaine, cannabis, 27Y82 years). All P values for the demo- opioids, tobacco, benzodiazepines, and The authors have reported no con- graphic characteristics and response to caffeine). In addition, both full and partial flicts of interest. risperidone were greater than 0.05, indi- positive treatment responses to risper- Nina Khachiyants, MD cating no significant correlation. idone were reported regardless of the prior Carilion Clinic-Virginia Tech Effective risperidone doses ranged or concurrent use of multiple combina- Carilion School of Medicine from 0.5 to 4.0 mg/d, with 92.7% of the tions of psychotropic medications (anti- Geriatric Psychiatry Fellowship Program fully and partially responding veterans depressants, anticonvulsants, anxiolytics, Roanoke, VA receiving risperidone doses from 0.5 to hypnotics, benzodiazepines, and opioid Rizwan Ali, MD 2.0 mg/d. There was no statistically sig- agonists; Table 1). The one exception was Psychiatry Service nificant correlation between the risperi- the statistically significant correlation for Veterans Affairs Medical Center done dose and the treatment effect within risperidone treatment in veterans with prior Salem, VA this dosage range (P = 0.868). There were atypical antipsychotic use (P =0.004). Department of Psychiatry no data indicating attempts to lower or Compared with those patients who were and Behavioral Medicine increase doses. antipsychotic naive, the 12 veterans with Virginia Tech-Carilion Roanoke, VA Of the 8 veterans receiving low ris- prior exposure to antipsychotics had and Department of Psychiatry peridone dose (0.5 mg/d), 50.0% respon- proportionally fewer full responses (8.3% Neurobehavioral Sciences ded fully and 25.0% responded partially. vs 51.9%) and greater no responses University of Virginia Of the 20 veterans on 1.0 mg of risper- (33.3% vs 11.4%). Salem, VA

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Csaba P. Kovesdy, MD case reports. Acta Psychiatr Scand. Digital Content 1, which shows reports Nephrology Department 2003;107(5):394Y396; discussion 396. of clozapine-associated pancreatitis, Salem Veterans Affairs Medical Center 5. Lambert MT. Aripiprazole in the http://links.lww.com/JCP/A30] and Sup- Salem, VA plemental online material, Background Department of Medicine management of post-traumatic stress disorder Virginia Tech-Carilion symptoms in returning Global War on [Supplemental Digital Content 2, Roanoke, VA Terrorism veterans. Int Clin Psychopharmacol. http://links.lww.com/JCP/A31]) and at- and Department of Medicine 2006;21(3):185Y187. tributed to toxic blood levels of clozapine. University of Virginia 6. Bartzokis G, Lu P, Turner J, et al. Adjunctive Interference with liver metabolic break- Salem, VA risperidone in the treatment of chronic down is believed to be the main culprit. Jonna G. Detweiler, MEd combat-related posttraumatic stress disorder. The CYP 1A2 isoenzyme is reported to Geriatric Research Group Biol. Psychiatry. 2005;57:474Y479. account for the largest part of the disposi- Veterans Affairs Medical Center tion of clozapine, yielding desmethylclo- 7. Hamner MB, Faldowski RA, Ulmer HG, et al. 1 Salem, VA Adjunctive risperidone treatment in zapine, although other isoenzymes, such Kye Y. Kim, MD post-traumatic stress disorder: a preliminary as 3A4, which is mainly responsible for 2 Psychiatry Service controlled trial of effects on comorbid N-oxide formation and, to a lesser extent, Veterans Affairs Medical Center psychotic symptoms. Inter Clin 2D6, seem to play some minor role in Salem, VA Psychopharmacol. 2003;18:1Y8. eliminating clozapine from the blood. Cloz- Department of Psychiatry 8. Monnelly EP, Ciraulo DA, Knapp C, et al. apine seems to be a weak inhibitor of and Behavioral Medicine the 2D6 isoenzyme.3 The roles of cloza- Virginia Tech-Carilion Low-dose risperidone as adjunctive therapy Roanoke, VA for irritable aggression in posttraumatic pine and its metabolites on exocrine pan- Department of Psychiatry stress disorder. J Clin Psychopharmacol. creatic function have not been thoroughly Neurobehavioral Sciences 2003;23:1993Y1996. investigated. University of Virginia 9. Reich DB, Winternitz S, Hennen J, et al. A We report a case of pancreatitis and Geriatric Research Group preliminary study of risperidone in the shortly after institution of clozapine treat- Veterans Affairs Medical Center treatment of posttraumatic stress disorder ment. The patient showed elevated serum Salem, VA related to childhood abuse in women. J Clin clozapine levels and hyperglycemia, but not Mark B. Detweiler, MD, MS Psychiatry. 2004;65:1601Y1606. hyperlipidemia, and improved after discon- Psychiatry Service 10. Padalla PR, Madison J, Monnahan M, et al. tinuation. She redeveloped pancreatitis at Veterans Affairs Medical Center Risperidone monotherapy for post-traumatic rechallenge with a lower dose of clozapine. Salem, VA stress disorder related to sexual assault Department of Psychiatry and domestic abuse in women. Int Clin and Behavioral Medicine Psychopharmacol. 2006;21:275Y280. CASE REPORT Virginia Tech-Carilion A 40-year-old white woman with Roanoke, VA 11. Ahern EP, Krohn A, Connor KN, et al. Department of Psychiatry Pharmacologic treatment of posttraumatic Diagnostic and Statistical Manual of Neurobehavioral Sciences of the stress disorder. A focus on antipsychotic use. Mental Disorders, Fourth Edition, Text University of Virginia Ann Clin Psychiatry. 2003;15:193Y201. Revision, schizophrenia, paranoid type, and Geriatric Research Group 12. Raskin MA, Peskind ER, Kanter ED, et al. had been involuntarily admitted to our Veterans Affairs Medical Center Reduction of PTSD nightmares and other acute care unit for psychotic exacerbation. Salem, VA PTSD symptoms in combat veterans by At admission, she was persecutory and [email protected] prazosin: a placebo-controlled study. Am J delusional. She had auditory hallucina- Psychiatry. 2003;160:371Y373. tions, psychomotor agitation, and dys- 13. Krystal AD, Davidson JRT. The use of phoric mood. She was overweight (body prazosin for the treatment of trauma mass index, 30) and dressed in a bizarre REFERENCES nightmares and sleep disturbance in combat way. All her routine laboratory tests were 1. Mellman TA, Kulick-Bell R, Ashlock LE, veterans with post-traumatic stress disorder. in the normal range, including blood glu- et al. Sleep events among veterans with Biol Psychiatry. 2007;61:925Y927. cose, cholesterol, low-density lipoprotein combat-related posttraumatic stress cholesterol, and triglycerides. She proved disorder. Am J Psychiatry. 1995;152(1): to be negative to alcohol and drug screen- 110Y115. ing tests. A heavy smoker (40Y60 ciga- 2. Van Liempt S, Vermetten E, Geuze E, Development of rettes per day), she reported no recreational et al. Pharmacotherapeutic treatment of Asymptomatic Pancreatitis substance use (alcohol and coffee). She nightmares and insomnia in posttraumatic scored 95 on the BPRS (see Supplemental stress disorder. An overview of the With Paradoxically High online material, Rating scales, Psychopa- literature. AnnNYAcadSci. 2006;1071: Serum Clozapine Levels thology [Supplemental Digital Content 2, Y 502 507. in a Patient With http://links.lww.com/JCP/A31]). 3. Presecki P, Mihanovi( M, Sili( A, et al. The patient_s objective psychiatric Venlafaxine-quetiapine combination in the Schizophrenia and the history dates back to age 20 years, when treatment of complicated clinical picture of CYP1A2*1F/1F Genotype she presented with frank psychotic symp- enduring personality changes following toms, comprising persecutory delusions PTSD in comorbidity with psychotic with bizarre characteristics focusing on depression. Psychiatr Danub. 2010;22(2): sexual issues, auditory hallucinations of 360Y362. To the Editors: multiple conversing voices, psychomotor 4. Jakovljevi( M, Sagud M, Mihaljevi(-Peles A. ancreatitis secondary to clozapine agitation, and aggressive behavior. Her Olanzapine in the treatment-resistant, P has been occasionally reported (see ﬁrst hospitalization, at age 21 years, had combat-related PTSDVa series of Supplemental Table A [Supplemental been involuntary. Since that time, she has

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 been followed by the National Health firming no abnormalities in the biliary tract, We classified the event as definitely Service_s Community Outpatient Facilities; revealed the existence of a radio-opaque associated with clozapine (see Supple- she received high-dose haloperidol (up to gallstone in the infundibulum. We immedi- mental online material, Rating scales, 15 mg/d) and switched to high-dose ris- ately started tapering off clozapine, con- Attribution of side effect and classifica- peridone (10 mg/d) during the last 3 years. cluding the process in 6 days; concomitantly, tion [Supplemental Digital Content 2, She also was receiving 7.5 mg/d lorazepam. we started the patient on oral haloperidol, http://links.lww.com/JCP/A31]). Her response to treatment was rated as 4 mg/d. We added appropriate antibiotic Pharmacogenomic analysis showed partial. Since her twenties, she has been (see Supplemental online material, Antibi- the patient to be a normal clozapine metab- hospitalized several times, compulsorily on otic treatment [Supplemental Digital Con- olizer (see supplemental online material, most occasions. She never reached a satis- tent 2, http://links.lww.com/JCP/A31]) and Pharmacogenomics, for further discus- factory level of remission or insight. Before subcutaneous insulin lispro and insulin sion [Supplemental Digital Content 2, her last exacerbation, she had completely glargine in variable doses, depending on http://links.lww.com/JCP/A31]). Overall, discontinued antipsychotic medication. her blood glucose levels. Her cholesterol there were no identifiable genetic reasons Because of unsatisfactory response dropped to 142 mg/dL and her triglyc- for which clozapine plasma levels should to previous treatments, after washout erides to 302 mg/dL. Ten days later, she had be so high with both full and reduced doses (see Supplemental online material, Wash- recovered completely from her pancreatitis, of clozapine in the absence of other con- out [Supplemental Digital Content 2, and all laboratory measures were normal. comitant factors (but sensitization may be http://links.lww.com/JCP/A31]), we intro- Shescored42ontheBPRS.Shewasdis- considered as a possibility). duced 25 mg/d oral clozapine, gradually charged with 4 mg oral haloperidol, thence Clozapine, like olanzapine, under reaching 300 mg/d in 1 month, with a se- transferred to a long-stay community reha- certain conditions, may form a toxic rum clozapine level of 831 ng/mL (thera- bilitation center. There, she was rechallenged transient nitrenium+ intermediate metab- peutic range, 350Y600 ng/mL),4 whereas with clozapine at the dose of 100 mg/d. olite (see Supplemental online material, norclozapine was 243 ng/mL, as measured One week later, she was again hyperglyce- Nitrenium toxicity [Supplemental Digital through liquid chromatography/tandem mic and with elevated pancreatic enzymes, Content 2, http://links.lww.com/JCP/A31]). mass spectrometry techniques (Q-Trap although less than in the preceding episode; This mechanism may be reasonably ad- 2000; Applied Biosystems, Foster City, hence, she returned to our unit. We imme- vocated for pancreatitis caused by planar Calif; our method was similar to that by diately suspended clozapine and instituted atypicals, such as clozapine and olanzapine, Aravagiri and Marder5). We administered again the same antibiotic and insulin regi- rather than for agranulocytosis, which is clozapine in 2 divided doses, at 9 A.M.and men as above. We withdrew blood for mea- more caused by fluperlapine than olan- 9 P.M., and withdrew blood for serum cloz- suring serum clozapine level 4 hours after zapine, yet the former lacks a nitrenium apine testing at 12 hours. We also admin- last clozapine intake; she had 364 ng/mL intermediate. istered 10 mg lorazepam to exploit its clozapine and 165 ng/mL norclozapine, Furthermore, we may hypothesize antianxiety and hypnotic properties. We which is within the therapeutic window. that there has been a sensitization to the were alerted for possible adverse events, We introduced 4 mg/d oral risperidone pancreatic exocrine effect of clozapine but 1 week later, the patient showed to be and 800 mg/d oral carbamazepine and because it reoccurred at a much lower more insightful and her psychosis had reintroduced the high-dose benzodiazepine dose approximately 2 weeks after she had improved (BPRS score, 41); hence, we as above. On this occasion, we withdrew recovered. Learning might have contrib- changed her hospitalization regimen from a 5-mL blood sample for DNA extraction, uted to sensitization. involuntary to voluntary and, regretfully, to analyze cytochrome P450 isoenzymes Therapeutic drug monitoring is not did not modify the dose regimen. After 1A2 (CYP1A2) and 3A4 (CYP3A4) (see suggested as routine procedure for cloza- 1 month at ward, her blood glucose level Supplemental online material, Pharmaco- pine.7 Among all reports on clozapine- rose to 459 mg/dL for the first time; this genomics [Supplemental Digital Content 2, associated pancreatitis (see Supplemental was approximately 10 days after clozapine http://links.lww.com/JCP/A31]). Table A [Supplemental Digital Content 1, assay. In the same time, her blood choles- She quickly improved (BPRS, 40) and http://links.lww.com/JCP/A30] and Sup- terol had risen to 256 mg/dL (reference returned to the community rehabilitation plemental online material, Comparison to range, 120Y220 mg/dL) and blood triglyc- center, where physicians abstained from other clinical reports [Supplemental Digital erides to 342 mg/dL (reference range, treating her with clozapine once more. Content 2, http://links.lww.com/JCP/A31]), 50Y180 mg/dL). We found elevated pan- She provided full, free, informed the only reported blood clozapine values creatic enzymes during routine laboratory consent for DNA analysis, treatments, and were those by Schmitz-Hu¨bschetal,8 which testing, with the patient complaining of no procedures during her hospital stay after were in the therapeutic range, as were levels physical symptoms; pancreatic amylase commutation of the involuntary to volun- at rechallenge in our case. In our case, we was 116 U/L (reference range, 8Y53 U/L) tary hospitalization regimen, as well as for recorded higher levels than the therapeutic and pancreatic lipase peaked at 759 U/L the publication of her case. window would allow at first assay; we pre- (reference range, 20Y300 U/L) 2 days later, sume that these had to do with the first whereas total serum calcium was slightly occurrence of pancreatitis and that the lower than normal for the first time and DISCUSSION second episode occurred at therapeutic persisted for further 3 days (8.1 mg/dL; We report a case of pancreatitis in a serum levels because of sensitization. reference values, 8.4Y10.2 mg/dL); ery- patient with treatment-resistant schizo- Our case compares with other cases throsedimentation rate was 69 mm/h (ref- phrenia who took clozapine. It is sup- reported in literature and differs from erence range, 0Y20 mm/h), and C-reactive ported that existing pancreatitis increases many of them in several aspects (see Sup- protein was 8.25 mg/dL (reference range, clozapine blood levels.6 However, we con- plemental Table A [Supplemental Digital 0Y0.5 mg/dL). Emergency abdominal ultra- sider this mechanism to be unlikely in our Content 1, http://links.lww.com/JCP/A30] sounds showed no abnormality; however, case, at least as concerns the induction and Supplemental online material, computerized tomography and magnetic phase. In fact, baseline values of pancreatic Comparison to other clinical reports resonance cholangiography, despite con- values were normal. [Supplemental Digital Content 2,

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors http://links.lww.com/JCP/A31]). One of the past 2 years, Dr Tatarelli has partici- clozapine by cDNA-expressed human the criteria to establish the strength of pated in Advisory Boards for Schering, cytochrome P450 enzymes. Drug Metab the association with a given side effect Servier, and Pfizer and received honoraria Dispos. 1997;25:1379Y1382. is the disappearance of the effect upon from Schering, Servier, and Pfizer. 3. Shin JG, Soukhova N, Flockhart DA. discontinuation and its reappearance Supplemental digital contents are Effect of antipsychotic drugs on human after rechallenge. Comprising our report, available for this article. Direct URL cita- liver cytochrome P-450 (CYP) isoforms 7 cases were rechallenged with cloza- tions appear in the printed text and are in vitro: preferential inhibition of CYP2D6. pine; in 5 cases, pancreatitis did reoccur, provided in the HTML and PDF versions Drug Metab Dispos. 1999;27:1078Y1084. and in 2, it did not (see Supplemental of this article on the Journal’s Web site 4. Baumann P, Hiemke C, Ulrich S, et al. The Table A [Supplemental Digital Content 1, (www.psychopharmacology.com). AGNP-TDM expert group consensus http://links.lww.com/JCP/A30] and Sup- guidelines: therapeutic drug monitoring in plemental online material, Comparison to psychiatry. Pharmacopsychiatry. 2004;37: other clinical reports [Supplemental Digital Gabriele Sani, MD 243Y265. Content 2, http://links.lww.com/JCP/A31]). Giorgio D. Kotzalidis, MD 5. Aravagiri M, Marder SR. Simultaneous Alessio Simonetti, MD determination of clozapine and its N-desmethyl and N-oxide metabolites in IMPLICATIONS FOR Andrea Solfanelli, MD plasma by liquid chromatography/electrospray CLINICAL CARE Iginia Mancinelli, MD tandem mass spectrometry and its application The fact that pharmacogenomic re- to plasma level monitoring in schizophrenic Giusy Calabro`, MD sults did not match actual clozapine serum patients. J Pharm Biomed Anal.2001;26: levels shows that it is premature to conduct Pietro De Rossi, MD 301Y311. NESMOS Department (Neurosciences expensive genomic analyses for clinical 6. Pfuhlmann B, Hiemke C, Unterecker S, purposes and that therapeutic drug moni- Mental Health and Sensory Functions) Sant_Andrea Hospital et al. Toxic clozapine serum levels during toring should be given priority in hospital 2nd Medical School inflammatory reactions. J Clin Y settings. The prediction that the extreme Sapienza University Psychopharmacol. 2009;29:392 394. interindividual variations in clozapine and Rome, Italy 7. Greenwood-Smith C, Lubman DI, Castle DJ. 9 its metabolites_ blood levels could be ex- [email protected] Serum clozapine levels: a review of their plained by different genes working on the Ottavia De Luca, PhD clinical utility. J Psychopharmacol. 2003;17: cytochromes that are responsible for clo- 234Y238. Giovanna Gentile, PhD zapine metabolism was not fulfilled. Sus- 8. Schmitz-Hu¨bsch T, Schlaepfer TE, pected pancreatitis should be an added Luana Lionetto, PhD Westheide J, et al. Clozapine: acquittal of the indication to the recommendations by DiMA (Advanced Molecular Diagnostics) usual suspect. World J Biol Psychiatry. 7 _ Greenwood-Smith et al for investigating Sant Andrea Hospital 2009;10:981Y984. clozapine serum levels. When administer- 2nd Medical School Sapienza University 9. Raedler TJ, Hinkelmann K, Wiedemann K. ing clozapine, biliary and pancreatic func- Rome, Italy Variability of the in vivo metabolism of tion deserve special attention because current clozapine. Clin Neuropharmacol. 2008;31: or past gallstones may have sensitivity to Giovanni Manfredi, MD 347Y352. the impact of clozapine on pancreatic func- Nicoletta Girardi, MD tion; pancreatic enzyme testing should be- Elisa Ambrosi, MD come routine when treating patients with NESMOS Department (Neurosciences clozapine or other new-generation antipsy- Mental Health and Sensory Functions) Diazepam Discontinuation chotics that have the potential to derange Sant_Andrea Hospital Through Agomelatine in glucose and lipid metabolism. The finding 2nd Medical School Schizophrenia With of off-window blood clozapine levels should Sapienza University prompt physicians to modify dosage. Rome, Italy Insomnia and Depression Maurizio Simmaco, MD DiMA (Advanced Molecular Diagnostics) ACKNOWLEDGMENTS Sant_Andrea Hospital To the Editors: The authors thank Prof Thomas 2nd Medical School chizophrenia is a chronic psychiatric Schla¨pfer and Dr Mike McPhillips for Sapienza University S disorder characterized by distortion of providing precious clinical information; Rome, Italy thinking and perception and by an inap- the Librarians of the Sant_Andrea Li- Roberto Tatarelli, MD propriate or blunted affect. Although sleep brary Ms. Felicia Proietti and Ms Mimma NESMOS Department (Neurosciences disorders do not pertain to the clinical Ariano for facilitating our bibliographic Mental Health and Sensory Functions) core of its symptoms, it affects the quality consultation; and Drs Emanuele Simonetti Sant_Andrea Hospital of life of schizophrenic patients.1 Sev- and Marco Bella, School of Chemistry, 2nd Medical School eral sleep disorders have been described Sapienza University, Rome, for having Sapienza University in patients with schizophrenia, insomnia,2 Rome, Italy discussed extensively with us all chemical arrhythmic circadian rest-activity cycles,3 issues in this paper. and sleep-disordered breathing.4 Pharma- REFERENCES cological strategies to treat insomnia in 1. Aitchison KJ, Jann MW, Zhao JH, et al. schizophrenia include adding sedative anti- AUTHOR DISCLOSURE Clozapine pharmacokinetics and psychotics and the use of hypnotics.5 INFORMATION pharmacodynamics studied with Cyp1A2-null Agomelatine, a new antidepressant Y The authors declare no conflicts of mice. J Psychopharmacol. 2000;14:353 359. with norepinephrine-dopamine disinhibi- interest for the present study; however, in 2. Linnet K, Olesen OV. Metabolism of tion properties because of its antagonism

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 on the 5-hydroxytryptamine 2C receptor,6 duced to 30 mg in the morning for the antipsychotics. Although the European has recently been approved by the Euro- same period. On the fifth day, agomelatine Medicines AgencyYapproved agomelatine pean Medicines Agency and has proved was increased to 25 mg at dinner whereas indication is for the treatment of major de- to be effective in the treatment of moder- duloxetine was suspended. The antipsy- pression, initial studies with agomelatine ate to severe major depressive disorder.7 chotic treatment was kept stable while the were focused on its hypnotic properties.12 Agomelatine is also a potent agonist at patient was instructed to reduce 10 mg of Insomnia in schizophrenia affects the melatonin receptors.6 Melatonin is the diazepam every week until the next ap- psychopathology and quality of life of main pineal hormone that plays a major pointment 1 month later. patients. Severe insomnia is one of the role in the induction and regulation of In the next appointment, the patient prodromal symptoms of psychotic relapse sleep.8 Schizophrenic patients with in- had completely suspended the intake of and is a relapse-predicting factor.13 Al- somnia have been reported to benefit from diazepam 1 week before the appointment. though insomnia problems should be taken melatonin treatment.9 Melatonin has also The patient had an improved sleep quality, into account in the global treatment of been used to diminish benzodiazepine in- but he was still complaining of depressed psychosis, we believe that agomelatine may take in patients with insomnia.10 mood. The MADRS score was 20, and the be an alternative to consider when schizo- In this article, we describe the case main improvement of the score was in item phrenic patients present depression and of a patient with chronic simple schizo- 4 (reduced sleep) that had gone from 4 insomnia. It may be argued that agomela- phrenia and severe insomnia and depres- points in the first evaluation to 0 points in tine’s disinhibitory effect on the dopami- sion that only had a partial response to the second evaluation. nergic system may act as a triggering factor high doses of benzodiazepines and se- The next appointment was set for of psychotic episodes. This risk has to be dating antipsychotics. Treatment with 1 month later, and we asked the patient to considered, and patients should be con- agomelatine permitted the patient to com- reduce 25 mg of levomepromazine every trolled frequently to check whether psy- pletely suspend benzodiazepines. week until the next appointment. Because chotic symptoms appear. mood had not improved, agomelatine was As far as we know, there are no re- increased until 37.5 mg at dinner. During ported cases of psychotic episodes attrib- CASE REPORT this appointment, once again, the patient utable to agomelatine treatment. However, Mr Y is a single 36-year-old man di- had completely suspended levomeproma- this risk with another antidepressant (bu- agnosed with simple schizophrenia (Inter- zine in 3 weeks when he was asked to re- propion), with a norepinephrine-dopamine national Classification of Diseases, 10th duce only 100 mg in 4 weeks. The patient reuptake inhibitor mechanism of action, has Revision, F20.6). He started psychiatric looked healthier and related that his been reported.14 We still have to wait for the treatment at the age of 16 years. Since the mood had improved. The MADRS score generalization of agomelatine use to know beginning of the disease, the patient has at this point was 9. The patient did not whether this risk exists with agomelatine. complained of problems with insomnia, present any sleep complaint with the Although our patient had a relapse while on initiating and maintaining sleep that had treatment. agomelatine, from our point of view, it was never remitted. He has been treated with Treatment indications for the next precipitated because the patient had sud- several typical and atypical antipsychotics appointment included reducing clotiapine denly stopped the treatment with levome- for his schizophrenia as well as with seda- from 120 to 80 mg, with a tapering strat- promazine. In fact, after levomepromazine tive antipsychotics and hypnotics for his egy of reducing 20 mg of clotiapine restoration, the clinical picture remitted. sleep problems. In the last 5 years, apart every 2 weeks. The next appointment was The fact that controlled discontinuation of from his psychotic disorder, the patient’s programmed 1.5 months later. Two weeks benzodiazepines in patients with chronic sleep problems moved to the forefront of after the last appointment, the patient had schizophrenia has not produced psychotic the clinical picture and were the core of the a relapse that was characterized mainly by relapses15 supports our interpretation about patient’s complaints. In the last 3 years, the aggressiveness and initiating and main- the cause of the relapse. treatment that the patient followed was taining sleep. Restoration to the initial dose To our knowledge, there are no data stable and consisted of 100 mg of diaz- of levomepromazine (300 mg before bed- on the use of agomelatine in schizophre- epam, 300 mg of levomepromazine, and time) controlled the clinical picture. In nia. Therefore, our results with 1 patient 120 mg of clotiapine every night. All the next appointment, the patient was clin- should be considered as preliminary until medication was orally administered. In the ically stable and without sleep problems. more data or studies with bigger sample last year, the patient presented a moderate The treatment was as follows: 37.5 mg of size are published. depression that was treated with 60 mg of agomelatine at dinner and 300 mg of duloxetine (by mouth) in the morning. His levomepromazine and 120 mg of clotiapine mood improved with the prescribed treat- before bedtime. ment, but 11 months later, it worsened. Three months later, the patient was AUTHOR DISCLOSURE To treat the worsening of mood, we clinically stable, without sleep problems INFORMATION proposed that the patient suspend duloxetine and following the same treatment. The None of the authors have conflict of and introduce agomelatine, in an attempt patient has been on agomelatine treatment interest to declare. to treat at the same time the mood worsen- for a total period of 7 months. ing and the sleep disorder. To measure the intensity of depression, the Montgomery- Armando L. Morera-Fumero, MD, PhD A˚ sberg Depression Rating Scale11 DISCUSSION Departamento de Medicina Interna (MADRS) was applied. In the basal mea- According to what we know so far, Dermatologia y Psiquiatria Facultad de Medicina surement, before introducing agomelatine, this is the first case in which agomelatine Universidad de La Laguna the MADRS score was 24, indicating a has successfully been used as a treatment Tenerife, Spain moderate depression. Agomelatine was in- of insomnia and depression in a schizo- and Consultoria Psiquiatrica SC troduced at the dose of 12.5 mg at dinner phrenic patient being treated with high Santa Cruz de Tenerife, Spain during 4 days, whereas duloxetine was re- doses of benzodiazepines and sedating [email protected]

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Pedro Abreu-Gonzalez, PhD worsening following antipsychotic though the index has been criticized for Departamento de Fisiologia withdrawal in schizophrenia. its lack of transparency in determining in- Facultad de Medicina Compr Psychiatry. 2002;43:393Y396. dividual drug values.3 Unlike DDDs, CE Universidad de La Laguna doses are not based solely on dosing for Tenerife, Spain 14. Neumann M, Livak V, Paul HW, et al. Acute psychosis after administration the primary indication. of bupropion hydrochloride (Zyban). The most common use of standard- REFERENCES Pharmacopsychiatry. 2002;35:247Y248. ized drug dosing for antipsychotics has 1. Ritsner M, Kurs R, Ponizovsky A, et al. 15. Nakajima S, Uchida H, Suzuki T, et al. been to compare the therapeutic properties Perceived quality of life in schizophrenia: An open-label trial of discontinuing of the drugs. However, an important prop- relationships to sleep quality. Qual Life Res. benzodiazepines in patients with chronic erty of any antipsychotic dosing framework Y 2004;13:783 791. schizophrenia. J Clin Psychopharmacol. should include its ability to predict the 4 2. Suresh Kumar PN, Andrade C, Bhakta SG, 2007;27:401Y403. drug’s adverse effects, as tolerability is a et al. Melatonin in schizophrenic major issue in antipsychotic treatment ad- outpatients with insomnia: a double-blind, herence and can potently affect quality of placebo-controlled study. J Clin Psychiatry. life. To our knowledge, there has never been 2007;68:237Y241. A Comparison of a direct comparison between the DDD and 3. Wirz-Justice A, Cajochen C, Nussbaum P. Antipsychotic Drug-Defined CE dosing systems of the motor adverse A schizophrenic patient with an arrhythmic Daily Doses Versus effects of antipsychotic drugs, which in- circadian rest-activity cycle. Psychiatry Res. clude the extrapyramidal symptoms (EPS). 1997;73:83Y90. Chlorpromazine Equivalent The purpose of the present study was thus 4. Takahashi KI, Shimizu T, Sugita T, et al. Doses in Patients With or to examine antipsychotic dosing in a large Prevalence of sleep-related respiratory Without Extrapyramidal diagnostically heterogeneous population, disorders in 101 schizophrenic inpatients. using the 2 different guidelines, and deter- Psychiatry Clin Neurosci. 1998;52: Motor Symptoms mine how well each predicted the presence 229Y231. of EPS. 5. Benson KL. Sleep in schizophrenia: Patients were recruited from 8 different community mental health teams in impairments, correlates, and treatment. To the Editors: 5 Psychiatr Clin North Am. 2006;29: Vancouver, British Columbia. These teams 1033Y1045. hereas antipsychotic drugs share the provide individuals living in defined catch- W common property of reducing the ment areas with psychiatric resources, 6. Stahl SM. Novel mechanism of symptoms of psychosis, they represent a including assessment, treatment, medica- antidepressant action: norepinephrine structurally diverse range of compounds tion management, and rehabilitation. The and dopamine disinhibition (NDDI) plus melatonergic agonism. Int J with distinct neurochemical and pharma- study protocol was approved by the Uni- Neuropsychopharmacol. 2007;10: cokinetic properties. Despite these differ- versity of British Columbia Research 575Y578. ences, a number of guidelines have been Ethics Board and conducted in accordance developed to allow direct comparison of with the principles of Good Clinical 7. Zajecka J, Schatzberg A, Stahl S, et al. dosing between different antipsychotic Practices and the Declaration of Helsinki. Efficacy and safety of agomelatine in the drugs. These include the expression of an- A total of 788 patients who gave written treatment of major depressive disorder: tipsychotic drugs as a defined daily dose consent to have their medical profiles a multicenter, randomized, double-blind, (DDD) or as a chlorpromazine equivalent reviewed were screened for the study. The placebo-controlled trial. J Clin 1,2 Psychopharmacol. 2010;30:135Y144. (CE) dose. The DDD is the interna- inclusion criteria required that: (1) the tional unit of drug use approved by the patient’s diagnosis was schizoaffective 8. Dijk DJ, Cajochen C. Melatonin and the World Health Organization for drug use disorder, schizophrenia, bipolar disorder, circadian regulation of sleep initiation, studies. Values are determined by re- depression, or psychosis not otherwise consolidation, structure, and the sleep EEG. searchers of the World Health Organiza- specified; (2) the patient’s comprehensive J Biol Rhythms. 1997;12:627Y635. tion collaborating centre of drug statistics medication profile was available through 9. Shamir E, Laudon M, Barak Y, et al. methodology. The DDD is defined as the BC PharmaNet (a provincewide electronic Melatonin improves sleep quality of Bassumed average maintenance dose per network linking all British Columbian patients with chronic schizophrenia. Y day for a drug used in its main indica- pharmacies to a central set of data sys- J Clin Psychiatry. 2000;61:373 377. tion in adults.[ Using DDD provides a tems; prospective studies have confirmed 10. Garfinkel D, Zisapel N, Wainstein J, convenient method to compare dosing that PharmaNet accurately predicts treat- et al. Facilitation of benzodiazepine between different drugs. Furthermore, it ment adherence for oral medications in discontinuation by melatonin: a new allows calculation of the cumulative dose chronic illness6); (3) the patient be treated clinical approach. Arch Intern Med. of antipsychotic drugs irrespective of with at least one antipsychotic; (4) the Y 1999;159:2456 2460. whether they are used as a single agent or patient did not receive any depot antipsy- 11. Montgomery SA, Asberg M. A new as part of an antipsychotic polypharmacy chotic; and (5) the patient had been treated depression scale designed to be sensitive to regimen. Chlorpromazine equivalent doses with the same medications and doses for change. Br J Psychiatry. 1979;134:382Y389. are well established in the scientific litera- at least 90 days; thus, antipsychotic dose 12. Cajochen C, Krauchi K, Mori D, et al. ture and have been used to compare dosing was calculated after anticholinergics were A single administration of melatonin or both within and between different classes introduced. the melatonin agonist S-20098 lengthens of antipsychotics. Values for chlorproma- Data collected from BC PharmaNet the first REM sleep episode. Sleep Res. zine equivalency are based on a number of included antipsychotics and anticholiner- 1995;24:40. different factors, including dopamine D2 gics. The presence of EPS in patients 13. Chemerinski E, Ho BC, Flaum M, et al. receptor occupancy and dosing used in was inferred from scripts for anticholin- Insomnia as a predictor for symptom registration and other clinical trials, al- ergic medications. Demographic data were

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 obtained from patients’ medical charts. ferences between those subjects treated of calculation in the subjects with or with- Dosing for the oral antipsychotics was with anticholinergics and those who were out EPS, only the CE approach reliably compared by converting to multiples of the not. A higher proportion of the subjects detects a difference between these 2 DDD or CE doses. Multiples of the DDD treated with anticholinergics than those groups. When all subjects were consid- were obtained by dividing the prescribed who were not had a diagnosis of schizo- ered, mean CE daily doses were 1.64 times daily dose (PDD) by the DDD. The DDD phrenia (P G 0.005). When the mean total higher in the subjects with EPS than in values were extracted from the Anatomical antipsychotic dose per day was calculated those without EPS, but only 1.11 times Therapeutic Chemical Classification Sys- according to the PDD/DDD ratio, there higher for PDD/DDD ratios. Interestingly, tem.7 Chlorpromazine equivalent doses was no significant difference between those this difference remains significant in the were calculated according to the Clinical treated with or without anticholinergic subjects treated with only atypical anti- Handbook of Psychotropic Drugs8;CE drugs (Table 1). However, the difference in psychotic drugs and exhibited a strong values provided by this source have been antipsychotic dosing between the groups trend toward significance in the subjects used in numerous studies in the literature by was highly significant when CE doses treated with only typical agents despite ourselves and other research groups.9 were analyzed instead (P G 0.005). This the latter group’s small sample size. Thus, Values were added for subjects prescribed effect was not restricted exclusively to ei- calculation of antipsychotic drug dosing more than one antipsychotic concurrently. ther the atypical or the typical drugs. with the CE method has better heuristic For statistical analysis, the average anti- Analysis of mean drug doses for the sub- value in predicting whether motoric ad- psychotic dose for patients with and with- jects who were medicated with only atypi- verse effects will occur in relation to the out EPS, as calculated by CE doses and cal antipsychotics (n = 342) indicated that dose of the drug used. When comparing PDD/DDD ratios, was compared using the although there was no difference in PDD/ between drugs, a system is required that Wilcoxon signed rank test (significance, DDD ratios between those treated with reflects the elevated risk for EPS as drug P G 0.05). Comparison of frequencies was anticholinergic drugs and those who were dose increases. Based on the present performed using the W2 test. not treated, there was a significant differ- study, converting all antipsychotic drugs A total of 406 subjects met the in- ence when doses were calculated as CE into a standardized value as the CE dose clusion criteria. The average age of sub- doses (P G 0.005). When subjects treated largely retained this important property. jects was 47.1 years, and sex was split with only typical antipsychotics were con- To our knowledge, this is the first evenly (Table 1). The most common di- sidered (n = 32), the difference in mean study to evaluate 2 different dosing guide- agnosis of subjects was schizophrenia daily dose between those treated with anti- linesontheabilitytodetectdifferences followed by schizoaffective disorder, bipo- cholinergic drugs was not different for in drug-induced adverse effects rather than lar disorder, major depression, and psy- PDD/DDD ratios, but there was a strong therapeutic efficacy. The reason for this chosis not otherwise specified. A total of trend for CE doses (P = 0.09). difference in dosing protocols is not im- 61 patients were prescribed anticholinergic mediately apparent. The CE dose is based medications for the treatment of EPS; the in part on D2 receptor affinity, and thus, most commonly used drug was benztropine DISCUSSION increasing CE will be predictive of in- (75% of the subjects; mean dose, 1.7 mg) The present study compared daily creased D2 receptor occupancy, with a followed by procyclidine (21% of the antipsychotic dosing using both the DDD greater risk for EPS. This may explain subjects; mean dose, 8.7 mg) and trihex- and CE guidelines in a diagnostically why a greater proportion of subjects with yphenidyl (4% of the subjects; mean dose, heterogeneous outpatient psychiatric pop- schizophrenia than any other diagnosis ex- 6.0 mg). Analysis of demographic vari- ulation. The main finding is that when dos- hibited EPS, as dosing was highest in this ables did not indicate any significant dif- ing is compared between these 2 methods group. However, this effect should be most pronounced for typical drugs, as higher doses of these are more likely to exceed the level of D2 receptor occupancy needed TABLE 1. Summary Characteristics and Chlorpromazine Equivalent Doses (CE) to induce EPS, yet we observed large and Versus PDD/DDD Ratios for Subjects With (+) and Without (j) EPS significant differences for CE doses in the +EPS (n = 61) jEPS (n = 345) P subjects with EPS who were being treated T with only atypical antipsychotic drugs. It Age SEM, y 48.1 (1.3) 46.9 (0.7) 0.450 is, therefore, likely that some antipsychotic Sex, male (%) 54.2 49.3 0.481 drugs are Bweighted[ more heavily in each Diagnosis dosing approach than the other, and the Schizoaffective disorder (%) 23.0 17.7 0.33 G drugs that increase the risk for EPS are Schizophrenia (%) 52.5 33.3 0.005 weighted more heavily in the CE than the Bipolar disorder (%) 9.8 20.0 0.06 DDD dose protocol. Greater transparency Depression (%) 4.9 13.3 0.06 in the determination of drug dose values Psychosis NOS (%) 3.3 7.8 0.20 T remain a controversial and complex issue, Antipsychotic dose ( SEM) and alternate strategies for values have All antipsychotics (n = 406) been proposed, such as using expert clinical PDD/DDD 1.29 (0.24) 1.16 (0.05) 0.67 4 G consensus. CE 263.3 (41.4) 160.3 (7.0) 0.005 Further study of this issue is strongly Atypical agents only (n = 342) warranted, as standardized drug dosing PDD/DDD 1.32 (0.14) 1.18 (0.05) 0.22 G guidelines are helpful in analyzing pat- CE 203.6 (17.6) 151.4 (6.7) 0.005 terns of antipsychotic drug use in large Typical agents only (n = 32) heterogeneous clinical populations with PDD/DDD 1.00 (0.53) 0.34 (0.08) 0.25 diverse patterns of antipsychotic drug CE 459.6 (211.8) 140.3 (35.7) 0.09 use.1,2 Others have already advocated for

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors developing new instruments of antipsy- William G. Honer, MD 9. Barr AM, Procyshyn RM, Hui P, et al. chotic drug dose standardization that take British Columbia Mental Health Self-reported motivation to smoke in greater account of the risk for drug ad- and Addictions Services Research Institute schizophrenia is related to antipsychotic verse effects.4 As a caveat to the present Vancouver, BC, Canada drug treatment. Schizophr Res. and Department of Psychiatry 2008;100:252Y260. study, the use of anticholinergic scripts as University of British Columbia a proxy for EPS (despite its widespread Vancouver, BC, Canada practice) has several limitations: the signs Joy L. Johnson, PhD, RN Alterations in Pain of EPS can be subtle and therefore over- Nursing and Health Behaviour Research Unit looked or misdiagnosed, the prescription University of British Columbia Perception During of anticholinergics may be based on the Vancouver, BC, Canada subjective decisions of physicians, and Benzodiazepine Withdrawal Tony K.Y. Wu, MD patients may continue to be treated with Department of Anesthesiology A Case Series anticholinergics even after being switched Pharmacology and Therapeutics to a different antipsychotic and no longer University of British Columbia To the Editors: experiencing EPS. Prospective studies Vancouver, BC, Canada ncreased pain perception is a typical addressing this issue with quantitative Ric M. Procyshyn, PharmD, PhD I symptom of benzodiazepine withdrawal, neurological scales are needed. Despite British Columbia Mental Health which is combined with increased gluta- this limitation, the present data provide and Addictions Services Research Institute matergic neurotransmission.1 Increased strong evidence to indicate that CE dosing Vancouver, BC, Canada glutamatergic neurotransmission has been may be more useful than PDD/DDD ratios and Department of Psychiatry assumed to modulate nerve growth factor when calculating standard drug doses in University of British Columbia (NGF) expression.2 Both increased gluta- relation to the motoric adverse effects of Vancouver, BC, Canada matergic neurotransmission and increased these drugs. NGF expression are thought to contrib- ute to hyperalgesia.3 In contrast, benzo- REFERENCES diazepines are thought to decrease pain ACKNOWLEDGMENTS 1. Nose M, Tansella M, Thornicroft G, et al. perception by modulation of GABAergic 4 The technical assistance of Ms Is the defined daily dose system a reliable tool neurotransmission. Here we present 4 RebeccaKoandMsSydMalchyis for standardizing antipsychotic dosages? Int cases of benzodiazepine-dependent patients Y acknowledged. Clin Psychopharmacol. 2008;23:287 290. in which we observed alterations in NGF 2. Rijcken CA, Monster TB, Brouwers JR, et al. plasma levels, mechanical pain threshold Chlorpromazine equivalents versus defined (MPT), and mechanical pain sensitivity AUTHOR DISCLOSURE daily doses: how to compare antipsychotic (MPS). drug doses? J Clin Psychopharmacol. INFORMATION In total, we investigated 4 inpatients 2003;23:657Y659. This research was supported by a (3men[26,54,and61years]and1woman grant from the National Cancer Institute 3. Rey MJ, Schulz P, Costa C, et al. [37 years]) with depressive disorder and of Canada with funds from the Canadian Guidelines for the dosage of neuroleptics. comorbid benzodiazepine dependence ac- I: chlorpromazine equivalents of orally Cancer Society (No. 016334), and the cording to International Statistical Classi- administered neuroleptics. Int Clin fication of Diseases, 10th Revision and British Columbia Mind Foundation. Psychopharmacol. 1989;4:95Y104. A.M.B. is both a Michael Smith Founda- Diagnostic and Statistical Manual of Men- tion for Health Research Scholar and a 4. Andreasen NC, Pressler M, Nopoulos P, tal Disorders, Fourth Edition (Department Canadian Institutes of Heath Research et al. Antipsychotic dose equivalents of Psychiatry and Psychotherapy, Uni- and dose-years: a standardized method New Investigator. versity of Erlangen-Nuremberg, Germany) for comparing exposure to different before (day 1) and after completion of Dr Honer was on the advisory board drugs. Biol Psychiatry. 2010;67:255Y262. of Pfizer in 2008 and Janssen from 2008 benzodiazepine withdrawal (day 2; diaze- to 2009. He has a consulting, educational 5. Procyshyn RM, Honer WG, Wu TK, et al. pam equivalent dose, 0 mg). Benzodiaze- grant (travel) at AstraZeneca. He was also Persistent antipsychotic polypharmacy and pine withdrawal was done by continuous excessive dosing in the community psychiatric a consultant at Novartis in 2009. Cur- tapering of the dose benzodiazepine treatment setting: a review of medication rently, he is on the scientific advisory patients took usually (lorazepam in 2 profiles in 435 Canadian outpatients. JClin patients, diazepam in 1 patient, oxazepam board of In-silicon. Psychiatry. 2010;71:566Y573. Dr Procyshyn reports that he received in 1 patient). Diazepam equivalent doses a consulting or advisory board fees from 6. Dahri K, Shalansky SJ, Jang L, et al. were 15 (3 patients) and 30 mg (1 patient) AstraZeneca, Janssen, and Pfizer; and lec- Accuracy of a provincial prescription on admission. Patients had no further Axis ture fees from AstraZeneca, Bristol-Meyers database for assessing medication 1 diagnosis and no severe somatic illnesses. adherence in heart failure patients. Squibb, GlaxoSmithKLine, Janssen, and Patients were not treated by electroconvul- Ann Pharmacother. 2008;42:361Y367. Pfizer. sive treatment and transcranial magnetic 7. World Health Organization. WHO stimulation. All patients received stable Collaborating Centre for Drug Statistics doses of antidepressant medication (tricyclic Alasdair M. Barr, PhD Methodology. Norwegian Institute for Public antidepressants). Intensity of benzodiaze- British Columbia Mental Health Health, Oslo, Norway. Available at: http:// pine withdrawal was measured using the and Addictions Services Research Institute www.whocc.no/atc_ddd_index/. Accessed Clinical Institute Withdrawal AssessmentV Vancouver, BC, Canada June 8, 2010. 5,6 and Department of Anesthesiology Benzodiazepines (CIWA-B). Pharmacology and Therapeutics 8. Virani AS, Bezchlibnyk-Butler KZ, Nerve growth factor plasma levels University of British Columbia Jeffries JJ. Clinical Handbook of were assessed using the DuoSet enzyme- Vancouver, BC, Canada Psychotropic Drugs. 18th ed. Ashland, linked immunosorbent assay Develop- [email protected] OH: Hogrefe & Huber Publishers; 2009. ment System (DY293 B; R&D Systems,

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TABLE 1. QST and NGF Measurements Obtained in the 4 Patients Investigated

Patient 1, 65, Male Patient 2, 26, Male Patient 3, 54, Male Patient 4, 37, Female P MPT (day 1) 103.97 (116.00) 10.56 (82.00) 168.90 (116.00) 29.86 (77.00) 0.62, 0.44 MPT (day 2) 32.00 73.52 9.19 27.86 0.01, 0.44 MPS (day 1) 0.56 (0.47) 1.66 (0.66) 0.44 (0.47) 2.93 (0.73) 0.21, 0.55 MPS (day 2) 2.87 0.36 0.82 3.49 0.14, 0.55 NGF (day 1), 148.90 (151.37 [60, male]) 168.50 (28.80 [26, male]) 159.90 (94.59 [54, male]) 163.60 (135.50 [30, female]) 0.08, 0.60 pg/mL NGF (day 2), 239.60 184.40 172.10 112.10 0.09, 0.60 pg/mL CIWA-B score 45.00 42.00 41.00 29.00 0.11 (day 1) CIWA-B score 28.00 41.00 34.00 24.00 0.11 (day 2) Control levels are displayed in parentheses. P values refer to group-to-group analysis between patients and healthy controls (ﬁrst value) and alterations during withdrawal in the patient’s group (second value).

Wiesbaden-Nordenstadt, Germany). All during withdrawal (Table 1). Concordant mission during benzodiazepine withdrawal the assays were performed according to with this result, MPS was tendentially leading to the typical benzodiazepine with- the manufacturer’s direction. Nerve growth increased in benzodiazepine-dependent drawal symptom of hyperalgesia. factor serum levels of the patient group patients before and after benzodiazepine The results obtained from the 4 were compared with NGF serum levels of withdrawal (Table 1). Nerve growth factor cases reported here point toward the pos- healthy controls. Controls were negative for plasma levels were tendentially increased sibility of an association between benzo- any psychiatric disease and received no in benzodiazepine-dependent patients in diazepine withdrawal, pain perception psychopharmacological treatment. the same time frame (Table 1 for details). (MPT and MST), and NGF expression. MPT and MPS were investigated Nevertheless, these preliminary results using a standardized program.7,8 Mechani- have to be justified in controlled studies cal pain threshold was assessed using DISCUSSION investigating larger samples. Moreover, weighted pinprick mechanical stimulators Benzodiazepines have been consis- explanatory power of the results obtained (flat contact area of 0.2 diameter) that tently reported to modulate pain percep- here is limited not only by the small exerted forces of 8, 16, 32, 64, 128, 256, tion.9 Preclinical studies suggest an number of patients investigated, but also and 512 nM. The stimulators were applied association between decreased pain per- by their depressive comorbidity, antide- in a 2-second on-off paradigm until patients ception and anti-inflammatory properties pressant treatment, lack of standardiza- reported a feeling of sharpness. Final of benzodiazepines.10,11 Other results tion of benzodiazepine treatment, and lack threshold was determined by the geometric show an association between decreased of blindness to dose tapering. In conclu- mean of 5 series of ascending and de- pain intensity and modulation of sion, quantitative sensory testing objecti- scending stimuli. Mechanical pain sensitiv- GABAergic neurotransmission afforded by vised withdrawal-induced hyperalgesia ity was assessed using the same 7 weighted benzodiazepine treatment.12,13 in benzodiazepine patients during with- pinprick stimulators. Pain intensity was Expression of NGF is known to be drawal. Moreover, NGF was increased in recorded on a numerical rating scale increased in neuroinflammation.14 Other the benzodiazepine patients, who had reaching from 0 (no pain) to 100 points study results suggest an association be- high intensity of benzodiazepine with- (most intensive pain intensity). Results tween increased glutamatergic neurotrans- drawal. Therefore, increased glutamatergic obtained from QST were compared with mission and increased NGF expression.2 neurotransmission due to benzodiazepine normative data according to Rolke et al.7 Increase in NGF expression and NGF sig- withdrawal may account to the altera- The investigation was conducted in naling via the TrkA receptor has been as- tions observed here. Controlled studies accordance with the Declaration of Hel- sociated with increased pain perception are necessary to justify these preliminary sinki of 1975 (revised 2008) and approved and in particular with hyperalgesia.15,16 results. by the local Ethics Committee of the Here, we presented 4 cases of University of Erlangen-Nuremberg. Each benzodiazepine-dependent patients in ACKNOWLEDGMENT participant gave written informed consent. which we observed decreased MPT and The authors gratefully acknowl- Group-to-group analyses between increased MPS. Nerve growth factor edge the support by a grant (to A.H., the healthy control group and the patient plasma levels were significantly increased T.H.) from ELAN fonds (BErlanger group were assessed by the t test for inde- in the same time frame. Mechanical pain Leistungsbezogene Anschubfinanzierung pendent samples. Alterations of measure- sensitivity increased during benzodi- und Nachwuchsfo¨rderung[), Friedrich- ments during benzodiazepine withdrawal azepine withdrawal. Benzodiazepine- Alexander-University of Erlangen- were assessed using t test for dependent dependent patients showed high CIWA-B Nuremberg, Germany. samples. Data were analyzed by GraphPad scores (915 points) mirroring subjective Prism 5.0 (GraphPad Software Inc, San perception of intensive withdrawal symp- AUTHOR DISCLOSURE Diego, Calif ). We found a tendency to- toms. Therefore, these preliminary re- INFORMATION ward decreased MPT in the benzodiazepine- sults may be interpreted as effects resulting None of the authors have a financial dependent patients, which decreased further from increased glutamatergic neurotrans- or personal conflict of interest.

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Annemarie Heberlein, MD benzodiazepine withdrawal in patients with clinic with delusional beliefs of religious Department of Psychiatry and Psychotherapy depression. Psychoneuroendocrinology. content, social isolation, and refusal to eat Friedrich-Alexander-University 2004;29:1101Y1108. or drink. of Erlangen-Nuremberg The patient had a 16-year history of Erlangen, Germany 7. Rolke R, Baron R, Maier C, et al. and Center for Addiction Research Quantitative sensory testing in the German delusional disorder of unspecified type, Department of Psychiatry Research Network on Neuropathic Pain and he was treated with haloperidol. He Social Psychiatry and Psychotherapy (DFNS): standardized protocol and reference had discontinued haloperidol 3 months Hannover Medical School values. Pain. 2006;123:231Y243. earlier. At the onset of the illness, the Hannover, Germany 8. Rolke R, Magerl W, Campbell KA, et al. patient presented briefly with delusional [email protected] Quantitative sensory testing: a jealousy, which was soon replaced with Rebecca Bu¨chl comprehensive protocol for clinical trials. hyperreligiosity; he gradually developed Department of Psychiatry and Psychotherapy Eur J Pain. 2006;10:77Y88. delusional ideas of religious content. He Friedrich-Alexander-University 9. Huffman JC, Stern TA. The use of joined a conservative denomination and of Erlangen-Nuremberg benzodiazepines in the treatment of chest became increasingly involved, assumed an Erlangen, Germany pain: a review of the literature. J Emerg Med. extreme ascetic lifestyle, ultimately decid- Michael Gro¨schl, PhD 2003;25:427Y437. ing to become a monk. His preoccupation Department of Pediatrics 10. Zavala F. Benzodiazepines, anxiety and with religious matters became increasingly University Hospital Erlangen intense, and he was eventually admitted Erlangen, Germany immunity. Pharmacol Ther. 1997;75: 199Y216. under an involuntary commitment order. Johannes Kornhuber, MD He was diagnosed with delusional disorder Department of Psychiatry and Psychotherapy 11. Taupin V, Gogusev J, Descamps-Latscha B, of unspecified type and discharged with et al. Modulation of tumor necrosis Friedrich-Alexander-University oral haloperidol. While on haloperidol, he of Erlangen-Nuremberg factor-alpha, interleukin-1 beta, interleukin-6, Erlangen, Germany interleukin-8, and granulocyte/macrophage maintained a baseline level of hyperreligiosity but returned to his previous level Stefan Bleich, MD colony-stimulating factor expression in human monocytes by an endogenous of functioning and resumed work. He re- Thomas Hillemacher, MD anxiogenic benzodiazepine ligand, mained employed throughout the 15 years Department of Psychiatry and Psychotherapy triakontatetraneuropeptide: evidence for a that ensued and has never experienced Friedrich-Alexander-University role of prostaglandins. Mol Pharmacol. hallucinations or other perceptual disturb- of Erlangen-Nuremberg Y ances, thus consistently fulfilling the Di- Erlangen Germany 1993;43:64 69. and Center for Addiction Research 12. Smirne S, Scarlato G. Clonazepam in cranial agnostic and Statistical Manual of Mental Department of Psychiatry neuralgias. Med J Aust.1977;1:93Y94. Disorder criteria for delusional disorder. On one occasion, he discontinued haloperidol, Social Psychiatry and Psychotherapy 13. Harkins S, Linford J, Cohen J, et al. Hannover Medical School and delusional ideas of religious content Administration of clonazepam in the Hannover, Germany reemerged. Upon resuming medication, the treatment of TMD and associated myofascial symptoms disappeared. Christian Maiho¨fner, MD pain: a double-blind pilot study. Department of Neurology J Craniomandib Disord. 1991;5:179Y186. Three months before admission, he University Hospital Erlangen discontinued medication again and delu- Erlangen, Germany 14. Levi-Montalcini R, Skaper SD, Dal Toso R, sional ideas of religious content reap- et al. Nerve growth factor: from neurotrophin peared. Four days before admission, he to neurokine. Trends Neurosci. started a continuous total fast. He re- 1996;19:514Y520. REFERENCES frained from eating or drinking anything. 15. Watson JJ, Allen SJ, Dawbarn D. Targeting At the same time, he exhibited an ex- 1. Allison C, Pratt JA. Neuroadaptive processes nerve growth factor in pain: what is the acerbation of his baseline hyperreligios- in GABAergic and glutamatergic systems in therapeutic potential? BioDrugs. ity, spent hours reading various religious benzodiazepine dependence. Pharmacol Ther. 2008;22:349Y359. 2003;98:171Y195. books, and stopped working. During an 16. Einarsdottir E, Carlsson A, Minde J, et al. all-night vigil at a monastery, he was 2. Zafra F, Lindholm D, Castren E, et al. A mutation in the nerve growth factor found lying down in a rigid state; he re- Regulation of brain-derived neurotrophic beta gene (NGFB) causes loss of pain sisted any passive movement of his limbs. factor and nerve growth factor mRNA in perception. Hum Mol Genet. 2004;13: He was transported to our department primary cultures of hippocampal neurons and Y 799 805. thereafter. astrocytes. J Neurosci. 1992;12:4793Y4799. Upon admission, he exhibited re- 3. Nielsen AN, Mathiesen C, Blackburn-Munro ligious delusional ideas, complained of G. Pharmacological characterisation of persistent blasphemous thoughts (curses acid-induced muscle allodynia in rats. A Case of Catatonia Y against saint figures), and refused food Eur J Pharmacol. 2004;487:93 103. Successfully Treated and drink. Admission global assessment 4. Zeilhofer HU, Witschi R, Hosl K. With Ziprasidone, in a of function score was 20, Brief Psychiat- Subtype-selective GABAA receptor ric Rating Scale (BPRS) score was 43, mimeticsVnovel antihyperalgesic agents? Patient With DSM-IV and Bush-Francis Catatonia Rating Scale J Mol Med. 2009;87:465Y469. Delusional Disorder (BFCRS) score was 8. Intravenous fluids 5. Busto UE, Sykora K, Sellers EM. A clinical were administered. He remained mostly scale to assess benzodiazepine withdrawal. To the Editors: motionless in bed and seemed to be praying J Clin Psychopharmacol.1989;9:412Y416. for most of the time. On the third day, the 6. Wichniak A, Brunner H, Ising M, et al. CASE REPORT patient exhibited worsening negativism, Impaired hypothalamic-pituitary-adrenocortical Our patient is a 52-year-old man who mutism, and ultimately waxy flexibility. At (HPA) system is related to severity of was urgently admitted to the psychiatric that time, the patient had a Brief Psychiatric

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Rating Scale score of 50 and a BFCRS catatonia8 (between 7% and 17%) among 4. Fink M, Taylor MA. Catatonia and NMS. rating of 25; results of electroencephalo- immediate psychiatric admissions. It is Psychiatr Bull. 2002;26:393. gram, brain computed tomographic scan, reasonable to claim that availability of a 5. Northoff G, Eckert J, Fritze J. Glutamatergic and a full laboratory workup were negative. syndrome-independent catatonic specifier dysfunction in catatonia? Successful With his autonomic status being sta- will facilitate identification of catatonic treatment of three acute akinetic catatonic ble, a formal diagnosis of nonmalignant symptoms in diseases outside the psy- patients with the NMDA antagonist catatonia was made. Given the need to chotic spectrum. Our case further supports amantadine. J Neurol Neurosurg Psychiatry. manage an acutely delusional patient and this claim, as we present a case of cata- 1997;62:404Y406. the lack of electroconvulsive therapy avail- tonia in a patient with a long-established 6. Thomas C, Carroll BT, Maley RT, et al. ability, we chose to administer an atypical history of delusional disorder, an unusual Memantine and catatonic schizophrenia. agent available parenterally and started clinical picture. Am J Psychiatry. 2005;162:626. the patient on ziprasidone at an initial There is a lack of inferential studies 7. Caroff SN, Mann SC, Campbell EC, et al. dosage of 40 mg 4 times a day. regarding superiority of benzodiazepine Movement disorders associated with atypical 9 On the fourth day, waxy flexibility, treatment over antipsychotics. Despite antipsychotic drugs. J Clin Psychiatry. negativism, and rigidity resolved; the pa- traditional usage of benzodiazepines in 2002;63(suppl 4):12Y19. tient resumed voluntary motor activity, cases of acute catatonia, chronic catatonia 8. Chalasani P, Healy D, Morriss R. and this is reflected as a BFRCS scale generally does not respond to benzodiaze- 10 Presentation and frequency of catatonia in score of 9. Given the positive response, pines. It seems that diagnosis of schizo- new admissions to two acute psychiatric we increased ziprasidone to 40 mg 2 times phrenic illness is a negative predictive admission units in India and Wales. 11 a day. On the fifth day, mutism and nega- factor for benzodiazepine efficacy. Al- Psychol Med. 2005;35:1667Y1675. though the literature lacks conclusive data tivism resolved. The patient was able to 9. Gibson RC, Walcott G. Benzodiazepines regarding the use of atypical agents in give account of his history, and BFCRS for catatonia in people with schizophrenia score dropped to 5. The patient remained catatonia, it has been suggested that cata- and other serious mental illnesses. tonic symptoms may markedly respond to hospitalized for a total of 38 days. Upon 12,13 Cochrane Database Syst Rev. 2008: discharge, his GAF score was 85. At antipsychotic agents. The mechanism CD006570. of this effect remains largely unknown, follow-up, he had returned to work, re- 10. Ungvari GS, Chiu HF, Chow LY, et al. sumed daily activities, and attended church but a complex interaction between GABA, glutamate, dopamine, and serotonin is pos- Lorazepam for chronic catatonia: a on Sundays, without delusional or other- randomized, double-blind, placebo-controlled tulated,14 the latter 2 relating to the atyp- wise excessive preoccupation. At 6 weeks cross-over study. Psychopharmacology after discharge, his family confirmed that ical agents’ usage in this clinical setting. (Berl). 1999;142:393Y398. Successful treatment of catatonia in our he has returned to the premorbid level of 11. Caroff SN. Catatonia: From functioning. patient with the atypical agent ziprasidone is in line with evidence that atypical agents Psychopathology to Neurobiology. 1st ed. Washington, DC: American Psychiatric DISCUSSION may be an option in the treatment of nonmalignant catatonia. Publishing; 2004. Catatonia is an established psycho- 12. Levy WO, Nunez CY. Use of ziprasidone to motor syndrome characterized by signs AUTHOR DISCLOSURE treat bipolar-associated catatonia. Bipolar and symptoms of motor behavior and vo- INFORMATION Disord. 2004;6:166Y167. lition. Catatonia is associated with a vari- 13. Peralta V, Campos MS, de Jalon EG, et al. ety of psychiatric and systemic medical The authors have nothing to declare. 1 DSM-IV catatonia signs and criteria in illnesses and toxic states. The treatment first-episode, drug-naive, psychotic patients: of catatonia traditionally included benzo- Elias K. Angelopoulos, MD 2 Psychometric validity and response to diazepines and electroconvulsive therapy. Michael Corcondilas, MD antipsychotic medication. Schizophr Res. Administration of antipsychotic agents Costas T. Kollias, MD 2010;118:168Y175. was generally contraindicated, as first- 14. Carroll BT. The universal field hypothesis generation antipsychotics worsened rather Kanellos T. Kioulos, MD 3,4 Joanna-Despoina Bergiannaki, MD of catatonia and neuroleptic malignant than relieved catatonia. Other drugs syndrome. CNS Spectr. 2000;5:26Y33. that regulate glutamatergic transmission, George N. Papadimitriou, MD such as amantadine5 and memantine,6 First Psychiatric Clinic have also been used. Second-generation an- Eginition Hospital tipsychotics, particularly for schizophrenic Athens University Medical School Partial Compliance as Athens, Greece patients predisposed to catatonia, were Determined From Plasma only subsequently evaluated as a possible [email protected] treatment alternative.7 Levels of Sertraline and Its REFERENCES In the current diagnostic criteria Metabolite in Depressed (Diagnostic and Statistical Manual of 1. Bush G, Fink M, Petrides G, et al. Catatonia, I. Mental Disorder, Fourth Edition), catato- Rating scale and standardized examination. Patients in Primary Care nia is not recognized as a separate disorder Acta Psychiatr Scand. 1996;93:129Y136. but is technically restricted to a feature of 2. Bush G, Fink M, Petrides G, et al. schizophrenia despite its frequent asso- Catatonia II. Treatment with lorazepam To the Editors: ciation with numerous psychiatric and and electroconvulsive therapy. Acta ompliance to antidepressant treatment medical conditions. Sporadic yet increas- Psychiatr Scand. 1996;93:137Y143. C has been recognized as an important ing evidences indicate that the claim for an 3. Taylor MA, Fink M. Catatonia in factor regarding optimal treatment out- 1Y4 independently classifiable catatonic syn- psychiatric classification: a home of its come. Patients are active, and treatment 3 drome has nosologic validity. A relatively own. Am J Psychiatry. 2003;160: regimens are modified rather than being 5 recent study found a high prevalence of 1233Y1241. completely accepted or rejected. Thus,

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2 partial compliance is an increasing prob- ylsertraline in all samples are considered (W 1 = 1.40, not statistically significant). lem, and it has been demonstrated that less to be compliant. Noncompliant patients Furthermore, whereas 63% of the non- than 50% of primary care patients with have no detectable concentrations of either compliant patients admitted that they had depression have complete compliance.6Y8 parent substance or metabolite in 1 or not taken the medication as prescribed, Therapeutic drug monitoring (TDM) more of the samples. Partially noncom- only 25.9% of the partially noncom- is an established method for assessing compliant patients are those having, in at least pliant patients admitted it (and 12.6% of pliance in the treatment of depression.9Y11 1 sample, a desmethylsertraline/sertraline the compliant patients revealed inconsis- Traditionally, only the parent substance ratio outside 2 SDs of a population mean tency in drug intake when questioned, has been taken into account. However, our ratio and a ratio deviating at least 50% according to TDM-RSM). Finally, there research group has previously improved from the patient’s own mean value. were significantly more responders among the validity of TDM by including also All serum samples on the 782 patients the compliant patients as compared with the major metabolite and scrutinizing the were scrutinized. Two thousand seventy-six partially noncompliant or noncompliant metabolite/parent substance ratio and its samples had quantifiable levels of sertraline patients (Table 1). changes over time,12 that is, the TDM-RSM and desmethylsertraline (median sertraline (TDMYratio screening method). concentration, 11 ng/mL [25thY75th per- DISCUSSION To validate and to further develop centile, 7.3Y17.5 ng/mL]; desmethylser- The main finding was that, by ap- the method by identifying partially non- traline, 29.4 ng/mL [19.2Y44.8 ng/mL]; plying TDM-RSM, it is possible to iden- compliant patients and to determine the desmethylsertraline/sertraline ratio, 2.8 tify partially noncompliant as well as consequences on response to treatment, [2.2Y3.3]; coefficient of variation [CV, totally noncompliant patients. Thus, the TDM-RSM was applied post hoc on a logarithmic values] for interindividual ratio, method previously described by us12 was large study population of patients with a 21%; CV intraindividual ratio, 23%). The validated. diagnosis of major depression and treated mean desmethylsertraline/sertraline ratio It is of considerable interest that in primary care. The details of the study T2 SDs interval (back transformed from whereas a majority of the noncompliant are reported by A˚ kerblad et al,13 but the log scale to original scale) was between patients admitted being noncompliant when main objective was to measure the effect 1.30 and 5.85. questioned, it was acknowledged only by of an educational compliance enhance- Six hundred twenty patients were a minority of the partially noncompliant ment program and the effect of TDM defined as compliant according to the patients. The validity of the concept of (presence or absence of sertraline in definition. Ninety-six patients had a partial noncompliance is further strength- serum) on drug compliance and treatment desmethylsertraline/sertraline ratio out- ened by the different response rates found response. Included in the present study are side T2 SDs. Of these, 81 patients had at between patients with full compliance and the 782 patients (mean age, 50 years; least 1 ratio deviating more than 50% patients with partial noncompliance. range, 19Y95 years; 73% women) from from his/her own mean ratio or no quan- The number of compliant and par- the original study13 who had completed tifiable metabolite and were consequently tially noncompliant patients is of the same 24 weeks’ treatment with sertraline dosed defined as partially noncompliant. Equally magnitude, indicating, in line with earlier according to the clinical routine. Sched- many, 81 patients, were defined as non- results,5 that partial noncompliance is an uled visits were at weeks 4, 12, and 24, compliant. To exclude that a drug-drug important problem. By using conventional and at each visit, the patients were asked interaction could be the cause of a devi- dichotomized TDM technique (presence or if the drug had been taken as prescribed. ating ratio, all concomitant medications absence of parent compound in serum), To be regarded as compliant, a Byes[ had taken by patients with deviating ratios or partially noncompliant patients will not be to be recorded at all 3 visits. Treatment with unquantifiable samples were com- found. response was assessed by means of the pared with all pharmacokinetic C and D Identifying partially noncompliant Montgomery-A˚ sberg Depression Rating interactions listed in the Swedish physi- patients is of great importance to under- Scale14 and the 2 Clinical Global Impres- cian desk reference book (FASS) and in stand insufficient treatment response. Ther- sion scales, Severity and Improvement.15 Swedish Finnish Interaction X-referencing apeutic drug monitoringYratio screening Extensive training sessions were held for (SFINX). method, as described, can be applied in all participating general practitioners. To Partial noncompliance and total non- everyday clinical practice. However, the be classified as a responder at week 24, compliance were about equally common methodhasnotyetbeentestedonother the patient had to have a reduction from in men and in women; 27.2% of the drugs than sertraline. Thus, the results baseline in total Montgomery-A˚ sberg De- noncompliant patients and 35.8% of the should not be generalized to other drugs pression Rating Scale of at least 50%, a partially noncompliant patients were men before further studies are made. Clinical Global ImpressionYSeverity score indicating normal to mildly ill, and a Clin- ical Global ImpressionYImprovement score indicating much or very much improved. TABLE 1. Relationship Between Compliance According to TDM-RSM and Finally, serum drug concentration samples Response to Treatment After 24 Weeks of Treatment With Sertraline were obtained as trough values under steady-state conditions. The serum samples Compliance According to TDM-RSM Response at Week 24 (LOCF) were all analyzed at the same laboratory using an established validated high- nn performance liquid chromatography with Noncompliance 81 46 (56.8%) ultraviolet detection.16 The limit of quan- Partial noncompliance 81 56 (69.1%) tification was 1.53 ng/mL (5 nmol/L). Compliance 620 511 (82.4%) 2 According to the published TDM- W 2 = 32.34, P G 0.001 12 RSM, patients with quantifiable serum LOCF indicates last observation carried forward. concentrations of sertraline and desmeth-

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Y AUTHOR DISCLOSURE psychiatry. Pharmacopsychiatry. vious drug exposures,2 4 a phenomenon INFORMATION 2004;37(6):243Y265. referred to as stepwise tachyphylaxis.4 Grants from the Swedish Medical 10. Hiemke C. Therapeutic drug monitoring Biological and/or psychological mech- Research Council (4345, Finn Bengtsson; in neuropsychopharmacology: does it hold anisms may explain the association between 15231, Lisa Ekselius). The original study its promises? Eur Arch Psychiatry Clin previous antidepressant history and sub- from which data are taken was sponsored Neurosci. 2008;258(suppl 1):21Y27. sequent decrements in response. Previous by Pfizer AB, Sweden. 11. Preskorn SH, Fast GA. Therapeutic drug antidepressant treatment overlaps with monitoring for antidepressants: efficacy, Btreatment-resistant depression,[ defined safety, and cost effectiveness. J Clin as 1 or more failed antidepressant trials in Margareta Reis, PhD 5,6 Department of Medical and Health Sciences Psychiatry. 1991;52(suppl 8):23Y33. the current episode. In this view, pre- Clinical Pharmacology 12. Reis M, A˚ berg-Wistedt A, A˚ gren H, et al. vious treatment might serve as a proxy Linko¨ping University Compliance with SSRI medication during for an inherently less tractable form or Linko¨ping, Sweden 6 months of treatment for major depression: course of depression or a form or course of [email protected] an evaluation by determination of repeated depression that is less responsive to in- Ann-Charlotte A˚ kerblad, PhD serum drug concentrations. J Affect Disord. tervention with conventional pharmaco- Y Lisa Ekselius, MD, PhD 2004;82(3):443 446. logical agents. Tolerance mechanisms also 13. A˚ kerblad AC, Bengtsson F, Ekselius L, et al. may operate such that repeated exposure Lars von Knorring, MD, PhD to antidepressant medication itself begets Department of Neuroscience, Psychiatry Effects of an educational compliance Uppsala University enhancement programme and therapeutic physiological adaptation and correspond- Uppsala, Sweden drug monitoring on treatment adherence in ing diminution of clinical response. In this depressed patients managed by general vein, stepwise tachyphylaxis has been ob- practitioners. Int Clin Psychopharmacol. served independent of treatment-resistant Y 2 REFERENCES 2003;18(6):347 354. depression. Psychological mechanisms as 14. Montgomery SA, A˚ sberg M. A new well, including patient expectations, nega- 1. Frank E, Perel JM, Mallinger AG, et al. depression scale designed to be sensitive tive cognitions, and classical conditioning Relationship of pharmacologic compliance to to change. Br J Psychiatry. 1979;134: phenomena, may play a role in decreased long-term prophylaxis in recurrent depression. 382Y389. response after previous antidepressant fail- Psychopharmacol Bull. 1992;28(3):231Y235. 7 15. Guy W. Clinical Global Impression, ure. Previous treatment has been shown 2. Melfi CA, Chawla AJ, Croghan TW, et al. 8 in ECDEU Assessment Manual for as a factor in placebo response as well The effects of adherence to antidepressant Psychopharmacology. Rev. Rockville, MD: as medication response, but the potential treatment guidelines on relapse and National Institute of Health, differential impact across treatments is recurrence of depression. Arch Gen Psychopharmacology Research Branch; 1976. not known. Psychiatry. 1998;55(12):1128Y1132. 16. Bjo¨rk H, Bengtsson F. A simple method for We addressed the relationship be- ˚ 3. Akerblad AC, Bengtsson F, von Knorring L, routine TDM of the SSRI sertraline and tween treatment history and subsequent et al. Response, remission and relapse in desmethylsertraline in serum by HPLC. medication and placebo treatment out- relation to adherence in primary care treatment Eur J Clin Pharmacol. 1997;52(suppl):A156. comes examining data from 72 Major of depression: a 2-year outcome study. Int Y Depressive Disorder (MDD) outpatient Clin Psychopharmacol.2006;21(2):117 124. subjects who completed 1 of 3 double- 4. Gopinath S, Katon WJ, Russo JE, et al. blind placebo-controlled antidepressant Clinical factors associated with relapse in Impact of Antidepressant treatment trials9 at the UCLA Laboratory primary care patients with chronic or Treatment History on of Brain, Behavior, and Pharmacology. recurrent depression. J Affect Disord. The trials used identical recruitment pro- Y Y Clinical Outcomes in 2007;101(1 3):57 63. cedures, inclusion/exclusion criteria, and 5. Noble L. Doctor-Patient Communication Placebo and Medication design features except for the active med- and Adherence to Treatment, in Adherence Treatment of Major ication (fluoxetine or venlafaxine). Sub- to Treatment in Medical Conditions. jects did not differ significantly across Myers L, Midence K, eds. London: Wiley; Depression trials on age, sex, or symptom severity. Y 1998:51 82. Screening consisted of a standard clinical 6. Demyttenaere K, Enzlin P, Dewe´ W, et al. evaluation, a structured clinical interview Compliance with antidepressants in a primary To the Editors: (Structured Clinical Interview for Axis I care setting, 1: beyond lack of efficacy revious courses of antidepressant treat- DSM-IV DisordersYPatient Edition, ver- and adverse events. JClinPsychiatry. ment have been related to subsequent sion 2.0),10 and the 17-item Hamilton De- 2001;62(suppl 22):30Y33. P 11 decrements in medication response. The pression Rating Scale (HamD17). Persons 7. Cantrell CR, Eaddy MT, Shah MB, et al. Sequenced Treatment Alternatives to Re- having psychotic symptoms or cluster A or Methods for evaluating patient adherence lieve Depression Trial, for example, used a B Axis II disorders were excluded. Enrollees to antidepressant therapy: a real-world design where subjects who did not remit had HamD17 scores of 16 or higher at entry comparison of adherence and economic during initial citalopram treatment received and were free of psychotropic medications outcomes. Med Care. 2006;44(4):300Y303. successive treatment alternatives until for 2 weeks prior. 8. Olfson M, Marcus SC, Tedeschi M, et al. achieving remission or reaching the end of All subjects received a 1-week pla- Continuity of antidepressant treatment for 4 treatment levels. An overarching finding cebo lead-in before 8 weeks of ran- adults with depression in the United States. was that of progressively lower rates of re- domized double-blind treatment with Am J Psychiatry. 2006;163(1):101Y108. sponse and remission observed at each medication (fluoxetine 20 mg or venla- 1 9. Baumann P, Hiemke C, Ulrich S, et al. The level. Retrospective studies also have found faxine 150 mg; n = 37) or placebo AGNP-TDM expert group consensus lower rates of antidepressant response as- (n = 35).9 Venlafaxine was dosed at guidelines: therapeutic drug monitoring in sociated with an increased number of pre- 150 mg after 10 days; fluoxetine dosing

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TABLE 1. Clinical and Demographic Characteristics of the Sample by Treatment Assignment and Treatment History

Total Sample Medication Group Placebo Group Treatment-Naive Treatment-Experienced (n = 72) (n = 37) (n = 35) Test (n = 31) (n = 41) Test

Age, y (TSD) 41.68 (12.08) 42.73 (12.30) 40.57 (11.91) t70 = j0.76; 40.48 (12.33) 42.59 (11.96) t70 = j0.73; P = 0.45 P = 0.47 Sex (% female) 60% 62% 57% W2 = 0.19; 45% 71% W2 = 4.80; P = 0.66 P = 0.03* Treatment history 57% 57% 57% W2 = 0.001; NA NA NA (% previously treated) P = 0.97

Depression severity 20.43 (6.53) 20.00 (6.90) 20.89 (6.18) t70 = 0.57; 20.65 (6.31) 20.27 (6.76) t70 = 0.24; Initial HamD17 (TSD) P = 0.57 P = 0.81 Family history of MDD 80% 78% 83% W2 = 0.29; 70% 88% W2 = 3.47; (% yes) P = 0.59 P = 0.06

No. previous episodes 2.39 (1.68) 2.68 (1.65) 2.09 (1.69) t70 = j1.50; 2.0 (1.03) 2.68 (2.00) t70 = j1.73; P = 0.14 P = 0.09 *P G 0.05. NA indicates not applicable.

was 20 mg/d. Placebo was administered history Â treatment type interaction improvement over 8 weeks of randomized on the same schedule as active drug within (F1,68 = 7.63, P = 0.007). treatment than did antidepressant-naive each trial to preserve blinding. In this Subsequent ANCOVAs examining subjects; however, the effect of previ- reanalysis, subjects were classified as medication and placebo subjects sepa- ous treatment depended significantly on either Bantidepressant-experienced[ or rately found that, among placebo subjects, treatment condition. In this sample, treat- Bantidepressant-naive[ based on historical treatment history was a significant pre- ment history had a negative impact on information recorded at intake indicating dictor (F3,33 = 9.68, P = 0.004) with placebo response but not on medication whether they had ever before been treated R2 = 0.23 and remained significant when response. One consequence of this differen- with an antidepressant medication. Clini- controlling for baseline illness severity, tial impact of treatment history on medica- cal outcomes included change in total sex, number of previous episodes, and tion versus placebo outcomes was that, HamD17 score from baseline to week family history of MDD (F5,29 = 9.18, whereas analysis of the total sample did 8 and remission (final HamD17, e7). P = 0.005). However, ANCOVAs used to not find significant drug-placebo separa- Antidepressant-experienced subjects examine these same models of symptom tion, analyses that were limited to treatment- (n = 31) did not differ from antidepressant- change in medication subjects were not experienced subjects found a statistically naive subjects (n = 41) with respect to age significant. We then used W2 analysis to higher rate of remission in the medication or baseline symptom severity (Table 1). examine remission rates to drug versus group. However, antidepressant-experienced sub- placebo for antidepressant-naive and Our observation of greater placebo jects were statistically more likely to be antidepressant-experienced subgroups. response among antidepressant-naive sub- female and showed trends toward a Whereas there was no statistically signif- jects is consistent with previous findings.8 greater number of previous episodes and icant separation between medication and One possible explanation for the ob- a greater likelihood of family history placebo remission rates in the total served greater placebo response among of MDD. Analysis of covariance sample (W2 = 1.58, P = 0.21) or in the antidepressant-naive subjects is that they (ANCOVA) was used to examine treat- antidepressant-naive subgroup (W2 = 0.26, were simply less ill. Indeed, placebo re- ment history (antidepressant-experienced P = 0.61), significant drug-placebo sep- sponse has previously been associated with or antidepressant-naive) along with sex, aration was observed in the analysis shorter duration of the depressive episode8 9Y12 baseline symptom severity (HamD17), and including only treatment-experienced sub- and less severe illness. Accordingly, treatment history Â treatment type (med- jects (W2 =5.24,P = 0.02). Among previous reports have consistently found ication or placebo) interaction as potential antidepressant-naive subjects, there was an association between greater depres- covariates to model change in HamD17 no significant difference in change in sion severity and greater drug-placebo 13Y17 score over 8 weeks (dependent variable) HamD17 scores between subjects who separation. In this study, however, in the total sample. The overall model was were randomized to medication (mean, treatment history was not associated with significant (F3,68 = 3.66, P = 0.009) with j12.19; SD, 5.74) versus placebo (mean, symptom severity at intake. Although a significant effect of treatment history j12.33; SD, 5.69) (t29 = 0.03, P = 0.98). antidepressant-experienced subjects showed (F1,68 = 12.43, P = 0.001). Subjects with In contrast, among antidepressant- a trend toward a greater number of pre- no previous history of medication treat- experienced subjects, HamD17 change vious episodes, and a greater likelihood of ment showed greater symptom improve- was significantly greater in medication family history of MDD, treatment history ment on the HamD17 (mean change, subjects (mean, j10.90; SD, 7.18) as was shown to predict placebo response j12.16; SD, 5.62) than did those subjects compared with placebo subjects (mean, even when controlling for these clinical who had previously received antidepres- j5.20; SD, 7.08) (t39 = 2.56, P = 0.01). characteristics. Another possibility is that sant treatment (mean, j8.12; SD, 7.61). the antidepressant-experienced subjects There was no evidence of an effect of were better able to correctly guess their sex (F1,68 = 0.35, P = 0.56) or symptom DISCUSSION treatment condition based on previous ex- severity (F1,68 = 0.02, P = 0.90). How- Overall, subjects with a previous his- perience with medication, including side ever, there was a significant treatment tory of antidepressant treatment showed less effects, and that this de facto Bunblinding[

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 rendered them less likely to respond on a consultant to Ascend Media, Bristol- antidepressant drug exposure in patients placebo. Treatment-naive subjects on pla- Myers Squibb, Cyberonics, Eli Lilly and with recurrent major depressive disorder. cebo may have been more likely to be- Company, Forest Laboratories, Janssen, Neuropsychobiology. 2009;59(4):227Y233. lieve that they were receiving medication. Neuronetics, Scale Venture Partners, and 5. Thase ME, Rush AJ. When at first you Subjects_ greater expectations that they the US Department of Justice; and has don_t succeed: sequential strategies for will receive active medication have been been a member of the speakers’ bureau for antidepressant nonresponders. JClin linked to higher placebo response rates,12,14 Bristol-Myers Squibb, CME LLC, Medical Psychiatry. 1997;58(suppl 13):23Y29. whereas lower expectations of receiving ac- Education Speakers Network, Pfizer, and 6. Nierenberg AA, Papakostas GI, Petersen T, tive medication have been linked to lower Wyeth. Dr Cook is not a shareholder in any et al. Nortriptyline for treatment resistant placebo response rates and, hence, greater pharmaceutical or medical device com- depression. J Clin Psychiatry. 2003;64: 16 drug-placebo separation. pany; his patents are assigned to the Uni- 35Y39. We did not find a significant effect of versity of California. 7. Leuchter AF, Cook IA, Hunter AM, et al. treatment history in the medication group. Andrew Leuchter, MD, has provided A new paradigm for the prediction of 2Y4 Differences between previous reports scientific consultation or served on advi- antidepressant treatment response. Dialogues and the present finding may be due to sory boards for Aspect Medical Systems, Clin Neurosci. 2009;11(4):435Y446. treatment history measures or the medi- Bristol-Myers Squibb, Eli Lilly and Com- 8. Brown WA, Johnson MF, Chen MG. Clinical cations studied. We examined antidepres- pany, Merck & Co., Otsuka Pharmaceu- features of depressed patients who do and sant treatment history as a dichotomous ticals, and Pfizer. He has served on a do not improve with placebo. Psychiatry Res. variable accounting for lifetime treatment speaker’s bureau for Bristol-Myers Squibb, 1992;41(3):203Y214. history, whereas other reports examined Eli Lilly and Company, Otsuka Pharma- 9. Cook IA, Hunter AM, Abrams M, et al. treatment history in the current episode, ceuticals, and Wyeth-Ayerst Pharmaceu- 4 Midline and right frontal brain function as a stratified by number of previous trials. ticals. He has received research/grant physiologic biomarker of remission in major Regarding medication, 24 of 37 of our support from the National Institute of depression. Psychiatry Res. 2009;174(2): medication subjects had been treated with Mental Health, the National Center for 152Y157. a mixed reuptake inhibitor medication, Complementary and Alternative Medicine, venlafaxine, whereas previous reports Aspect Medical Systems, Eli Lilly and 10. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV have suggested greater tachyphylaxis with Company, Wyeth-Ayerst Pharmaceuticals, Axis I Disorders Y Patient Edition (SCID-I/P, selective serotonin reuptake inhibitor Merck & Co., Pfizer, Sepracor, Vivometrics, 18,19 Ve r s io n 2 .0 ). New York: Biometrics Research medications. and MedAvante. He also is a former equity Department, New York State Psychiatric Results of this study suggest that shareholder in Aspect Medical Systems. Institute; 1996. previous treatment may be an important factor in determining placebo response 11. Hamilton M. A rating scale for depression. Aimee M. Hunter, PhD JNeurolNeursurgPsychiatry. 1960;23:56Y62. and drug-placebo separation in placebo- controlled antidepressant treatment trials Ian A. Cook, MD 12. Stein DJ, Baldwin DS, Dolberg OT, et al. in MDD. Future work should replicate Andrew F. Leuchter, MD Which factors predict placebo response in results in a larger sample and should Laboratory of Brain, Behavior anxiety disorders and major depression? examine expanded aspects of previous and Pharmacology An analysis of placebo-controlled studies of treatment by systematically obtaining in- and the Depression Research and escitalopram. JClinPsychiatry. 2006;67(11): 1741Y1746. formation regarding the number and ade- Clinic Program Semel Institute for Neuroscience quacy of trials and nature of response.20 13. Khan A, Leventhal RM, Khan SR, et al. and Human Behavior at University of Severity of depression and response to Y California Los Angeles antidepressants and placebo: an analysis of Department of Psychiatry the Food and Drug Administration database. ACKNOWLEDGMENTS and Biobehavioral Sciences J Clin Psychopharmacol. 2002;22(1):40Y45. This work was supported by grants David Geffen School of Medicine from the National Institute of Mental at University of CaliforniaYLos Angeles 14. Khan A, Kolts RL, Thase ME, et al. Research Health, Eli Lilly and Company, Wyeth- Los Angeles, CA design features and patient characteristics Ayerst Laboratories, and Aspect Medical [email protected] associated with the outcome of antidepressant Systems. clinical trials. Am J Psychiatry. 2004;161(11): The authors thank Michelle Abrams, 2045Y2049. REFERENCES RN, for data collection and patient 15. Khan A, Schwartz K, Kolts RL, et al. evaluation. 1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Relationship between depression severity Acute and longer-term outcomes in depressed entry criteria and antidepressant clinical outpatients requiring one or several treatment trial outcomes. Biol Psychiatry. 2007; AUTHOR DISCLOSURE steps: a STAR*D Report. Am J Psychiatry. 62(1):65Y71. Y INFORMATION 2006;163:1905 1917. 16. Papakostas GI, Fava M. Does the probability Aimee Hunter reports no financial 2. Amsterdam JD, Maislin G, Potter L. of receiving placebo influence clinical trial conflicts of interest. Fluoxetine efficacy in treatment resistant outcome? A meta-regression of double blind In the past 5 years, Dr Cook has depression. Prog Neuropsychopharmacol randomized clinical trials in MDD. Eur received grant support from Aspect Med- Biol Psych. 1994;18(2):243Y261. Neuropsychopharmacol. 2009;19(1):34Y40. ical Systems, Cyberonics, Eli Lilly and 3. Amsterdam JD, Shults J. MAOI efficacy and 17. Fournier JC, DeRubeis RJ, Hollon SD, et al. Company, the John A. Hartford Founda- safety in advanced stage treatment-resistant Antidepressant drug effects and depression tion, MedAvante, the National Institutes depressionYa retrospective study. J Affect severity: a patient-level meta-analysis. JAMA. of Health, Neuronetics, Novartis, Pfizer, Disord. 2005;89(1Y3):183Y188. 2010;303(1):47Y53. Vivometrics, and the West Coast College 4. Amsterdam JD, Williams D, Michelson D, 18. Posternak MA, Zimmerman M. Dual of Biological Psychiatry; has served as et al. Tachyphylaxis after repeated reuptake inhibitors incur lower rates of

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tachyphylaxis than selective serotonin regions in subjects treated with antidepres- Disorders, Fourth Edition criteria. All de- reuptake inhibitors: a retrospective study. sant medications at the time of death, com- pressed PD patients had a score of at least J Clin Psychiatry. 2005;66(6):705Y707. pared with untreated depressed subjects,10 16 points at the 21-item Hamilton Rating 19. Thase ME, Entsuah AR, Rudolph RL. whereas the brains of depressed patients Scale for Depression. Remission rates during treatment with showed decreased levels of GDNF in limbic All patients were treated with 11 venlafaxine or selective serotonin reuptake areas and basal ganglia. It is interesting levodopa/carbidopa alone or in combina- inhibitors. Br J Psychiatry. 2001;178: that some second-generation antipsychotic tion with DA agonists (bromocriptine, 234Y241. drugs, such as olanzapine, also increase selegiline, biperiden, amantadine, and pra- 20. Posternak MA, Young D, Sheeran T, et al. BDNF serum levels in schizophrenic mipexole). Depressed patients with Par- Assessing past treatment history: test-retest patients, generating the idea that these drugs kinson disease also received daily doses reliability of the Treatment Response to may have a neuroprotective action in the of selective serotonin reuptake inhibitors 12 Antidepressant Questionnaire. J Nerv mesolimbic DA system. Basedonthese (SSRIs) (50Y150mg/dsertraline,20mg/d Ment Dis. 2004;192(2):95Y102. findings a plausible hypothesis is that de- citalopram, and 20 mg/d paroxetine) ac- pressed patients with Parkinson disease cording to the medical judgment and psy- could have altered BDNF or GDNF levels chopathological status. and that antidepressant drugs may restore Venous blood was collected into Antidepressant Treatment them and, potentially, have beneficial ef- sampling tubes that were centrifuged Restores Brain-Derived fects for depressive as well as parkinsonian within 20 minutes after sampling at 2000g symptoms. for 20 minutes. Serum was then aliquoted Neurotrophic Factor Serum With this in mind, the aim of our and stored at j80-C until analysis. Levels and Ameliorates study was (a) to investigate whether de- BDNF (cat. N- DY248; R&D Systems) Motor Function in Parkinson pressed patients with Parkinson disease and GDNF (cat. N- G7620; Promega) had altered peripheral levels of trophic were detected in sandwich enzyme-linked Disease Patients factors, when compared with nonde- immunosorbent assays according to the pressed PD patients and healthy subjects, instructions of manufacturers. All assays and (b) explore the possibility that anti- were performed on F-bottom 96-well plates To the Editors: depressant drugs, in conjunction with (Nunc, Wiesbaden, Germany). The de- ne working hypothesis for motor antiparkinsonian drugs, may either induce tection limits for BDNF and GDNF were O disturbances observed in Parkinson the expression of these factors or signifi- 15 pg/mL. Measurements were performed disease (PD) is that the degeneration of the cantly modify clinical outcome of de- in duplicate, and values are expressed as dopaminergic (DA) neurons of the sub- pressed patients with Parkinson disease. nanograms per milliliter (BDNF) and pico- stantia nigra pars compacta and the re- Thus, we measured by enzyme-linked im- grams per milliliter (GDNF). sulting loss of their nerve terminals in the munosorbent assay the serum levels of Comparisons among the experimen- striatum are due to decreased levels of tro- BDNF and GDNF in depressed patients tal groups (PD patients, depressed patients phic factors,1 survival factors for selected with Parkinson disease, nondepressed with Parkinson disease with or without populations of central nervous system patients, and healthy subjects and corre- antidepressants, and healthy subjects) on neurons. lated them with clinical observations. BDNF and GDNF serum levels were per- A body of evidence describes the We included in the study 46 patients formed using univariate analyses of vari- protective role of brain-derived neuro- with idiopathic PD recruited from the ance followed by Fisher protected least trophic factor (BDNF)2 on midbrain DA Movement Disorders Clinic of Catholic significant difference post hoc test. The W2 neurons, whereas glial cellYderived neu- University of Sacred Heart, Policlinico test was used to compare categorical data. rotrophic factor (GDNF), which belongs Gemelli, Rome. Twenty-six of these Statistical significance was set at P G 0.05. to a family of related proteins that inpatients had the diagnosis of major de- There were no significant differences clude neurturin, artemin, and persephin, pression disorder according to the Diag- in age and sex between PD patients and supports the development and survival of nostic and Statistical Manual of Mental healthy subjects. Depressed and nonde- mesencephalic DA neurons.3 These find- Disorders, Fourth Edition criteria, and 15 pressed PD patients did not differ in dis- ings have generated considerable excite- of them were under antidepressant treat- ease duration, disease stage (Hoehn and ment about the possibility to establish a ment. Patients were excluded if they had a Yahr Scale), and evaluation of motor therapy with neurotrophic factors for PD. history of seizures, major head trauma, (UPDRS III) or mental (Mini Mental State Interestingly,antidepressant drugs may dementia, previous neurological surgeries, Examination) function. The group of de- bust brain production of trophic factors, an or psychotic symptoms. Patients were also pressed PD patients was characterized by effect associated with improvement of clin- excluded if they were seropositive for significantly higher scores in depression, ical symptoms. Depression is a common HIV or if they had a history of alcohol melancholia, and pleasure scales and psychiatric disorder in PD occurring in ap- abuse or dependence and addiction to presence of negative symptoms as com- proximately half of patients.4 Preclinical drugs. Fourteen control subjects individ- pared with nondepressed PD patients. studies have found that chronic antidepres- ually matched with the PD patients with Analysis of variance showed a sig- sant treatment increases the expression of regard to age, sex, and education level nificant main effect (P G 0.0001) for BDNF and neurogenesis in the adult rat were recruited. BDNF levels (Fig. 1). Post hoc compar- hippocampus,5,6 and intracerebral infusion Neurological evaluation of PD pa- isons showed that PD depressed and non- of BDNF itself produces antidepressant tients was conducted during the ON-state depressed patients had lower BDNF serum effects.7 Also, the mood stabilizers, lithium and included the Hoehn and Yahr Scale levels as compared with healthy subjects and valproate, increase GDNF levels, both and the Unified Parkinson Disease Rating (P G 0.001 and P G 0.05, respectively). In in vivo and in vitro.8,9 Consistent with these Scale (UPDRS, motor part III). Depres- addition, in PD patients, depression fur- animal studies, increased BDNF expression was diagnosed according to Diag- ther reduced BDNF as compared with sion was recently found in hippocampal nostic and Statistical Manual of Mental nondepressed PD patients (P G 0.01). Vice

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FIGURE 1. Brain-derived neurotrophic factor serum levels in PD patients and healthy subjects. Data are the mean T SEM. Values are expressed in nanograms per milliliter. Asterisk indicates significant difference between the groups. *P G 0.05, **P G 0.01, ***P G 0.001. versa treatment with antidepressant drugs a worsening of clinical state. This hy- tions appear in the printed text and are restored BDNF to levels similar to those pothesis is somehow supported and re- provided in the HTML and PDF versions of healthy subjects, as shown in Figure 1. vealed by the finding that depressed PD of this article on the Journal’s Web site No significant main effect for GDNF patients, although treated with antiparkin- (www.psychopharmacology.com). serum levels was observed. Furthermore, sonian drugs, display a significant worsen- post hoc analyses did not reveal signifi- ing of motor function, as measured by cant differences among groups. Depressed UPDRS Scale. Valerio Ricci, MD patients with Parkinson disease showed If this is true, then we can assume Department of Clinical and GDNF serum levels comparable to those that a therapeutic approach for depression Behavioral Neurology of nondepressed patients. Also, antide- may also produce beneficial effects on PD IRCCS Santa Lucia Foundation pressant treatment did not significantly and that antidepressant and antiparkin- and Institute of Psychiatry Catholic University alter GDNF levels. sonian drugs may interact in producing Rome, Italy Unified Parkinson Disease Rating beneficial effects on central nervous sys- Scale III values were compared in de- tem neurons. Supporting this notion, some Massimiliano Pomponi, MD pressed, nondepressed, and antidepres- studies have evidenced that sertraline, an Giovanni Martinotti, MD Institute of Psychiatry sant-treated PD patients to evaluate the SSRI, is useful for treating depression in Catholic University differences in motor function among PD without aggravating or even improv- Rome, Italy groups. We found that depressed patients ing19 parkinsonian symptoms, whereas Annarita Bentivoglio, MD were characterized by a greater deficit in the antiparkinsonian agent, selegiline, motor function as compared with nonde- exerts neuroprotective effects by modu- Giovanna Loria, MD Institute of Neurology pressed PD patients (P G 0.01), but anti- lating BDNF production in selected areas 20 Catholic University depressant treatment reversed this deficit. of the mouse brain. Rome, Italy In fact, antidepressant-treated PD patients In conclusion, this study indicates Sergio Bernardini, MD showed UPDRS values comparable to those that PD patients are characterized by a Department of Internal Medicine of nondepressed PD patients (see Supple- reduction of BDNF serum levels and that Tor Vergata University mental Tables 1 to 4, Supplemental Digital depression may exacerbate this effect and Rome, Italy Content 1, http://links.lww.com/JCP/A32 and worsen PD symptoms. Given the simul- Carlo Caltagirone, MD Supplemental Figure 2, Supplemental Digital taneous action of BDNF on DA and se- Department of Clinical and Content 2, http://links.lww.com/JCP/A33). rotonergic neurons, it is proposed that Behavioral Neurology Thus, our data indicate that depres- association between antiparkinsonian treat- IRCCS Santa Lucia Foundation sion can potentially represent an adjunc- ment and SSRI could be a good therapeu- Rome, Italy tive worsening factor for PD symptoms tic chance not only for treating depression Pietro Bria, MD and that BDNF is implicated in these events. in PD but also for improving PD symptoms. Institute of Psychiatry Catholic University Indeed, BDNF may have a common role in Rome, Italy PD and depression. Decreased levels of Francesco Angelucci, PhD BDNF in the substantia nigra pars com- AUTHOR DISCLOSURE Department of Clinical and pacta in postmortem examinations of PD INFORMATION Behavioral Neurology 13 patients have been detected, whereas in The authors have no conflicts of in- IRCCS Santa Lucia Foundation depression, a reduced BDNF synthesis has terest to report. This work was supported Rome, Italy been repeatedly demonstrated in brain re- by the Italian Ministry of Health. The [email protected] gions of humans and animal models.14,15 funding source had no involvement in Moreover, alteration of different monoam- study design; in the collection, analysis, inergic pathways, such as noradrenergic and interpretation of data; in the writing REFERENCES and serotonergic projection, which are de- of the report; and in the decision to submit 1. Connor B, Dragunow M. The role of 16 fective in depression, has been also the paper for publication. neuronal growth factors in neurodegenerative 17,18 reported in PD, suggesting that most Supplemental digital contents are disorders of the human brain. Brain Res probably the 2 diseases interact in producing available for this article. Direct URL cita- Brain Res Rev. 1998;27:1Y39.

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2. Castreń E. Neurotrophins as mediators of 15. Brunoni AR, Lopes M, Fregni F. CASE REPORT drug effects on mood, addiction, and A systematic review and meta-analysis of The patient was a 36-year-old nurse, neuroprotection. Mol Neurobiol. clinical studies on major depression and married with 2 children ages 10 and 14 2004;29:289Y302. BDNF levels: implications for the role of years, and her medical and family history neuroplasticity in depression. Int J 3. Lin LF, Doherty DH, Lile JD, et al. GDNF: was significant only for migraine. a glial cell lineYderived neurotrophic Neuropsychopharmacol. 2008;11: 1169Y1180. Six years earlier, she had received a di- factor for midbrain dopaminergic neurons. agnosis of migraine without aura. Al- Science. 1993;260:1130Y1132. 16. Krishnan V, Nestler EJ. The molecular though her migraine attacks at first had neurobiology of depression. Nature. 4. Cantello R, Aguggia M, Gilli M, et al. occurred 2 to 3 times per month, they had 2008;455:894Y902. Major depression in Parkinson’s disease become more frequent in the last 2 years and the mood response to intravenous 17. Scatton B, Javoy-Agid F, Rouquier L, et al. andhadbeguntooccur6to7timesper methylphenidate: possible role of the Reduction of cortical dopamine, month. One year ago, for migraine pro- B [ hedonic dopamine synapse. J Neurol noradrenaline, serotonin and their metabolites phylaxis, 150 mg/d of venlafaxine therapy Y in Parkinson’s disease. Brain Res. Neurosurg Psychiatry. 1989;52:724 731. was started. Because of its benefit in re- 1983;275:321Y328. 5. Malberg JE, Eisch AJ, Nestler EJ, et al ducing the patient’s migraine attacks, the Chronic antidepressant treatment increases 18. Chen CP, Alder JT, Bray L, et al. drug was continued. In the past 1 month, neurogenesis in adult rat hippocampus. Post-synaptic 5-HT1A and 5-HT2A the patient reported a complaint of ga- J Neurosci. 2000;20:9104Y9110. receptors are increased in Parkinson’s lactorrhea occurring without any pain in disease neocortex. Ann N Y Acad Sci. 6. Nibuya M, Morinobu S, Duman RS. or enlargement of the breasts. She addi- 1998;861:288Y289. Regulation of BDNF and trkB mRNA in rat tionally complained of menstrual irregu- brain by chronic electroconvulsive seizure 19. Barone P, Scarzella L, Marconi R, et al. larities. She said that her period lasted and antidepressant drug treatments. Pramipexole versus sertraline in the longer than normal and involved a greater Y J Neurosci. 1995;15:7539 7547. treatment of depression in Parkinson amount of bleeding (menometrorrhagia). disease: a national multicenter parallel-group 7. Shirayama Y, Chen AC, Nakagawa S, et al. To investigate these complaints, serum randomized study. J Neurol. 2006;253: Brain-derived neurotrophic factor produces 601Y607. levels of prolactin, follicle-stimulating hor- antidepressant effects in behavioral models of mone, luteinizing hormone, progesterone, depression. JNeurosci. 2002;22:3251Y3261. 20. Gya´rfa´s T, Knuuttila J, Lindholm P, et al. and estradiol were examined in the follic- Regulation of brain-derived neurotrophic 8. Castro LM, Gallant M, Niles LP. Novel ular phase and were found to be within factor (BDNF) and cerebral dopamine targets for valproic acid: upregulation of neurotrophic factor (CDNF) by normal limits. Thyroid hormones were also melatonin receptors and neurotrophic anti-parkinsonian drug therapy in vivo. within normal limits. To look for pituitary factors in C6 glioma cells. J Neurochem. Cell Mol Neurobiol. 2010;30: pathology, cranial magnetic resonance im- 2005;95:1227Y1236. 361Y368. aging was done, and findings were normal. 9. Angelucci F, Aloe L, Jimenez-Vasquez P, Ultrasound investigations of breasts and et al. Lithium treatment alters brain pelvis also gave normal findings. In the concentrations of nerve growth factor, patient’s gynecologic, endocrinologic, and brain-derived neurotrophic factor and breast examinations, no pathological lesion glial cell lineYderived neurotrophic factor Late-Onset Galactorrhea was evident. Because of the possibility that in a rat model of depression. Int J and Menometrorrhagia the patient’s symptoms were arising from Neuropsychopharmacol. 2003;6: venlafaxine use, the drug was tapered and 225Y231. With Venlafaxine Use in stopped. The patient’s galactorrhea stopped 10. Chen B, Dowlatshahi D, MacQueen GM, a Migraine Patient within 2 weeks after cessation of the drug, et al. Increased hippocampal BDNF and the menometrorrhagia stopped within immunoreactivity in subjects treated with 4 weeks. An objective causality assessment antidepressant medication. Biol Psychiatry. using the Naranjo Probability Scale sug- To the Editors: 2001;50:260Y265. gested that venlafaxine was the probable 11. Michel TM, Frangou S, Camara S, et al. enlafaxine is a dual-effect antidepres- cause of the galactorrhea and menomet- Altered glial cell lineYderived Vsant. It is a reuptake inhibitor of both rorrhagia.4 (The scale score was 6.) 1 neurotrophic factor (GDNF) concentrations serotonin (5-HT) and norepinephrine. in the brain of patients with depressive While mainly inhibiting 5-HT reuptake at disorder: a comparative post-mortem study. low doses, at higher doses it also mod- DISCUSSION Eur Psychiatry. 2008;23:413Y420. erately inhibits norepinephrine reuptake, Although the occurrence of galac- 12. Rizos EN, Papadopoulou A, Laskos E, et al. and only at high doses do its slight effects torrhea secondary to venlafaxine use is Reduced serum BDNF levels in patients with as a dopamine (DA) reuptake inhibitor very rare, it has been reported in the lit- 1 5,6 chronic schizophrenic disorder in relapse, appear. Venlafaxine is indicated for use erature. The possibility of menorrhagia who were treated with typical or atypical in the treatment of psychiatric conditions and/or menstrual irregularities has also antipsychotics. World J Biol Psychiatry. such as major depression and generalized been reported in premarketing and post- 2010;11:251Y255. anxiety disorder. In recent studies, it has marketing data. However, we did not en- 13. Howells DW, Porritt MJ, Wong JY, et al. also been reported to be effective in mi- counter any cases in the literature other 2,3 Reduced BDNF mRNA expression in the graine prophylaxis. than 1 report of amenorrhea occurring Parkinson’s disease substantia nigra. Here a patient is presented whose first after 7 days of venlafaxine use.7 The pre- Exp Neurol. 2000;166:127Y135. year of venlafaxine therapy for migraine sent report is the first one in which galac- 14. CastreńE,Rantama¨ki T. Role of brain-derived prophylaxis resulted in both galactorrhea torrhea and menometrorrhagia have been neurotrophic factor in the aetiology of and menometrorrhagia, a co-occurrence of seen together in 1 patient. That these ad- depression: implications for pharmacological adverse effects that has not been reported verse effects were seen so late in the drug’s treatment. CNS Drugs. 2010;2:1Y7. before. period of use is also an interesting finding.

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To explain venlafaxine’s capacity to behavior.10 However, venlafaxine specifi- 10. Gupta RK, Tiller JW, Burrows GD. lead to galactorrhea, the drug’s effects in cally has minimal P450 inhibitory effects. Dual action antidepressants and some inhibiting DA reuptake have been put In conclusion, to the best of our important considerations. Aust N Z J forward as being responsible.5,6 It has knowledge, the patient reported here is Psychiatry. 2003;37:190Y195. also been reported that venlafaxine can en- the first to have developed galactorrhea hance transmission at postsynaptic 5-HT1A and menometrorrhagia in association with 7 receptors. This increase in 5-HT1A neu- venlafaxine use. These effects cannot yet Lamotrigine Effective rotransmission has been proposed as a be fully explained. The drug’s capacity to possible promoter of galactorrhea, having produce these types of adverse effects may in Postmenstrual both a direct effect on prolactin release be due to its effects on monoamines, but Dysphoric Disorder via serotonergic neurons in the hypothal- this is uncertain. amus and an indirect effect via dopami- A Case Report nergic transmissionYmediated inhibition of 5-HT.4,5,7,8 With venlafaxine used for AUTHOR DISCLOSURE To the Editors: 3 months in a male patient, serum pro- INFORMATION large body of literature exists regard- lactin and estradiol levels were reported The authors declare no conflicts of A ing the premenstrual dysphoric disor- to be higher than normal.9 That venla- interest. der and its management.1 However, except faxine has an effect on DA reuptake at for a brief mention about postmenstrual high doses and that this effect is less po- M. Said Berilgen, MD syndrome,2,3 no detailed studies or case tent than others are known.1 However, Department of Neurology reports pertaining to postmenstrual syn- prolactin levels of our patient were within Faculty of Medicine drome and or dysphoric disorder could be reference range, and the patient’s symp- FNrat U¨ niversitesi Hastanesi traced through MEDLINE search. I am toms improved after discontinuation of No¨roloji Servisi reportingacaseofawomanwhohad Elazig, Turkey medication because serum hormone levels [email protected] symptoms suggestive of typical postmen- were not reassessed. It is possible that strual dysphoric disorder, which partially the prolactin level, although in the refer- responded to paroxetine but remitted fully ence range, was higher than this patient’s REFERENCES with lamotrigine. normal and hence capable of producing 1. Stahl SM. Essential Psychopharmacology: A 19-year-old woman pursuing her pathology. Neuroscientific Basis and Practical graduate course presented in the psychiatric Given that high doses were not used Application. 2nd ed. Cambridge: outpatient department with the complaints in the patient reported here, the mech- Cambridge University Press; 2000. of nausea, vomiting, epigastric pain, rest- anism of galactorrhea is not known, but a lessness, irritability, sadness, lethargy, dif- 2. Bulut S, Berilgen MS, Baran A, et al. relation to the drug’s long-term use is a Venlafaxine versus amitriptyline in the ficulty in concentration, and decreased possibility that may be considered. prophylactic treatment of migraine: sleep. The symptoms were cyclic, lasting The possibility of venlafaxine- randomized, double-blind, crossover study. for 14 to 15 days every month postmen- associated menometrorrhagia/menorrhagia Clin Neurol Neurosurg. 2004;107:44Y48. strually for the last 2 years. The patient and other urogenital effects has been re- hailed from a middle-class affluent family. 3. Ozyalcin SN, Talu GK, Kiziltan E, et al. ported in premarketing and postmarketing She had one elder brother and caring par- The efficacy and safety of venlafaxine data. As for our patient, after 12 months of in the prophylaxis of migraine. Headache. ents. She was described to be an introvert, venlafaxine use and while continuing the 2005;45:144Y152. sensitive, obedient, and intelligent woman. drug, menometrorrhagia occurred. In the Menarche was established at the age of subsequent examinations and radiological 4. Naranjo CA, Busto U, Sellers EM, et al. 13 years, and her periods were regular, with investigations, no pathological lesion was A method for estimating the probability normal flow and duration without dys- of adverse drug reactions. Clin Pharmacol found. The drug’s capacity to cause these menorrhea. At the age of 15 years, she Ther. 1981;30:239Y245. types of effects is not completely under- started having cyclic distress starting with stood. The emergence of these effects is 5. Sternbach H. Venlafaxine-induced the onset of menses, crippling her for 14 to possibly due to the drug’s effects on hor- galactorrhea. J Clin Psychopharmacol. 15 days postmenstrually every month. Out Y monal modulation. One theory suggests 2003;23:109 110. of these, the first 4 to 5 days were marked that the pulsatile release of gonadotropin- 6. Wichman CL, Cunningham JL. by nausea and vomiting, whereas irrita- releasing hormone (GnRH) is regulated by A case of venlafaxine-induced bility, sadness, lethargy, and decreased sleep endogenous catecholamines. Norepineph- galactorrhea? J Clin Psychopharmacol. dominated the next 9 to 10 days. Notably, rine is thought to exert stimulatory effects 2008;28:580Y581. the patient used to be totally asymptomatic on GnRH, whereas DA is thought to exert 7. Linnebur SA, Saseen JJ, Pace WD. during the 14 to 15 days of premenstrual an inhibitory effect. Serotonin is believed Venlafaxine-associated vaginal bleeding. period. The patient had consulted different to affect the menstrual cycle by stimulating Pharmacotherapy. 2002;22:652Y655. medical and gynecologic specialists and luteinizing hormone, prolactin, estradiol, 8. Egberts AC, Meyboom RH, had been prescribed proton pump inhibitors 10 and progesterone secretion, but our De Koning FH, et al. Non-puerperal and hormonal courses without any notice- patient’s hormone levels are all within ref- lactation associated with antidepressant able relief. The past family and psycho- erence range and serum GnRH levels were drug use. Br J Clin Pharmacol. 1997;44: social history was unremarkable. Mental not measured. 277Y281. state examination revealed an anxious, Another theory suggests that inhibi- 9. Karakurt F, Kargili A, Uz B, et al. sad, and groaning patient, preoccupied by tion of the cytochrome P450 system by Venlafaxine-induced gynecomastia her nonremitting cyclic distress. Thyroid antidepressants may inhibit metabolism in a young patient: a case report. functions, hormonal profile, and result of of estrogen and other gonadal steroids, Clin Neuropharmacol. 2009; endoscopic and ultrasonographic inves- causing changes in ovulation and cycle 32:51Y52. tigations of the abdomen and pelvis were

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors normal. On the basis of typical cyclic In this letter, the author has cited estro- 2. Watts DL. Pre- and post menstrual symptoms seen during the postmenstrual gen progesterone imbalance translating in- syndrome. TEI Newsletter. phase with full remission during the pre- to elevated tissue zinc-to-copper ratio as 1995;3:4. menstrual period, normal laboratory test one of the etiological explanations for this 3. Post-menstrual syndrome: is it a myth. results, and negative physical examination, syndrome. In the present case, the initial Available at: http://www.always-health.com/ a diagnosis of postmenstrual dysphoric dis- postmenstrual distress was characterized womenshealth_post_menstrual.html. order was made. by symptoms pertaining to upper gastro- Accessed January 26, 2010. After assurance, dietary advice, and intestinal tract (such as nausea, vomiting, 4. Knobil E. The neuroendocrine control of the psychoeducation, cyproheptadine 4 mg/d and epigastric pain), and this distress was menstrual cycle. Recent Prog Horm Res. (for nausea and vomiting), alprazolam further compounded by another set of 1980;36:53Y58. 0.75 mg/d (for anxiety), and fluoxetine symptoms (such as restlessness, irritability, 5. Strickland JL, Wall JW. Abnormal uterine 20 mg/d (for depressive symptoms) were sadness, lethargy, difficulty in concentra- bleeding in adolescents. Obstet Gynecol prescribed. After 14 days, the patient was tion, and decreased sleep), which resem- Clin North Am. 2003;30:321Y335. asymptomatic, and the same treatment bled features of agitated depression. Unlike 6. Becker OV, Rasgon NL, Marsh WK, et al. was continued. The next follow-up noted the above-mentioned newsletter,2 symp- Lamotrigine therapy in treatment resistant emergence of similar symptoms only toms suggestive of water retention and menstrually-related rapid cycling bipolar during the postmenstrual period. Now breast soreness were not seen in the present disorder: a case report. Bipolar Disord. fluoxetine was continued; alprazolam was case; however, depressive and anxiety 2004;6:435Y436. tapered off and replaced by clonazepam symptoms were a common finding in both. 0.5 mg/d. During the third follow-up, Also, seeing the nature and severe psy- symptoms starting with the onset of men- chosocial distress associated with these ses were again noticed. Fluoxetine was ta- postmenstrual symptoms, a diagnosis of A Brief Self-Report Measure pered off, and medicines such as divalproex postmenstrual dysphoric disorder seemed to Assess Antidepressant sodium 250 mg/d, domperidone 20 mg/d, more appropriate for this patient. The pa- prochlorperazine 15 mg/d, and imipramine tient had cyclic symptoms suggestive of Adherence Among 75 mg/d, were tried alternatively without agitated depression, which showed marked Spanish-Speaking Latinos any relief. During the fifth month, quetia- improvement with lamotrigine therapy. pine 25 mg at bedtime and paroxetine Lamotrigine has been found to be poten- 10 mg twice a day were started. Post- tially useful in a treatment-resistant men- To the Editors: menstrual symptoms decreased during the strually related rapid cycling bipolar II t is important that researchers and clin- next 3 cycles to 7 to 10 days but not fully. disorder with follicular phase depressive I icians have a practical tool for assessing At this stage, lamotrigine was titrated to symptoms,6 which raises a possibility that antidepressant adherence among Latinos. 50 mg twice a day for 8 weeks, whereas postmenstrual dysphoric disorder may Although low antidepressant adherence paroxetine and quetiapine were tapered represent a cyclic variant of a depressive is a fairly common occurrence1 across a off. The patient’s distress reduced to 1 to disorder. However, prolonged follow-up range of racial/ethnic groups, it occurs 2daysduringthenext3to4cycles. of this patient as well as more studies on more commonly among racial/ethnic mi- Lamotrigine was continued for another such patients are needed to know whether norities such as Latinos.2 Low antide- 9 months and was then tapered off gra- this so-called postmenstrual dysphoric dis- pressant adherence is a concern, given dually. At the time of submitting this order is a depressive variant or a separate that it complicates depression treatment article, the patient was asymptomatic for entity. and may be a source of racial/ethnic dis- 8months. The index case not only calls for parities in depression treatment outcome. Postmenstrually approximately during identifying patients with postmenstrual Early discontinuation can increase like- 14-day period, ovarian follicle develop- dysphoric disorder but underlines the ef- lihood of depressive relapse by 77%3 and ment and endometrial growth stimulation fectiveness of lamotrigine in curtailing the lead to lower likelihood of achieving full occur. The main hormone secreted during distress and disability associated with remission, shorter symptom-free periods, this phase is estrogen, and its production such disorder. and longer time to remission of symptoms.4 depends on various hormones, including Thus, depression treatment outcomes can gonadotropin-releasing hormone, follicle- AUTHOR DISCLOSURE be improved by efforts to enhance antide- stimulating hormone, luteinizing hormone, INFORMATION pressant adherence. and inhibin. Gonadotropin-releasing hor- The capacity to research and clini- The author declares no conflict of mone stimulates the production of follicle- cally address antidepressant adherence is interest. stimulating hormone and luteinizing constricted by the complications of mea- hormone. The rate of production of these Ravi Chand Sharma, MD suring adherence. The most robust ad- pituitary gonadotropins depends on the Department of Psychiatry herence measure is perhaps the use of secretion of estrogen and progesterone Indira Gandhi Medical College electronic medication container caps, from the ovaries, as well as gonadotropin- Shimla, Himachal Pradesh, India which record the time and date of each releasing hormone from the hypothala- [email protected] bottle opening (eg, Medication Event mus. Therefore, hypothalamic, pituitary, or [email protected] Monitoring System [MEMS]). Although ovarian dysfunction can all lead to men- providing the most precise data, systems, strual disorders.4,5 REFERENCES such as MEMS, can increase study and The term postmenstrual syndrome, 1. Cunningham J, Yonkers KA, O’Brien S, clinical costs and may therefore not al- characterized by symptoms of anxiety, de- et al. Update on research and treatment ways be feasible. Other measures typically fensiveness, indecision, agitated depres- of premenstrual dysphoric disorder. used include self-reported discontinuation 2 sion, water retention, breast soreness, and Harv Rev Psychiatry. 2009;17: of medication or dose taking, pharmacy others, has been mentioned in 1 newsletter.2 120Y137. refill data,1 pill counts,5 and blood sample

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Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 analysis.5 Each measure for adherence has trial examining an intervention to improve item. Respondents indicated Byes/no[ to a different profile of advantages and dis- antidepressant adherence. Specifically, each dose-taking problem represented by advantages. For example, blood sample participants were receiving outpatient the 4 SMTS items, yielding a score of 0 analyses place demands on patients and services at a community mental health to 4 (higher scores indicate poorer adher- also add to costs. Furthermore, examina- center and were randomized to receive a ence). Our analysis used data from the tion of whether an antidepressant was motivational adherence intervention or end-point research evaluation, which oc- discontinued or refilled provides a limited usual care. Given that participants were curred 5 weeks after baseline. This allowed picture of adherence, as patients may receiving community mental health center a comparison of the end point (5-week) continue their antidepressant but engage usual care, their psychopharmacological SMTS with the daily adherence data for in irregular dose taking. treatment was naturalistic, and therefore, that 5-week period (MEMS). The MEMS Dimensional self-report measures of prescriptions varied across individuals. adherence was calculated as the number of adherence have the advantage of provid- All antidepressants prescribed were as days the medication was taken, divided by ing more information than what can be follows: serotonin-norepinephrine reup- the total number of days (% of days medi- obtained from a dichotomous indicator. In take inhibitors (51.1%), selective sero- cation taken). addition, they are cost-effective and prac- tonin reuptake inhibitors (44.7%), or The percentages of respondents pro- tical to administer, increasing the likeli- norepinephrine-dopamine reuptake inhib- ducing different SMTS scores (0Y4) were hood that they will be more frequently itors (4.3%). Participants were enrolled if as follows: 0 = 27.7%; 1 = 19.1%; 2 = included in research studies or clinical they met criteria for major depression or 21.3%; 3 = 21.3%; and 4 = 10.6%. The practice. Such increased measurement dysthymia within the previous month to SMTS was internally consistent (> = 0.70) of antidepressant adherence would hold baseline (assessed with the Structured and demonstrated a moderate negative promise for better understanding and Clinical Interview for DSM-IV7), were correlation with MEMS adherence (r = managing this common problem. How- being treated with an antidepressant, self- j0.43), indicating that more self-reported ever, self-report measures of adherence identified as Latino(a), and were of ages dose-taking problems were associated have the drawback of being influenced 18 to 65 years. Exclusions were made if with lower adherence. For each score on by bias. Given their potential benefits, it criteria were met for mania or substance- the SMTS, the mean MEMS adherence is therefore necessary to evaluate the va- related disorder within the last year (as- rate was as follows: 0 = 74.1% (SD, 12); lidity of self-report measures of adherence sessed with Structured Clinical Interview 1 = 70.9% (SD, 36.59); 2 = 60.2% (SD, against a well-established criterion, such for DSM-IV), were medically unstable, or 30.16); 3 = 44.1% (SD, 44.06); and 4 = as an electronic medication container. were pregnant/nursing at the time of the 23.4% (SD, 39.27). An omnibus test in- Accordingly, 1 study examined 3 methods study. Nearly all of the participants were dicated that these means were significantly of antidepressant adherence assessment predominantly Spanish speaking (89.4%). different (F = 2.80; P G 0.05). (4-item self-report questionnaire, blood All research procedures were approved by Next, to maximize comparability analysis, and pill counts), comparing their the University of Medicine and Dentistry between studies, we chose an MEMS ad- performance with the MEMS.5 They found of New JerseyYRobert Wood Johnson herence criterion that is commonly used that blood analyses were impractical be- Medical School institutional review board, in studies to identify the adherent partici- cause of high rates of patient refusal (39%) and all participants signed an approved pants (Q80%) and examined different andthattabletcountsoverestimatedadher- consent form. SMTS cutoffs (Table 1).5,8 Using the cut- ence. The authors reported that the 4-item This letter presents data generated off proposed by George et al,5 an SMTS self-report measure (Self-reported Medica- from the 4-item SMTS and MEMS. The score of 1 or more yielded a sensitivity tion Taking Scale [SMTS]6) was practical to MEMS was provided to participants at and specificity of 45% and 85.2%, re- administer and demonstrated a sensitivity/ baseline. The SMTS was made specific to spectively, for identifying adherent parti- specificity of 72.2% and 74.1%, respec- antidepressants by replacing the wording cipants. However, improved classification tively, for detecting nonadherence. in each item from Bmedicine/medication[ was demonstrated with an SMTS cutoff However, in using the SMTS to study to Bantidepressant medicine/medication.[ of 2 or more. Specifically, endorsing 2 antidepressant adherence among Latinos, We then generated a Spanish translation or more items on the SMTS demon- there may be concerns about the cultural of the measure using a forward/backward strated a sensitivity and specificity of 70% and linguistic appropriateness of this translation procedure. The Appendix dis- and 70.4%, respectively, which amounted measure, as the SMTS_s psychometric plays the translated SMTS in its entirety, to a total classification accuracy of 70.2%. properties have not been examined for along with endorsement rates for each Given that the respondents were in antidepressant adherence with Spanish- speaking populations. Given that the SMTS is a practical measure that can be easily included in research studies or as part of standard clinical practice, this letter TABLE 1. Sensitivity/Specificity of SMTS Cutoffs for Identifying 80% or Greater is to present data on the use of SMTS5,6 MEMS Adherence for measuring antidepressant adherence G Q among Spanish-Speaking Latinos. Our Nonadherent (MEMS, 80%) Adherent (MEMS, 80%) study capitalizes on a design where the SMTS 1+ cutoff SMTS was administered, while MEMS SMTS = 1Y4 23 (85.2%) 11 (55%) data were concurrently collected. The SMTS = 0 4 (14.8%) 9 (45%) MEMS provides a very suitable criterion SMTS 2+ cutoff by which to examine the SMTS_s criterion- SMTS = 2Y4 19 (70.4%) 6 (30%) related validity, especially in light of re- SMTS = 0Y1 8 (29.6%) 14 (70%) call error and bias concerns. Participants Figures represent frequencies. Percentages reflect the proportion within column. (N = 47) were enrolled in a randomized

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different adherence conditions (ie, usual lems related to the relatively small sam- Alejandro Interian, PhD care vs motivational intervention) and ples. For this reason, the current results Department of Psychiatry were receiving different antidepressant should be studied further to determine University of Medicine and Dentistry Y prescriptions, a logistic regression exam- the best SMTS cutoff for case finding. of New Jersey Robert Wood _ Johnson Medical School ined whether the relationship between The SMTS s performance in the Piscataway, NJ the SMTS cutoff of 2 or greater and current study is noteworthy, given how [email protected] MEMS (Q80%) was confounded by re- practical and feasible this measure is to ceiving the intervention or antidepressant administer clinically or in a research class.Participants with an SMTS score protocol. Other more involved methods REFERENCES of 2 or higher remained 83% less likely (pharmacy data, pill counts, and use of to have MEMS adherence of 80% or the MEMS) may indeed yield more ro- 1. Akincigil A, Bowblis JR, Levin C, et al. more, after adjusting for intervention bust data. However, for the studies that Adherence to antidepressant treatment condition and antidepressant class (odds require less involved or less costly as- among privately insured patients diagnosed with depression. Med Care. 2007;45: ratio, 0.17; 95% confidence interval, sessment of adherence among Spanish- 363Y369. [0.04Y0.77]; P G 0.05). The covariates speaking Latinos, the current results show werenotsignificant(P 9 0.05). that the SMTS moderately corresponded 2. Olfson M, Marcus SC, Tedeschi M, et al. with MEMS adherence. In addition, the Continuity of antidepressant treatment for adults with depression in the United States. total classification accuracy of 70.2% Y DISCUSSION seems very similar to the SMTS estimate Am J Psychiatry. 2006;163:101 108. These results describe the perfor- (73%)5 generated for antidepressant ad- 3. Melfi CA, Chawla AJ, Croghan TW, et al. mance of a brief self-report measure to herence with a mostly English-speaking, The effects of adherence to antidepressant assess antidepressant adherence among non-Latino white population in the treatment guidelines on relapse and Spanish-speaking Latinos. The SMTS United Kingdom (written communication, recurrence of depression. Arch Y demonstrated acceptable reliability and March 2010). Gen Psychiatry. 1998;55:1128 1132. was statistically and meaningfully related Given the limited sample size, gen- 4. Melartin TK, Rytsala HJ, Leskela US, et al. to a robust adherence criterion (MEMS). eralizability is likely limited, and future Continuity is the main challenge in treating With each increase in SMTS score, a studies should seek to replicate these major depressive disorder in psychiatric care. corresponding decrease in mean MEMS results. In addition, the current study was J Clin Psychiatry. 2005;66:220Y227. adherence was observed. Our sensitivity/ limited by the lack of a comparison group 5. George CF, Peveler RC, Heiliger S, et al. specificity analysis showed that an SMTS (either English-speaking Latinos or other Compliance with tricyclic antidepressants: cutoff of 2 or more was the most appro- racial/ethnic groups) for determining if the value of four different methods of priate. This finding diverged from that of there are between-group differences with assessment. Br J Clin Pharmacol. 2000;50: a previous study, and the reason for this regard to the SMTS_s psychometrics. 166Y171. is not clear.5 One explanation would per- 6. Morisky DE, Green LW, Levine DM. tain to cultural differences. As a possible Concurrent and predictive validity of a example, there may be culturally influ- ACKNOWLEDGMENT self-reported measure of medication adherence. Med Care. 1986;24:67Y74. enced differences in a duteous style of This work was funded by a grant from reporting adherence problems. The the National Institute of Mental Health 7. First MB, Spitzer RL, Gibbon M, et al. divergent finding also may be related to (K23 MH074860). Structured Clinical Interview for DSM-IV language differences. However, given the Axis I Disorders. New York, NY: Biometric very few English-speaking Latino parti- Research Department, New York State cipants, our data cannot differentiate Psychiatric Institute; 1998. whether the divergent findings were more AUTHOR DISCLOSURE 8. Hansen R, Kim MM, Song L, et al. related to language or culture. The di- INFORMATION Comparison of methods to assess medication verging findings regarding cutoff also The author has no conflicts of inter- adherence and classify nonadherence. Ann could be related to generalizability prob- est to disclose. Pharmacother. 2009;43:413Y422.

APPENDIX

Self-Reported Medication Taking Scale

MEMS MEMS Adherence, Adherence, Item Response Q80% G80% 1. Do you ever forget to take your antidepressant medicine? Yes/No 11 (55%) 19 (70%) >Alguna vez se ha olvidado de tomar su medicina anti-depresiva? 2. Are you careless at times about taking your antidepressant medicine? Yes/No 5 (25%) 17 (63%) >Algunas veces, eres descuidada(o) en tomar su medicina antidepresiva? 3. When you feel better, do you sometimes stop taking your antidepressant medicine? Yes/No 4 (20%) 14 (51.9%) >Cuando se siente mejor, algunas veces ha dejado de tomar su medicina anti-depresiva? 4. Sometimes if you feel worse when you take the antidepressant medicine, do you stop taking it? Yes/No 1 (5%) 8 (29.6%) >A veces, si se siente peor cuando se toma su medicina anti-depresiva, deja de tomarsela? Figures represent the frequency (percentage) who endorsed Byes[ on each item, separately by 80% MEMS criterion.

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Delayed-Onset mirtazapine daily and 50 mg of quetiapine AUTHOR DISCLOSURE daily at bedtime, with no adverse effects, INFORMATION Mirtazapine-Related and is monitored regularly for hematological The authors declare no conflicts of Leukopenia and problems. Her ANC level has remained in interest. Rechallenge the lower reference range (2200Y2800/HL) since rechallenge and never reached her Rashesh Dholakia, MD, MPH prior nadir of 1900/HL or followed a con- Department of Psychiatry To the Editors: sistent suppressed pattern, nor have clinical New Jersey Medical School leukopenic manifestations emerged. The Newark, NJ ost cases of drug-related leukope- [email protected] nia develop within the first few weeks patient’s medical history was negative for M any endocrine or hematologic problems or Steven J. Schleifer, MD of treatment; however, delayed-onset drug- Department of Psychiatry related leukopenia has also been reported, other medical conditions that would pre- dispose to leukopenia. New Jersey Medical School including that with psychotropic medica- Newark, NJ tions.1,2 Mirtazapine is reported to be as- and Department of Psychiatry sociated with leukopenia, neutropenia, and Hackensack University Medical Center agranulocytosis.3 We present a case of leu- DISCUSSION Hackensack, NJ In premarketing trials, the incidence kopenia in a patient treated with mirtaza- Yasir J. Ahmad, MD of agranulocytosis/severe leukopenia with pine for dysthymia and posttraumatic stress 5 Department of Psychiatry disorder, which was found only after ex- mirtazapine was 1.1 in 1000 subjects. Since Hackensack University Medical Center tended treatment with the agent. After drug its introduction in 1996, less than 10 cases of Hackensack, NJ discontinuation and unsuccessful treatment mirtazapine-related leukopenia/neutropenia, Ishdeepsingh S. Narang, MD with 3 other antidepressants, the patient has including with concomitant medication, tolerated rechallenge with a lower dose of have been reported. Our patient’s clinical REFERENCES mirtazapine. course is consistent with her developing delayed-onset leukopenia as a consequence 1. Stoner SC, Deal E, Lurk JT. Delayed-onset of prolonged treatment for 5 years. The neutropenia with divalproex sodium. CASE REPORT patient had no documented history of ill- Ann Pharmacother. 2008;42:1507Y1510. Our case patient, a 41-year-old nesses suggestive of previous leukopenia, 2. Thinn SS, Liew E, May AL, et al. Reversible woman, had presented to the hospital clinic and her prior routine laboratory monitor- delayed onset olanzapine-associated with symptoms of depressed mood, poor ing had not identified any neutropenic leukopenia and neutropenia in a energy, irritability, flashbacks, and night- trends as per the patient. According to the clozapine-naive patient on concomitant depot 6 mares of her mother’s homicide. She met Naranjo probability scale, mirtazapine can antipsychotic. J Clin Psychopharmacol. the Diagnostic and Statistical Manual of be postulated to have caused our patient’s 2007;27:394Y395. Mental Disorders, Fourth Edition, Text leukopenia with intermediate probability. 3. Civalier KA, Krahn LE, Agrwal N. Repeated Revision criteria for dysthymia and post- Whereas the sequence of events and the episodes of neutropenia triggered by traumatic stress disorder. After being stable lack of other risk factors suggest that mirta- mirtazapine. Psychosomatics. 2009;50: on mirtazapine at 45 mg/d at bedtime and zapine was associated with the leukopenia, 299Y300. quetiapine at 50 mg/d at bedtime for 5 years the effect may be unrelated to mirtazapine, 4. Khan AY, Golewale MH, Kahn DA. A case (both off-label use), the patient was di- accounted for by other explanations such of chronic drug-induced neutropenia. agnosed with asymptomatic moderate leu- as idiopathic leukopenia with genetic vul- J Psychiatr Pract. 2008;14:246Y250. kopenia on routine medical workup, with nerability or cyclic leukopenia. It is also white blood cell (WBC) count, 3900/HL possible that leukopenia was facilitated by 5. Hartmann PM. Mirtazapine: a newer (reference range, 4800Y10,800/HL);4 neu- antidepressant. Am Fam Physician. concurrent quetiapine. Y trophils, 39% (reference range, 50%Y75%); The mechanisms of leukopenia with 1999;59:159 161. and absolute neutrophil count (ANC), mirtazapine therapy are not well under- 6. Naranjo CA, Busto U, Sellers EM, et al. 1900/HL (reference range, 2500Y7500/HL); stood. Hypersensitivity/immune-mediated A method for estimating the probability other cell components were within the mechanisms have been suggested, including of adverse drug reactions. Clin Pharmacol Y reference range. Mirtazapine was discon- complement-mediated toxicity7 and drug- Ther. 1981;30:239 245. tinued, and within 2 weeks, her WBC induced antibodies against committed stem 7. Lahdelma L, Ahokas A, Andersson LC, count returned to normal (5000/HL; neu- cells, proliferating precursors, or mature et al. Mitchell B. Balter Award. Human trophils, 55%; ANC, 2800/HL). She was blood cells.8,9 Long-term administration of leukocyte antigen-A1 predicts a good later switched sequentially to fluoxetine, es- the drug may result in haptenation and ac- therapeutic response to clozapine with a citalopram, and paroxetine, each of which celerated apoptosis.10 The current tolerated low risk of agranulocytosis in patients with was discontinued owing to adverse effects rechallenge at a moderately reduced dose schizophrenia. JClinPsychopharmacol. Y and/or nonresponse but with no evidence of 30 mg of mirtazapine suggests that even 2001;21:4 7. of leukopenia. Quetiapine at 50 mg/d at with evidence of mirtazapine-related leuko- 8. Vincent PC. Drug-induced aplastic anemia bedtime was continued throughout (no penia, subsequent use of the drug in clini- and agranulocytosis. Incidence and serum levels for quetiapine or mirtazapine cally indicated settings can be considered. mechanisms. Drugs. 1986;31:52Y63. were obtained). Owing to persistent clini- In the absence of guidelines for manag- 9. Hardin TC, Conrath FC. Desipramine-induced cal symptoms, the patient was restarted on ing hematologic adverse effects of psy- agranulocytosis. A case report. Drug Intell mirtazapine approximately 18 months after chotropic agents other than for clozapine, Clin Pharm. 1982;16:62Y63. the medication was initially discontinued, especially considering the risk of late emer- 10. Bhatt V, Saleem A. Review: drug-induced and the dose was gradually increased to gence of the adverse effect, long-term he- neutropeniaVpathophysiology, clinical 30 mg/d at bedtime. For the past 2 years, matologic monitoring of patients such as features and management. Ann Clin Lab Sci. she has clinically improved on 30 mg of ours seems indicated. 2004;34:131Y137.

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Behavioral Disinhibition awareness disturbance, spatial or temporal Zolpidem has shown clinical improvement disorientation, lethargy, or myoclonus in patients with Broca’s aphasia following With Baclofen were found. His state was very similar to subcortical and striatal lesions. This im- the one he usually presents under alco- provement was associated to an increased hol or benzodiazepine. The 60 mg/d of metabolism of the mesial frontal and 10 To the Editors: baclofen was maintained. The next day, in orbitofrontal cortexes. Amelioration of revention of relapse is considered the the same state of disinhibition, the patient behavioral disinhibition in schizophrenic P major challenge in the treatment of took advantage of a nurse trainee opening patients associated to an increase in the alcohol dependency. Baclofen, a GABA-B the door of the unit to shove her violently, metabolism of the mesial frontal cortex throwing her to the floor, and run away. He has also been documented,8 as has its effi- agonist, has recently demonstrated effi- 11 ciency to reduce consumption and en- returned, 3 days later, brought again by his ciency in the treatment of catatonia. In the hance abstinence in animal models family. He had stopped his medication latter condition, abnormal activations of throughout this period. Upon his return, mesial frontal and orbitofrontal cortex have of alcoholism and alcohol-dependent 12 1Y5 he was very calm, criticizing with regrets been demonstrated and are corrected by patients. We report a case of baclofen- and astonishment his previous conduct. In 13 related disinhibition. lorazepam, demonstrating both dysfunc- the presence of these recurrent episodes tional mesioprefrontal-striatal loops and of disinhibition, a diagnostic reevaluation potential benefits of benzodiazepines. A was performed, looking for possible ex- similar phenomenon, behavioral disinhi- CASE REPORT planations for this substance-induced be- bition, occurring with GABA-B agonists Mr A, a well-known physician and havioral disorder. No personality disorder has never been reported so far and was academic, is a 66-year-old white man with was again found, a result supported by the observed here in a patient presenting me- a long history of alcohol consumption. He high social and professional functioning sioprefrontal hypoperfusion. According to started abusing alcohol at a young age in and performance of the patient. No mood the Naranjo probability scale, return to the festal settings, but shortly after, he began disorder, anxiety disorder, cognitive dete- basal clinical state on drug discontinuation drinking abusively at home alone. Since rioration, or other psychiatric disorder was and then reappearance on rechallenge argue a few years, he was drinking a bottle of found. No cortical atrophy or subcortical for a baclofen causal role in this disinhi- vodka each night after work. Several lesion was found on cerebral magnetic bition.14 Encephalopathy with EEG per- hospitalizations took place in the last resonance imaging. A cerebral perfusion turbations, that is, periodic sharp wave couple of years, with an early relapse soon scintigraphy, using the 99mEC-ECD pattern, quasi-periodic generalized epilep- after discharge except for 10 months of marker, was done. It showed a bilateral tiform discharges, generalized bursts of abstinence with a daily dose of disulfiram. hypoperfusion of the internal temporal sharp wave discharges, or burst-suppression No personality disorder was found on structures and a mild hypoperfusion of the pattern, has been described in baclofen- psychometric tests, and no mood disorder left temporal parietal associative cortex treated patients, especially with intrathecal or anxiety disorder preceded or compli- and the mesial frontal region. An elec- administration.15 Nevertheless, in the case cated his dependency. On April 2009, he troencephalogram (EEG) was done and of our patient, none of the previously de- was admitted, again, in the protected unit showed no abnormality. In the absence of scribed perturbations was found. Baclofen of our department, brought by his family an organic etiology for these episodes administration resulted in delta waves and the police for alcohol abuse. On ad- of disinhibition, including encephalopathy, originating from structures showing hy- mission, he was agitated, easily irritable, baclofen was then restarted at the dose of poperfusion on scintigraphy, and most im- and aggressive with a blood alcohol level 10 mg/d. Five days later, the patient was portant, our findings were associated to a of 2.8 g/L. A treatment with diazepam, mildly disinhibited and euphoric. The EEG clinical state characterized by disinhibition 30 mg/d, was started. The next day, a psy- showed intermittent left temporal and pari- and impulsivity in the total absence of chiatric evaluation was performed, and the etal subcortical puffs of delta waves, lasting confusion, disorientation, sedation, or any diagnosis of alcohol dependency with no from 1 to 3 seconds with no signs of en- other sign in favor of a baclofen-related other psychiatric comorbidity was made. cephalopathy. In the absence of any meta- encephalopathy. The alcohol withdrawal phase occurred bolic disturbances, these findings were Therefore, this case report expands without any complication except for a state attributed to baclofen. This drug was then paradoxical reactions to all GABAergic of disinhibition, which he had previously stopped. Eight days later, the EEG was drugs, including GABA B medication, and presented in the same settings, character- normal again, and the patient_s disinhibi- reinforces the hypothesis of a functional ized by irritability, psychomotor agitation, tion had disappeared. deficiency in the mesioprefronto-striatal and verbal aggressiveness. This state was loops underlying behavioral disinhibition. identical to the one he frequently presents Psychiatrists should be aware of this po- after alcohol ingestion and reminded us of tential adverse drug reaction in the light of his clinical state on admission. DISCUSSION the growing prescription of baclofen. At the ending of the withdrawal Behavioral disinhibition occurring phase, and to enhance this patient_s ab- secondary to benzodiazepine intake is stinence, a treatment with 20 mg/d of known and has been frequently reported.7 baclofen was initiated. At day 5, the dose A plausible explanation of this GABA-A AUTHOR DISCLOSURE was increased to 40 mg/d, and at day 7 to agonistYrelated paradoxical effect is an INFORMATION 60 mg/d, to achieve a high but safe daily increased metabolism in previously dys- The authors declare no conflicts of dose of baclofen, as recently suggested functional mesioprefrontal-striatal loops.8,9 interest and report no financial affiliations for the treatment of alcoholism.6 At this This hypothesis is in line with other re- or other relationships relevant to the sub- dose, the patient became disinhibited, ported studies on GABAergic drugs, in- ject of this letter. easily irritable, and verbally and physi- cluding papers on zolpidem, a selective The subject of this letter has never cally aggressive. No signs of confusion, GABA-A >1 subunit receptor agonist. been previously presented.

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Michel Soufia, MD REFERENCES Cognitive facilitation and behavioral University Hospital disinhibition with benzodiazepine: a case 1. Ameisen O. Treatment of alcohol-use Department of Professor Olie´ report. J Clin Psychiatry. 2007;68: disorders. Lancet. 2009;373:1519; author Protected Unit 1305Y1306. Sainte-Anne Hospital reply 1519Y1520. 9. Northoff G. What catatonia can tell us about Paris, France 2. Malcolm RJ. GABA systems, benzodiazepines, Btop-down modulation[: a neuropsychiatric [email protected] and substance dependence. JClinPsychiatry. hypothesis. Behav Brain Sci. 2002;25: 2003;64(suppl 3):36Y40. Marion Plaze, MD, PhD 555Y577; discussion 578Y604. University Hospital 3. Maccioni P, Bienkowski P, Carai MA, et al. 10. Cohen L, Chaaban B, Habert MO. Transient Department of Professor Olie´ Baclofen attenuates cue-induced reinstatement Head of the Protected Unit improvement of aphasia with zolpidem. of alcohol-seeking behavior in Sardinian Sainte-Anne Hospital N Engl J Med. 2004;350(9):949Y950. alcohol-preferring (sP) rats. Drug Alcohol Paris, France Depend. 2008;95:284Y287. 11. Thomas P, Rascle C, Mastain B, et al. Test Bernard Gueguen, MD 4. Garbutt JC, Kampov-Polevoy AB, Gallop R, for catatonia with zolpidem. Lancet. 1997; Department of Neurophysiology 349(9053):702. Sainte-Anne Hospital et al. Efficacy and safety of baclofen for Head of the Department alcohol dependence: a randomized, 12. Northoff G, Ko¨tter R, Baumgart F, et al. Paris, France double-blind, placebo-controlled trial. Orbitofrontal cortical dysfunction in akinetic Alcohol Clin Exp Res. 2010;[Epub ahead Gilles Demigneux, MD catatonia: a functional magnetic resonance University Hospital of print]. imaging study during negative emotional Department of Professor Olie´ 5. Johnson BA. Medication treatment of stimulation. Schizophr Bull. 2004;30(2): Y Sainte-Anne Hospital different types of alcoholism. Am J Psychiatry. 405 427. Paris, France 2010;167(6):630Y639. 13. Richter A, Grimm S, Northoff G. Lorazepam Jean-Pierre Olie´, MD 6. Ameisen O. Complete and prolonged modulates orbitofrontal signal changes University Hospital suppression of symptoms and consequences during emotional processing catatonia. Hum Department of Professor Olie´ of alcohol-dependence using high-dose Psychopharmacol. 2010;25(1):55Y62. Head of the Department baclofen: a self-case report of a physician. 14. Naranjo CA, Busto U, Sellers EM, et al. A Sainte-Anne Hospital Alcohol Alcohol. 2005;40:147Y150. Paris, France method for estimating the probability of 7. Kandemir H, Yumru M, Kul M, et al. adverse drug reactions. Clin Pharmacol Ther. Raphael Gaillard, MD, PhD Behavioral disinhibition, suicidal ideation, 1981;30(2):239Y245. University Hospital and self-mutilation related to clonazepam. Department of Professor Olie´ 15. Hormes JT, Benarroch EE, Rodriguez M, Head of the Open Unit J Child Adolesc Psychopharmacol. et al. Periodic sharp waves in baclofen-induced Sainte-Anne Hospital 2008;18:409. encephalopathy. Arch Neurol. 1988;45: Paris, France 8. Gaillard R, Hemras A, Habert MO, et al. 814Y815.

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