Quetiapine for Hypersexuality and Delusional Jealousy After Stroke

Letters to the Editors

1 mg at bedtime at another hospital. Halo- stroke patients. Our case suggests that Quetiapine for peridol was titrated to 5 mg/d, bupropion quetiapine is effective in treating hypersex- was maintained at a dose of 100 mg/d, and uality and psychotic symptoms after a stroke, Hypersexuality and flunitrazepam was titrated to 2 mg at bedtime. without a worsening of motor functions. We Delusional Jealousy In November 2004, carbamazepine 200 mg/d think that this case warrants further well- was added and titrated to 400 mg/d. The controlled research. After Stroke dosage of antipsychotics could not be raised because his motor functions began to worsen Beang-Jin Chae, MD* due to extrapyramidal symptoms. His symp- Byung-Jo Kang, MD toms could not be controlled, and he was To the Editors: *Department of Psychiatryy referred to our hospital in March 2005. Hypersexuality and psychotic Magnetic resonance imaging was obtained, Daedong Hospital symptoms are occasionally associated and Department of Psychiatry and we could find no recent onset brain y with Parkinson’s disease, dopamine infarction or hemorrhage except for the right School of Medicine agonist therapy for Parkinson’s dis- hemisphere old infarction in the M1 branch of Kyungpook National University 1–6 6,7 ease, dementia, and temporal lobe the middle cerebral artery distribution. Mag- Taegu, Republic of Korea seizures,8 but rarely with stroke.6,8–11 netic resonance imaging showed large ence- [email protected] Although some studies have shown that phalomalacia in the right frontoparietal lobe quetiapine is effective in treating psy- and right basal ganglia of the middle cerebral chosis and motor functions in Parkin- artery territory except for some parts of the REFERENCES son’s disease,12–17 as far as we know, head of right caudate supposed to be the 1. Tison F, Ghorayeb I. Parkinson’s disease there have not been any treatment anterior cerebral artery territory. and associated disorders. Rev Prat. 2005; On the Wechsler Adult Intelligence response studies in the area of hyper- 15(55(7)):741–747. Scale, his IQ was 104, his Mini-Mental State 2. Kashihara K, Ohno M, Katsu Y. Psychosis in sexuality and psychosis after a stroke. Examination score was 26, and his Brief patients with Parkinson’s disease; their fre- We present a case in which hypersex- Psychiatric Rating Scale (BPRS) score was quency, phenomenology, and clinical corre- uality and delusional jealousy after a 53. (In our hospital, the BPRS score of lates. Rinsho Shinkeigaku. 2005;45(1):1–5. stroke were successfully managed with admitted psychotic patients ranged from 3. Schrag A. Psychiatric aspects of Parkinson’s disease—an update. J Neurol. 2004;251(7): quetiapine. 38 to 63 and that of psychotic outpatients 795–804. ranged from 25 to 40). These scores were 4. Berger Ch, Mehrhoff FW, Beier KM, et al. measured by one psychologist in our hospi- Sexual delinquency and Parkinson’s disease. tal. The psychologist was not informed Nervenarzt. 2003;74(4):370–375. CASE REPORT about any information associated with the 5. van Deelen RA, Rommers MK, Eerenberg A 63-year-old right-handed man with dosing of medication. JG, et al. Hypersexuality during use of Diagnostic and Statistical Manual of Mental We started treatment with quetiapine levodopa. Ned Tijdschr Geneeskd. 2002; Disorder, Fourth Edition psychotic disorder 50 mg twice a day and zolpidem 10 mg at 146(44):2095–2098. due to a stroke, with delusions, was referred bedtime. On the second day after treatment, 6. Nagaratnam N, Gayagay G Jr. Hypersexual- ity in nursing care facilities—a descriptive to our outpatient clinic in March 2005 for his wife began to feel that his symptoms study. Arch Gerontol Geriatr. 2002;35(3): worsening psychotic symptoms. His main (demanding sexual intercourse and express- 195–203. symptoms were hypersexuality and delu- ing delusional jealousy) had remarkably 7. Hashimoto M, Akimoto T, Watanabe Y. sional jealousy. These symptoms troubled decreased. One month after treatment, his Hypersexuality. Hypersexuality in persons his wife very much. BPRS score was 42, and quetiapine was with dementia. Nippon Rinsho. 2004;62 He had been diagnosed with a right titrated to 125 mg/d. Four months after (suppl 4):67–72. hemisphere infarction in the middle cerebral treatment, the BPRS score was 34. He 8. Monga TN, Monga M, Raina MS, et al. artery distribution in September 1991. Mild developed no severe adverse effects includ- Hypersexuality in stroke. Arch Phys Med weakness of the left extremities developed, ing a worsening of motor functions, and his Rehabil. 1986;67(6):415–417. but he could manage his daily routine. 9. Spinella M. Hypersexuality and dysexecu- wife became more comfortable in living tive syndrome after a thalamic infarct. Int J In March 1995, he began to develop with him. Neurosci. 2004;114(12):1581–1590. symptoms of hypersexuality and delusional A review of literature suggests that 10. Kumral E. Paranoid (delusional) disorder jealousy (he believed that his wife had hypersexuality and psychotic behavior are associated with tuberothalamic artery terri- sexual intercourse with his relative and that rare after cerebrovascular accident, but when tory infarction. Cerebrovasc Dis. 2001; his son was not his own). At the time, he did such behavior does occur, the lesion is 11(2):137–138. not receive any treatment because these usually in the right hemisphere,18,19 and 11. Nagaratnam N, Pathma-Nathan N. Behav- symptoms were expressed intermittently. psychotic symptoms may occur immediately ioural and psychiatric aspects of silent In September 2004, his symptoms after a stroke or months to years later.20 Our cerebral infarction. Br J Clin Pract. 1997; 51(3):160–163. persisted and became aggravated (he repeat- patient also presented hypersexuality and 12. Baron MS, Dalton WB. Quetiapine as treat- edly demanded sexual intercourse and delusional jealousy 2 years after the onset of ment for dopaminergic-induced dyskinesias doubted his wife’s chastity). Thus, treatment a right cerebral infarction. As in Parkinson’s in Parkinson’s disease. Mov Disord. 2003; was started with haloperidol 0.75 mg/d, disease, a deterioration of motor functions is 18(10):1208–1209. bupropion 100 mg/d, and flunitrazepam the main obstacle in managing geriatric 13. Fernandez HH, Trieschmann ME, Burke

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MA, et al. Long-term outcome of quetiapine history of chills, headache, shortness of fluid hydration. Her oral temperature use for psychosis among parkinsonian breath, chest pain, cough, abdominal pain, returned to 36.98C with no external warming patients. Mov Disord. 2003;18(5):510–514. diarrhea, constipation, nausea, vomiting, dys- 40 hours after admission, and her mental 14. Reddy S, Factor SA, Molho ES, et al. The phagia, or choking on food. The patient status improved. effect of quetiapine on psychosis and motor function in parkinsonian patients with and denied any changes in urine color or dysuria. Mild hypothermia is most likely to be without dementia. Mov Disord. 2002;17(4): She lived in assisted living, used a walker to responsible for this patient’s symptoms. 676–681. walk, and needed help with feeding, dressing, Hypothermia has been reported in association 15. Targum SD, Abbott JL. Efficacy of quetia- and managing her bills but, otherwise, with risperidone. The patient had been re- pine in Parkinson’s patients with psychosis. interacted well with her helpers. Her medical ceiving risperidone for 6 months before this J Clin Psychopharmacol. 2000;20(1):54–60. history included hypertension, depression, hospital admission with no previous episodes 16. Fernandez HH, Friedman JH, Jacques C, dementia, and history of hallucinations. She of hypothermia. The introduction of parox- et al. Quetiapine for the treatment of drug- had cataract surgery and bilateral hip replace- etine may have raised risperidone levels and induced psychosis in Parkinson’s disease. ment a few years ago. She had no known Mov Disord. 1999;14(3):484–487. caused hypothermia in our patient. 17. Parsa MA, Bastani B. Quetiapine(Seroquel) allergies, and her medications before admis- in the treatment of psychosis in patients with sion included risperidone 0.25 mg orally BID, Parkinson’s disease. J Neuropsychiatry Clin amlodipine 5 mg daily, galantamine hydro- Neurosci. 1998;10(2):216–219. bromide 8 mg in the morning and 4 mg in 18. Braun CM, Dumont M, Duval J, et al. the evening, docusate sodium 100 mg daily, DISCUSSION Opposed left and right brain hemisphere celecoxib 200 mg daily, and calcium citrate The hypothalamus is responsible contributions to sexual drive: a multiple 600 mg BID. Her primary care physician for thermal regulation. Hypothermia lesion case analysis. Behav Neurol. 2003; added paroxetine 10 mg daily for her (defined as core body temperature of less 14(1–2):55–61. depression 4 weeks before her presentation 19. Richardson JK. Psychotic behavior after than 358C) can be caused by accidental right hemispheric cerebrovascular accident: to the hospital. The patient had no history of cold exposure or dysfunction of hypo- a case report. Arch Phys Med Rehabil. alcohol or intravenous drug abuse. thalamic thermoreguation.1 An underly- 1992;73(4):381–384. On physical examination, her blood ing illness is often the predisposing 20. Dupont RM, Cullum CM, Jeste DV. Post- pressure was 129/67 mm Hg; pulse, 61 beats/ stroke depression and psychosis. Psychiatr factor; this includes hypothyroidism, min and regular; respiratory rate, 16 breaths/ heart failure, uremia, hepatic encepha- Clin North Am. 1988;11(1):133–149. min; and rectal temperature, 33.4 C. She was 8 lopathy, stroke, shock or sepsis, hypo- lethargic but easily arousable and followed 1 commands.Her mucousmembranes weredry. glycemia, or burns. None of these She had normal breath sounds bilaterally, no medical conditions are present in our jugularvenousdistension,andnormalfirstand patient, as evidenced by her laboratory Hypothermia in a second heart sounds. Her abdominal exami- values, computed tomography scan Patient Receiving nation revealed no tenderness or guarding; results, and negative blood, urine, and bowel sounds were normal. Neurological cerebrospinal fluid cultures. Risperidone and examination showed equal pupils which were Medications that can cause hy- reactive to light, extraocular movements were pothermia include sedative-hypnotics, Paroxetine intact. Her cranial nerves were normal. No focal motor deficits were noted. Muscle alcohol, antithyroid medications, narcot- strength was 4 of 5 bilaterally in the upper ics, and typical antipsychotic medications To the Editors: 1 and lower extremities, and sensation to light such as haloperidol and phenothiazines. We describe a case of hypother- touch was intact. There were no signs of Hypothermia has been reported as an mia in a patient taking risperidone in the rigidity or cerebellar signs, and her reflexes adverse effect of the atypical anti- absence of other causes of hypothermia. were normal. psychotic medications quetiapine, olan- The introduction of paroxetine may Laboratory evaluation on admission zapine, and risperidone.2–4 Cases of have facilitated the development of revealed normal serum chemistries, mild risperidone-induced hypothermia have hypothermia in this patient. Clinicians anemia and thrombocytopenia (hemoglobin been reported by Brevik and Farver5 2 should be aware of the potential of 12.8 g/dL, platelet count 122,000/mm ), and and by Razaq and Samma.6 a normal thyroid-stimulating hormone. A risperidone to cause hypothermia as Risperidone is an atypical anti- computed tomography scan of the brain well as the drug interaction between psychotic medication that is used in the showed mild atrophy with no evidence of risperidone and paroxetine, 2 common- treatment of both positive and negative ly used agents in the elderly population. acute bleeding or stroke. Her chest radio- graph was normal with no infiltrates or symptoms of schizophrenia. Risperi- done is a serotonin 5HT2 and dopamine effusions. Urine analysis was normal, and 7 urine toxicology screen was negative. A D2 receptor antagonist. It is metabo- CASE lumbar puncture was performed demon- lized in the liver mainly by cytochrome P450 (CYP)2D6 to form 9-hydroxyris- A 79-year-old African American strating normal protein and glucose levels, 1 red blood cell, and no white blood cells or peridone (9-OH risperidone), which woman with a history of mild dementia also blocks 5HT2 and D2 receptors. presented to our emergency department with organisms. Blood, urine, and cerebrospinal mental status changes, lethargy, and de- fluid cultures grew no organisms. Combined serum levels of risperidone creased oral intake for the past 2 weeks. She Paroxetine, risperidone, and galant- and the active metabolite 9-OH risperi- was accompanied by her daughters who amine were discontinued and the patient done are responsible for the therapeutic provided collateral history. There was no received warming blankets and intravenous effects of risperidone.8 Recent studies

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors indicate that risperidone may aid in the should take note of this interaction an autistic child. J Child Adolesc Psychophar- treatment of depression by augmenting between these 2 agents that are common- macol. 2004;14(3):342–343. 12. Hamilton S, Malone K. Serotonin syndrome the activity of selective serotonin reup- ly used in the elderly population. 9 during treatment with paroxetine and risper- take inhibitors, including paroxetine. idone. J Clin Psychopharmacol. 2000;20(1): Risperidone and paroxetine interaction 103–105. can lead to weight gain,10 priapism,11 M. Obadah Al Chekakie, MD* 13. Paroxetine[packageinsert].ResearchTriangle and rarely to serotonin syndrome.12 Jeffrey M. Ketz, PharmD Park, NC: GlaxoSmithKline Pharmaceuti- y cals; January 2005. Paroxetine is a substrate and in- Christopher M. Whinney, MD 14. Spina E, D’Arrigo C, Migliardi G, et al. hibitor of CYP2D6. Metabolism by *Department of Cardiologyz Plasma concentrations of risperidone and 9- the CYP2D6 enzyme is saturable at Loyola University Medical Center hydroxyrisperidone during combined treat- usual doses of paroxetine in 90% of Maywood, IL; ment with paroxetine. Ther Drug Monit. 2004; 13 Department of Pharmacy 26(4):386–390. patients. Paroxetine is known to raise y 15. Galantamine [package insert]. Titusville, NJ: the plasma concentration of risperidone Cleveland Clinic Foundation Janssen Pharmaceutica; March 2005. and 9-OH risperidone. When paroxetine Cleveland, OH 16. Bentue-Ferrer D, Tribut O, Polard E, was added to risperidone therapy, Spina and Section of Hospital Medicine et al. Clinically significant drug interac- z tions with cholinesterase inhibitors: a guide et al14 observed a 45% increase in mean Department of General Internal Medicine Cleveland Clinic Foundation for neurologists. CNS Drugs. 2003;17(13): risperidone plus 9-OH risperidone (ris- 947–963. Cleveland, OH peridone active moiety) concentrations 17. Huang F, Lasseter KC, Janssens L, et al. [email protected] in 10 CYP2D6 extensive metabolizers. Pharmacokinetic and safety assessments of galantamine and risperidone after the Our patient was also receiving galant- two drugs are administered alone and amine, a competitive inhibitor of acetyl- together. J Clin Pharmacol. 2002;42(12): cholinesterase. Galantamine is metabolized REFERENCES 1341–1351. via CYP2D6 and CYP3A4 but it does not 18. Scott LJ, Goa KL. Galantamine: a review of 15,16 1. Yoder E. Disorders due to heat and cold. In: its use in Alzheimer’s disease. Drugs. 2000; inhibit those enzymes. Coadministra- William P, Arend MD, et al, eds. Cecil Text 60(5):1095–1122. tion of galantamine and risperidone does Book of Medicine, Vol 1. 5th ed. New York, 19. Bores GM, Huger FP, Petko W, not increase the serum concentration of NY: WB Saunders; 2004:626–628. et al. Pharmacological evaluation of novel risperidone active moiety.17 Paroxetine 2. Parris C, Mack JM, Cochiolo JA, et al. Alzheimer’s disease therapeutics: acetylcho- can raise galantamine levels by inhibit- Hypothermia in 2 patients treated with linesterase inhibitors related to galantha- ing CYP2D6 leading to a 40% increase atypical antipsychotic medication. J Clin mine. J Pharmacol Exp Ther.1996;277(2): 16,18 Psychiatry. 2001;62(1):61–63. 728–738. in its bioavailability. Galantamine 3. Schwaninger M, Weisbrod M, Schwab S, 20. Gordon CJ. Thermoregulatory aspects of has been reported to cause hypothermia et al. Hypothermia induced by atypical neu- environmental exposure to anticholinester- in animal models,19 but there are no roleptics. Clin Neuropharmacol. 1998;21(6): ase agents. Rev Environ Health. 1996; reported cases of galantamine-induced 344–346. 11(3):101–117. 4. Phan TG, Yu RY, Hersch MI. Hypothermia hypothermia in humans in the English induced by risperidone and olanzapine in a literature. In organophosphate poison- patient with Prader-Willi syndrome. Med J ing, which usually leads to irreversible Aust. 1998;169(4):230–231. inhibition of acetylcholinesterase, hu- 5. Brevik A, Farver D. Atypical antipsychotic Impact of Orally mans usually have a hyperthermic induced mild hypothermia. S D J Med. 2003; 56(2):67–70. response compared with the hypother- Disintegrating 20 6. Razaq M, Samma M. A case of risperidone- mic response noted in rodents. Galant- induced hypothermia. Am J Ther. 2004;11(3): Olanzapine on Use of amine potentially may have contributed 229–230. to this patient’s hypothermia because of 7. Leysen JE, Janssen PM, Megens AA, et al. Intramuscular the pharmacokinetic interaction of gal- Risperidone: a novel antipsychotic with bal- anced serotonin-dopamine antagonism, recep- Antipsychotics, antamine and paroxetine or to a possible tor occupancy profile, and pharmacologic pharmacodynamic interaction between activity. J Clin Psychiatry. 1994;55(suppl): Seclusion, and galantamine and risperidone. However, 5–12. accumulated clinical data in humans do 8. Heykants J, Huang ML, Mannens G, et al. The Restraint in an Acute not support this hypothesis. The de- pharmacokinetics of risperidone in humans: Inpatient Psychiatric crease in oral intake might be a result of asummary.JClinPsychiatry.1994;55(suppl): hypothermia and not the cause of it, 13–17. 9. Ostroff RB, Nelson JC. Risperidone augmen- Setting especially since the patient had no tation of selective serotonin reuptake inhibi- clinical signs of dehydration. tors in major depression. J Clin Psychiatry. To our knowledge, this is the sixth 1999;60(4):256–259. To the Editors: reported case of risperidone-induced hy- 10. Fukui H, Murai T. Severe weight gain Intramuscular (IM) conventional pothermia. The drug interaction between induced by combination treatment with antipsychotics have long been used to risperidone and paroxetine. Clin Neurophar- paroxetine and risperidone may also have macol. 2002;25(5):269–271. manage agitation and aggression in the 1 been a factor in the development of 11. Yang P, Tsai JH. Occurrence of priapism psychiatric inpatient setting. Although hypothermia in this patient. Clinicians with risperidone-paroxetine combination in generally effective, these preparations n 2006 Lippincott Williams & Wilkins 333

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 have multiple drawbacks, both in terms in the 6 months after its introduction substance use disorders (excluding sub- of side effects2–6 and as a consequence (the ‘‘POST’’ group). The PICU is a stance-induced psychotic disorder), and of their route of administration. In locked, 12-bed psychiatric ‘‘crisis’’ unit (6) all other diagnoses.11 addition to these factors, treatment for the most acutely ill psychiatric invoking the principle of the ‘‘least patients treated at the West Los Angeles Administration of restrictive environment or intervention’’ VA. The study protocol was approved Intramuscular and Oral has become generally accepted in the by the West Los Angeles VAMC Antipsychotics for Acute psychiatric community.7 This ethical Institutional Review Board. An exemp- Agitation standpoint serves as a compromise tion to the requirement for informed The data regarding the number of between individual rights and severely consent was obtained by excluding administrations of emergent IM con- mentally ill patients’ need for treatment, identifying data and by other security ventional antipsychotics for both study particularly in cases in which impaired measures to protect confidential patient groups and of olanzapine Zydis in the reality testing or impulse control may information. POST group are shown in Table 1. be associated with potentially danger- There were no significant differences between the 2 groups. ous behavior. From this perspective, it Patient Demographics is important to reduce the use of both and Diagnoses Seclusion and Restraint invasive routes of medication adminis- The demographic and diagnostic In the PRE group, 16 patients tration and seclusion and restraint. information for the 2 groups are pre- (8.8%) were placed in seclusion, and 13 Finally, a reduction in the number of sented in Table 1. For purposes of (7.2%) were placed in restraints. In the violent outbursts and episodes of seclu- analysis, diagnoses assigned at the time POST group, 16 patients (9.4%) were sion and restraint may improve patient placed in seclusion, and 12 (7.0%) were 8,9 of discharge or transfer were divided into and staff morale. 6categories:(1)primarypsychoticdis- placed in restraints. There were no signif- Recently, literature has emerged orders (ie, schizophrenia and schizoaffec- icant differences between the 2 groups. showing that, in patients willing to take tive disorder), (2) substance-induced them, oral atypical antipsychotics are as psychotic disorder and psychotic disorder DISCUSSION effective as IM conventional antipsy- not otherwise specified, (3) type I bipolar The results of this study do not sup- chotics in treating acute psychotic disorder, (4) dementia or delirium, (5) port our hypothesis that the availability of agitation.10 We report on the use of a rapidly dissolving oral formulation of TABLE 1. Patient Demographics, Diagnoses, and Use of p.r.n. Antipsychotics an atypical antipsychotic (olanzapine; Zyprexa, Eli Lilly and Co, Indianapolis, PRE Group POST Group IN; Zydis, Cardinal Health Pharmaceu- (n = 181) (n = 171) tical Technologies and Services, Som- Age, mean ± SD, y 46.6 ± 8.5 47.5 ± 9.2 erset, NJ) on a high-intensity acute Male, n (%) 166 (92) 161 (94) inpatient ward. Length of stay, mean ± SD, d 7.4 ± 8.7 8.2 ± 10.2 In November 2002, the psychiat- Caucasian, n (%) 78 (43) 69 (40) ric intensive care unit (PICU) at the West Los Angeles Veterans’ Affairs African American, n (%) 75 (41) 87 (51) Medical Center (VAMC) replaced 5 mg Hispanic, n (%) 20 (11) 13 (8) oral haloperidol with 10 mg olanzapine Other, n (%) 8 (4) 2 (1) Zydis (an oral, rapidly disintegrating Primary psychotic disorder, n (%) 44 (24.3) 46 (26.9) ‘‘wafer’’ formulation) as the ‘‘as need- Substance-induced psychosis/psychosis 19 (10.5) 15 (8.8) ed’’ oral antipsychotic of choice for not otherwise specified, n (%) agitation. We hypothesized that the Bipolar disorder, n (%) 22 (12.2) 15 (8.8) availability of oral olanzapine Zydis Dementia/delirium, n (%) 7 (3.9) 7 (4.1) would reduce the use of IM antipsy- Substance use disorder, n (%) 62 (34.3) 66 (38.6) chotics in this setting. We also exam- All emergent IM conventional 27 (14.9) 26 (15.2) ined the impact of olanzapine Zydis on antipsychotics, n (%) the use of seclusion and restraint. ‘‘First-line’’ emergent IM N/A 20 (11.7) In a retrospective chart review, conventional antipsychotics, n (%) we collected data on the use of p.r.n. ‘‘Second-line’’ emergent IM N/A 9 (5.3) IM antipsychotics, seclusion, and re- conventional antipsychotics, n (%) straint for all patients admitted to the Emergent oral olanzapine Zydis, n (%) N/A 37 (21.6) PICU at the VAMC in West Los PRE indicates patients admitted in 6-month period before addition of olanzapine Zydis to the ward Angeles in the 6 months before the formulary; POST, patients admitted in six-month period after addition of olanzapine Zydis to the ward introduction of olanzapine Zydis to the formulary; N/A, not applicable; first-line, before administration of olanzapine Zydis; second-line, after ward formulary (the ‘‘PRE’’ group) and administration of olanzapine Zydis (for a given episode of agitation).

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors a rapidly disintegrating formulation of medication. Thus, there may have been Los Angeles, CA an atypical antipsychotic for emergent a tradeoff between use of benzodiaze- [email protected] use would reduce the use of IM anti- pines and olanzapine Zydis after the psychotics or of seclusion or restraint in introduction of the latter. A study in an acute inpatient psychiatric setting. In which only antipsychotics were used comparison with a similar patient popu- might provide a more definitive com- REFERENCES lation admitted before the addition of parison of the utility of oral atypical 1. Buckley PF. The role of typical and atypical olanzapine Zydis to the ward formulary, antipsychotics versus IM medications in antipsychotic medications in the management the study group demonstrated no change controlling severe agitation. of agitation and aggression. J Clin Psychiatry. in use of IM antipsychotics, seclusion, 1999;60(suppl 10):52–60. It should also be remembered that 2. Ayd FJ Jr. A survey of drug-induced ex- or restraint. While this may suggest that although olanzapine Zydis dissolves tra pyramidal reactions. JAMA. 1961;175: the introduction of olanzapine Zydis to rapidly in the mouth, its absorption 1054–1060. the ward formulary did not reduce the occurs via the gastric mucosa. There- 3. Van Putten T, Marder SR. Behavioral toxicity use of more restrictive interventions, the fore, its onset of action is equivalent to of antipsychotic drugs. J Clin Psychiatry. lack of a quantitative measurement of the tablet form.12 This relatively slow 1987;48(suppl 9):13–19. illness severity (eg, a Global Assessment onset of action (peak plasma level at 6 4. Keck PE Jr, Pope HG Jr, Cohen BM, et al. of Functioning score at the time of Risk factors for neuroleptic malignant syn- hours after administration) may in part drome: a case-control study. Arch Gen admission) precludes drawing any firm explain the lack of effect seen for conclusions regarding the impact or lack Psychiatry. 1989;46:914–918. olanzapine Zydis in reducing emergent 5. Casey DE. Motor and mental aspects of of impact of the availability of p.r.n. IM use and seclusion and restraint in the extrapyramidal syndromes. Int Clin Psycho- olanzapine Zydis on these outcome present study. It is possible that IM pharmacol. 1995;10(suppl 3):105–114. measures. In other words, it is possible antipsychotics, seclusion, or restraint 6. Czekalla J, Beasley CM Jr, Dellva MA, et al. that a difference in overall illness se- was used before the onset of the clinical Analysis of the QTc interval during olanza- verity between the 2 groups may have effect of olanzapine Zydis. pine treatment of patients with schizophrenia obscured any potential benefits such as The use of IM atypical antipsy- and related psychosis. J Clin Psychiatry. reduced use of IM antipsychotics, seclu- 2001;62:191–198. chotics, such as olanzapine and ziprasi- sion, or restraint. However, this possible 7. Munetz MR, Geller JL. The least re- done, both of which have been recently explanation seems less likely when strictive alternative in the postinstitutional approved for acute use in the United era. Hosp Community Psychiatry. 1993;44: considering the lack of any known States, would avoid this pharmacokinetic 967–973. changes in the VA population accessing 8. Brennan W. We don’t have to take this: services during the 12 months of the disadvantage of oral olanzapine while maintaining atypical antipsychotic effica- dealing with violence at work. Nurs Stand. study and the similar demographics and 2000;14(suppl 28):3–17. distribution of diagnoses in the 2 groups. cy. These agents greatly reduce the fre- 9. Chengappa KNR, Levine J, Ulrich R, et al. This study has several limitations. quency of many of the adverse reactions Impact of risperidone on seclusion and Patients must agree, if only by assent, to seen with conventional antipsychotics, restraint at a state psychiatric hospital. Can take any oral medication. Patients who but obviously not those consequent to the J Psychiatry. 2000;45:827–832. IM route of administration. Neverthe- 10. Currier GW, Simpson GM. Risperidone are extremely ill or acutely agitated may liquid concentrate and oral lorazepam refuse oral medications, precluding this less, these agents may address the acute treatment needs of patients too agitated versus intramuscular haloperidol and intra- treatment option and necessitating IM muscular lorazepam for treatment of psy- medication when agitation requires to benefit from an oral agent. chotic agitation. J Clin Psychiatry. 2001;62: emergent medication. We did not assess 153–157. the role of patient refusal in the 11. American Psychiatric Association. Diagnos- ACKNOWLEDGMENT tic and Statistical Manual of Mental Dis- selection of interventions for emergent orders. Fourth Edition, Text Revision. agitation. Similarly, we did not address The authors thank George Bartzokis, Washington, DC; American Psychiatric As- the role of nursing staff’s clinical MD, for his help with data analysis and sociation; 2000. judgment regarding these interventions. interpretation. 12. Zyprexa Zydis Product Information. Indian- Another limitation of the study is apolis, IN: Eli Lilly and Co; June 2005. its naturalistic design. We did not Joseph R. Simpson Jr, MD, PhD* address variables such as standing Christopher R. Thompson, MD Altered Expression of antipsychotic or mood-stabilizing med- Mace Beckson, MD y ication orders or the use of p.r.n. oral *University of Southern California Keckzx Myeloperoxidase benzodiazepines. In fact, in the acute School of Medicine, Institute of Psychiatry, inpatient setting studied here, oral Law and Behavioral Science, Precursor, Myeloid Cell benzodiazepines, primarily lorazepam, University of California, Los Angeles Nuclear Differentiation are used frequently on a p.r.n. basis for y Neuropsychiatric Institute, anxiety and agitation. It is possible that University of California and Antigen, Fms-related those who did not respond to benzodia- Psychiatricz Intensive Care Unit Tyrosine Kinase 3 zepines had a more severe level of Departmentx of Veterans’ Affairs agitation more likely to require IM Greater Los Angeles Healthcare System Ligand, and Antigen n 2006 Lippincott Williams & Wilkins 335

the study. None of the patients had been in the clozapine-treated cells compared CD11A Genes in treated with clozapine previously. with the nontreated HL-60 cells. A list Leukocytes of Patients were excluded for the presence of genes with altered expression is of other Axis I diagnoses, besides available from the authors upon request. Clozapine-treated schizophrenia, such as chronic medical For quantitative RT-PCR analysis, we illnesses or any medication (other selected 4 of these genes, because they Schizophrenic Patients than psychopharmacological treatment) had been implicated in the maturation known to interfere with immune or or apoptosis of granulocytes for quan- endocrine function. Concomitantly with titative RT-PCR analysis. Two genes, To the Editors: the clozapine medication, the patients Fms-related tyrosine kinase 3 ligand Clozapine is an atypical antipsy- received other psychotropic drugs in- (FLT3LG) and myeloperoxidase pre- chotic drug that has been found to be cluding olanzapine (n = 6), ketiapine cursor (MPO), showed down-regulated superior in the treatment of schizophre- (n = 1), chlorpromazine (n = 2), expression; whereas 2 genes, myeloid nia resistant to conventional medication. valproic acid (n = 1), topiramate (n = cell nuclear differentiation antigen Its use is, however, limited by the asso- 1), sertraline (n = 1), citalopram (n = 2), (MNDA) and antigen CD11A, lym- ciated risk of agranulocytosis in approxi- diazepam (n = 3), temazepam (n = 1), phocyte function–associated antigen 1 mately 1% of the patients. The exact zopiclone (n = 4), and lorazepam (n = 3). 1 (ITGAL), were overexpressed after pathogenesis of clozapine-induced agranu- All of the patients gave their written treatment with clozapine. locytosis is still unclear. Several mecha- informed consent to participate in the Tables 1A and B show the ex- nisms such as immune-mediated cytolysis study, which had been approved by pression profiles of selected genes in and triggering of apoptosis or cytotoxicity the independent ethics committees of HL-60 cells and in the mononuclear have been suggested to cause depletion the respective hospitals. 2 leukocytes of the clozapine-treated pa- of granulocytes. In addition, clozapine Peripheral blood samples were tients. Enough RNA could not be is metabolized to the stable metabolites collected before starting the clozapine extracted from the granulocytes of in- demethyl-clozapine and clozapine N-oxide. treatment and during the treatment in dividual patients to allow RT-PCR Therefore, not only the parent com- time series of 0 hour, 3 hours, 3 days, analysis. We therefore pooled the sam- pound itself but also its metabolites may 2 months, and 4 months. The blood ples at each time point. Tables 1C and D be toxic. Agranulocytosis could hence sample preparation and RNA extraction demonstrate the alterations in gene be a complex entity with involvement were performed with minor modi- expression. Myeloperoxidase precursor of several molecular mechanisms. fications as described earlier; RNA gene was significantly underexpressed We investigated the effect of concentration was measured using a and MNDA overexpressed already 3 clozapine on gene expression in granu- spectrophotometer (Gene Quant Pro; hours after drug intake, resembling the locytes by performing a microarray Amersham Pharmacia Biotech, NJ).3 kinetics of altered gene expression seen analysis on RNA isolated from the HL-60 cells were cultured for 3 days in the HL-60 cells. Moreover, both genes remained down-regulated or up- blood leukocytes of schizophrenic in RPMI-1640 medium supplemented patients who started clozapine treatment regulated after 3 days, 2 months, and with 10% fetal bovine serum. To for the first time. In addition, the gene 4 months, respectively. Also, the compare the gene expression pattern expression pattern was compared in FLT3LG gene showed linear down- between clozapine-treated and non- vitro between clozapine-treated and regulation at all time points but less treated HL-60 cells, we performed the nontreated granulocytic human pro- significantly. In contrast, the ITGAL myelocytic leukemia (HL-60) cells. We complementary DNA (cDNA) array. gene was up-regulated after 3 hours but then performed a quantitative real-time We then performed the RT-PCR on down-regulated at 3 days and 2 months, reverse transcriptase-polymerase chain selected genes from the cDNA to yet up-regulated again at 4 months. reaction (RT-PCR) analysis to validate validate the changed gene expressions By using the cDNA microarray the biologically interesting changed in the HL-60 cells after clozapine technique, we could identify 4 genes im- gene expression patterns in the lympho- treatment and in the lymphocytes of plicated in the maturation or apoptosis cytes of the clozapine-treated patients clozapine-treated patients. In the patient of granulocytes that displayed altered and compared them with the changes in leukocytes, quantitative RT-PCR anal- expression. Because the respective gene expression in the HL-60 cells ysis was also used to reveal differences changed expression profiles of the before and after exposure to clozapine. in gene expression at 5 different time MPO and MNDA genes persisted in a Eight white Finnish-born inpa- points of clozapine treatment. A de- linear curve through all time points up tients (7 men and 1 woman; mean age, tailed description of all the procedures until four months, these gene alterations 29.8 years; range, 19–43 years) who can be requested from the authors. Two- may have significance in clozapine- met the Diagnostic and Statistical tailed nonlinear equation model Student induced agranulocytosis. It is notewor- Manual of Mental Disorders, Fourth t tests were used to evaluate the fold thy that most clozapine- induced agran- Edition (Text Revision) diagnostic cri- changes in gene expression, and signif- ulocytosis occurs within 3 months of teria for schizophrenia and who icance was defined as P less than 0.05. starting treatment.1 Also, the findings responded insufficiently to other anti- Twenty four of the 588 genes in the HL-60 cells supported this ob- psychotic treatments were included in analyzed showed a different expression servation. As the patients used other

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors antipsychotics including olanzapine, control group. The similar kinetics in the clozapine-treated HL-60 cells, however, their involvement in the results cannot patient lymphocytes, where clozapine supports a role of clozapine in the altered be excluded because we did not have a was started for the first time, and in the gene expression pattern. Furthermore, the recent findings point toward a unique role of clozapine in these alterations.4,5 TABLE 1. Kinetics of altered expression of the MPO, MNDA, FLT3LG, and ITGAL genes (shown as fold changes) after treatment with clozapine in HL-60 cells (A), in A lower expression of MPO gene in the mononuclear leukocytes of individual schizophrenic patients (B), in pooled RNA granulocytes may be caused by its direct (8 individuals) from mononuclear leukocytes (C), and from granulocytes (D) inhibition of MPO gene transcription by quantitated by real-time RT-PCR clozapine. Alternatively, clozapine treatment may select for subclones of gran- MPO MNDA FLT3LG ITGAL ulocytes with low natural MPO A. HL-60 cells expression, whereas cells with high 3 d, cDNA 0.179 2.116 0.182 1.97 expression of MPO are eliminated by nitrenium ion toxicity. Immunodestruc- 3 d, RT-PCR 0.036 5.526 0.606 0.637 tion of leukocytes, which are antigenical- B. Mononuclear leukocytes ly modified by binding of clozapine Patient 1 metabolites, should still be considered a 3 h 0.991 1.116 0.8154 1.5832 pathogenetic event in agranulocytosis.6–8 3 d 0.9645 0.987 0.6875 1.3337 Our observations in this prelimi- Patient 2 nary study suggest that the expression 3 h 0.9865 0.841 1.30259 0.5719 of MPO and MNDA genes is altered in 3 d 0.9638 0.3941 0.99312 0.4084 granulocytes after clozapine adminis- Patient 3 tration. This may have some bearing 3 h 0.9895 2.797 0.80501 — on the clozapine-induced hematotoxic 3 d 0.9769 1.969 0.6992 — reaction in schizophrenic patients. The Patient 4 altered gene expression patterns of the FLT3LG and ITGAL genes may also 3 h 0.976 0.563 0.9146 1.272 suggest their involvement. 3 d 0.9656 1.032 0.7764 1.247 Patient 5 3 h 0.9406 1.055 0.84156 0.971 Liisa Lahdelma, MD* 3 d 0.97518 1.056 0.52967 0.976 Kowan Ja Jee, PhDy Patient 6 Grigori Joffe, MD, PhDy 3 h 0.9984 1.028 0.396 1.522 Evgueni Tchoukhine, MDz 3 d 0.9709 1.055 0.489 1.4408 Jorma Oksanen, MDz Patient 7 Sippy Kaur, MScx 3 h 1.015 1.214 0.8014 2.583 Sakari Knuutila, MD, PhD y 3 d 1.0417 1.195 0.5985 2.8679 Leif C. Andersson, MD, PhDyk Patient 8 *Department of Psychiatryyk 3 h 0.9839 1.047 0.8607 1.508 University of Helsinki, Finland, 3 d 0.9748 0.906 1.4894 0.943 Department of Pathology y P for patients 1–8 for 3 h 0.0446* 0.2057 0.0556 0.0589 Haartman Institute P for patients 1–8 for 3 d 0.0281* 0.3214 0.7367 0.1549 University of Helsinki C. Pooled RNA from mononuclear leukocytes Helsinki, Finland, Kellokoski Hospital 3 h 0.98 1.06 0.92 0.88 Hospitalz District of Helsinki 3 d 0.96 1.12 0.82 0.92 and Uusimaa, Finland, 2 mo 0.84 0.74 0.92 1.23 Aurora Hospital 4 mo 0.74 1.68 0.83 4.02 City of Helsinki Healthx Care Center P 0.061 0.249 0.194 0.009* Helsinki, Finland D. Pooled RNA from granulocytes and HUSLAB, Helsinki University 3 h 0.76 1 0.967 1.007 Centralk Hospital, Helsinki, Finland 3 d 0.599 1.037 0.662 0.947 [email protected] 2 mo 0.521 1.044 0.602 0.939 4 mo 0.5 2.85 0.82 6.46 P 0.0018* 0.0002* 0.2010 0.0757 ACKNOWLEDGMENTS This study was supported by the *Significant difference at P < 0.05 by t test. Finnish Cultural Foundation (Helsinki, n 2006 Lippincott Williams & Wilkins 337

Finland) and the Jalmari and Rauha inactivation of neurotransmitters, in- pants were men (Study 1, 80%; Study 2, Ahokas Foundation/Vuorisalo Founda- cluding dopamine, norepinephrine, and 86%) and African American (Study 1, tion (Helsinki, Finland). The authors serotonin. A common functional poly- 54%; Study 2, 58%). Mean duration of also thank Novartis Finland Oy, Espoo morphism at codon 158 in the gene participation in the 2 studies was 10.7 for the donation of clozapine. controlling COMT results in substantial weeks (SD, 3.7 weeks). Treatment re- differences in enzyme activity: the Met sponse was measured in terms of change allele is associated with low enzyme in Positive and Negative Syndrome REFERENCES activity and the Val allele, with high Scale (PANSS) total score from baseline 1 1. Alvir JM, Lieberman JA, Safferman AZ, et al. activity. The MAOA gene, located on to end point. Participants showing a Clozapine-induced agranulocytosis. Incidence the X chromosome, is associated with a reduction of at least 20% from baseline and risk factors in United States. N Engl J 30-base pair variable number tandem Med. 1993;329:162–167. were classified as ‘‘responders’’. Mean repeat located in the promoter that PANSS change (baseline-end point) did 2. Williams DP, Pirmohamed M, Naisbitt DJ, 2 et al. Induction of metabolism-dependent and affects enzyme activity. The 3.5 and not differ significantly between studies -independent neutrophil apoptosis by cloza- 4 repeat alleles confer high enzyme (F = 0.97, df = 1, 102; P = 0.327). How- pine. Mol Pharmacol. 2000;58:207–216. activity, whereas the 3 and 5 repeat ever, more of the genotyped participants 3. Airla N, Luomala M, Elovaara I, et al. Suppres- alleles confer low activity. The status of sion of immune system genes by methylprednis- were classified as responders in Study 1 olone in exacerbations of multiple sclerosis. the 2 repeat allele is unclear, but some (44.3% vs 26% in Study 2; m2 = 3.98, Preliminary results. JNeurol.2004;251:1215– investigators have classified it as low 3 df = 1; P = 0.046). 1219. activity based on its short length. Table 1 shows the mean PANSS 4. Mosyagin I, Dettling M, Roots I, et al. Impact Illi et al4 examined the relation- of myeloperoxidase and NADPH-oxidase changes and numbers of responders and polymorphisms in drug-induced agranulocy- ship between COMT and MAOA geno- nonresponders as a function of geno- tosis. J Clin Psychopharmacol. 2004;24:613– types and response to treatment in 94 types. Analysis of covariance using 617. schizophrenic patients receiving a first baseline severity and study as covari- 5. Fehsel K, Loeffler S, Krieger K, et al. generation antipsychotic. The low activ- Clozapine induces oxidative stress and proa- ates revealed no significant difference poptotic gene expression in neutrophils of ity (Met/Met) COMT genotype was among COMT genotypes in either mean schizophrenic patients. J Clin Psychopharma- significantly more common in nonres- change in PANSS (F = 0.05, df = 2, 102; col. 2005;25:419–426. ponders. Although MAOA genotype P = 0.621) or number of responders 6. Utrecht JP. The role of leukocyte-generated 2 reactive metabolites in the pathogenesis of alone did not differentiate between the (m = 0.24, df = 2; P = 0.888). Although idiosyncratic drug reactions. Drug Metab Rev. responders and nonresponders, signifi- the L/L genotype was more than twice 1992;24:299–366. cantly fewer subjects with both the low as frequent in nonresponders as com- 7. Williams DP, Pirmohamed M, Naisbitt DJ, activity COMT and MAOA genotypes pared with responders, the effect was et al. Neutrophil cytotoxicity of the chemi- not significant. To facilitate comparison cally reactive metabolite(s) of clozapine: were responders. possible role in agranulocytosis. J Pharmacol We examined the relationship with Illi et al, we contrasted L/L subjects Exp Ther. 1997;283:1375–1382. between COMT and MAOA genotypes with H/H and H/L combined. Again, 8. Liu ZC, Utrecht JP. Clozapine is oxidated and response to treatment in a com- no significant differences were found, by activated human neutrophils to a reac- either on mean change in PANSS tive nitrenium ion that irreversibly binds bined sample of patients with schizophrenia or schizoaffective disorder from 2 (F = 0.51, df = 1,104; P = 0.475) or to cells. J Pharmacol Exp Ther. 1995;275: 2 1476–1483. randomized, double-blind studies con- number of responders (m = 0.13, df = 1, ducted at the same facility, using very P = 0.722; odds ratio, 0.797; 95% comparable procedures, assessments, confidence interval, 0.228–2.784). and schedules. Volavka et al5 compared Three alleles (2, 3, and 4) of the Catechol-O- clozapine, haloperidol, olanzapine, and MAOA gene promoter polymorphism risperidone in treatment resistant pa- were observed in this sample. The 3 methyltransferase and tients (Study 1) and Krakowski et al6 and 4 alleles constituted approximately Monoamine Oxidase-A compared olanzapine and clozapine to 46% and 49%, respectively, of the ob- haloperidol in persistently violent pa- served alleles. We designated subjects Polymorphisms and tients (Study 2). with the 3-repeat low-activity allele(s) The COMT and MAOA genotypes as ‘‘Low MAOA’’ and all others as Treatment Response to were determined for 108 (Study 1, 58/ ‘‘High MAOA.’’ There were no signifi- Typical and Atypical Study 2, 50) and 106 participants (Study cant differences between Low and High 1, 60/Study 2, 46), respectively. Both MAOA groups in change in PANSS Neuroleptics genotypes were in Hardy-Weinberg (F = 0.16, df = 1,102; P = 0.690) or equilibrium in the sample. Because number of responders (m2 = 1.95, df = 1, genotyping was not initiated at the P = 0.163). To the Editors: beginning of either study, the genotyped The small number of Low COMT Monoamine oxidase (MAO) and subsets were not necessarily representa- subjects precluded a valid test of the catechol-O-methyltransferase (COMT) tive of the larger study samples from MAOA COMT interaction. Change are important enzymes in the metabolic which they were drawn. Most partici- in PANSSÂ total score was greatest in

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TABLE 1. COMT and MAOA Genotypes and Response to Treatment (Baseline-End Point)

Genotype Change in PANSS total* Nonresponders, n (%) Responders, n (%) COMT L/L 5.05 (15.72) 9 (69.2) 4 (30.8) L/H 2.72 (17.75) 38 (65.5) 20 (34.5) H/H 7.38 (14.54) 23 (62.2) 14 (37.8) MAOAy High 3.02 (15.82) 40 (70.2) 17 (29.8) Low 5.70 (18.79) 28 (57.1) 21 (42.9) COMT Highz/MAOA High 2.05 (16.17) 35 (71.4) 14 (28.6) COMT High/MAOA Low 5.39 (18.33) 23 (54.8) 19 (45.2) COMT Low/MAOA High 10.25 (12.12) 4 (66.7) 2 (33.3) COMT Low/MAOA Low 0.025 (10.82) 5 (83.3) 1 (16.7) À *Mean (Standard Deviation). yMAOA ‘‘High’’ genotype includes subjects with one or more copies of the 4 alleles; all other MAOA genotypes were classified as ‘‘Low.’’ zCOMT ‘‘High’’ genotype includes subjects with at least one copy of the high activity (Val) allele. COMT ‘‘Low’’ genotype includes only low activity (Met) homozygotes.

subjects with Low COMT and High personal interview but did not quantify Xingqun Ni, MD, PhD MAOA genotype (Table 1), but this change in psychopathology. In contrast, Jeffrey Lieberman, MD x difference was not statistically signifi- we prospectively measured change in Miranda Chakos, MDk{# cant (F = 1.73, df = 1, 98; P = 0.191). psychopathology with the PANSS and Jan Volavka, MD, PhD* We were unable to confirm the defined treatment response as a mini- y 4 *Nathan Kline Institute for Psychiatric results reported by Illi et al. In this mum 20% reduction from baseline in a Research, Orangeburg, NY; sample, neither the COMT nor MAOA randomized clinical trial. The COMT New York University School of Medicine polymorphism had any significant effect L/L genotype was comparatively rare y New York, NY; on response to antipsychotic treatment. in our ethnically heterogeneous sample. Albert Einstein College of Medicine However, all of Illi et al’s subjects Furthermore, our analyses combined z Bronx, NY; were treated with a first generation anti- the results of 2 studies that differed University of Toronto x psychotic as compared with 25% of in patient eligibility criteria, baseline Toronto, Ontario, Canada; our subjects. Antipsychotic medications symptom severity, and other aspects College of Physicians and Surgeons k differ in dopamine receptor affinity, that may have increased variance and Columbia University, New York, NY; with clozapine and olanzapine binding New York State Psychiatric Institute confounded the results of our compar- { more loosely to and releasing more rap- isons. Our sample combined patients New York, NY and idly from D2 receptors than haloperidol 5 #State University of New York Downstate 7 with treatment resistance and persis- and risperidone. As a result, pharma- tent aggression,6 perhaps confounding Medical Center, Brooklyn, NY cogenetic associations with treatment pharmacogenetic phenotypes. Resolu- [email protected] response might vary across medications. tion of the question of how COMT and Therefore, we also analyzed the rela- MAOA genotypes may be related to tionship between COMT and MAOA antipsychotic treatment response will REFERENCES genotypes and change in PANSS scores, require a prospective study designed 1. Lachman HM, Papolos DF, Saito T, et al. contrasting subjects who received clo- Human catechol-O-methyltransferase phar- zapine or olanzapine versus those who with sufficient power to compare re- macogenetics: description of a functional received haloperidol or risperidone. Anal- sponse to typical and atypical medica- polymorphism and its potential application tions in an ethnically and phenotypically to neuropsychiatric disorders. Pharmacoge- yses of covariance using treatment dura- netics. 1996;6:243–250. tion and ethnicity as covariates revealed homogeneous sample. 2. Sabol SZ, Hu S, Hamer D. A functional poly- no significant genotype medication morphism in the monoamine oxidase A gene interactions. Â promoter. Hum Genetics. 1998;103:273–279. Karen A. Nolan, PhD* 3. Caspi A, McClay J, Moffitt TE, et al. Role of The studies differed in other ways y genotype in the cycle of violence in mal- that also might have contributed to the Pa´l Czobor, PhD* treated children. Science. 2002;297:851–854. discrepant results. Illi et al based their Leslie L. Citrome, MD, MPH*y 4. Illi A, Mattila KM, Kampman O, et al. determination of treatment response on Menachem Krakowski, MD, PhD*y Catechol-O-methyltransferase and mono- y amine oxidase A genotypes and drug response retrospective evaluation of hospital Herbert M. Lachman, MD to conventional neuroleptics in schizophrenia. records, personal medical history, and a James L. Kennedy, MDz J Clin Psychopharmacol. 2003;23:429–434. x n 2006 Lippincott Williams & Wilkins 339

5. Volavka J, Czobor P, Sheitman B, et al. lasting minutes to hours, occurring once or EEG. Magnetic resonance imaging showed Clozapine, olanzapine, risperidone, and halo- twice a day, and accompanied by gustatory no mass or structural abnormalities. peridol in treatment-resistant patients with hallucinations of dog feces. The patient schizophrenia and schizoaffective disorder. He began taking topiramate 25 mg Am J Psychiatry. 2002;159:255–262. complained of abdominal pain (by which he BID, which was soon titrated to 75 mg 6. Krakowski M, Czobor P, Citrome L, et al. may have meant nausea) after the hallucina- BID, along with risperidone 1 mg BID, Atypical antipsychotic agents in the treat- tions. He felt that all jail staff was persecuting which was increased to 2 mg BID. His ment of violent schizophrenic and schizo- him with these horrible smells. He threatened symptoms improved remarkably over 5 affective patients. Arch Gen Psychiatry. 2006, unidentified others he believed responsible for days. He no longer voiced paranoid in press. ‘‘spraying smells’’ into his cell. He was thoughts about staff or officers spraying 7. Seeman P. Atypical antipsychotics: mecha- observed apparently attempting to rid himself nism of action. Can J Psychiatry. 2002;47: smells on him. He reported that the smells 27–38. of the sensations of smell and taste by had ceased. One month after discharge, washing his mouth frequently with soap and topiramate was decreased to 50 mg BID, to eating his toothpaste, which led to buccal decrease a side effect of gastrointestinal erosions and oral pain. upset. Shortly after this decrease in dose, Treatment of Olfactory He appeared moderately distressed, his olfactory hallucinations returned. He paced about his cell, and accused staff of accepted an increase in dosage to top- Hallucinations with ‘‘spraying smells.’’ His affect was anxious, iramate 75 mg BID and then eventually to Topiramate full, and congruent. He quickly escalated to 125 mg BID. At the time of this writing, he anger when discussing his olfactory halluci- is on topiramate 125 mg BID and is nations. His speech was rapid, although not hallucination-free. He has been on risperidone 2 mg BID throughout the period of pressured, and normal in volume and tone. To the Editors: topiramate adjustment. He has also been His thought process was tangential. Mini- free of paranoid delusions and other The authors report a case of Mental State Examination score was 20 of psychotic symptoms during this time. olfactory hallucinations in a schizo- 27, with deficits in attention and delayed phrenic patient. The patient’s symptoms recall. A neurological examination indicated were described as intermittent smells of abnormality of the olfactory system; when he ‘‘dog feces,’’ ‘‘wet dog,’’ and/or ‘‘fun- was asked to identify smells with his eyes DISCUSSION gus,’’ lasting from ‘‘minutes’’ to closed, he initially identified the smell of Olfactory dysfunction, misinter- ‘‘hours,’’ occuring once or twice daily hand soap as ‘‘urine.’’ No automatisms, pretation of odor, deficits in olfactory for four years prior to presentation. posturing, or confusion were observed sensitivity threshold, and abnormalities These symptoms persisted despite anti- around the periods when he reported expe- in odor memory are common in schizo- 1 psyhotic treatment. but were treated to riencing hallucinations. phrenia. The prevalence of olfactory complete resolution with topiramate. He was started on risperidone 1 mg hallucinations has been reported be- BID and lithium carbonate 300 mg BID. His tween 11% and 36% of schizophrenic risperidone was soon increased to 2 mg BID. patients.2–4 Other neuropsychiatric dis- CASE REPORT Although he continued to believe that his orders may present with olfactory hal- olfactory hallucinations were caused by lucinations, including traumatic brain A 36-year-old man, with a 10-year unidentified others spraying smells into his injury, cluster and migraine headaches, history of psychotic disorder, presented to room, he was willing to accept that there jail psychiatric inpatient services after ac- seizure disorders, central nervous system may be a ‘‘medical cause’’ for them and tumors, cerebral aneurysms, substance cusing corrections officers of ‘‘throwing stopped making retaliatory threats. As such, smells of feces’’ into his room. He had had abuse, mood disorders, eating disorders, despite his remaining olfactory hallucina- a similar presentation with olfactory halluci- the olfactory reference syndrome (an tions, he was discharged from the inpatient unit nations. He reported multiple previous trials excessive, irrational fear that one is to the general jail population. of antipsychotics. A short trial of valproic emitting a foul or unpleasant odor), and acid was discontinued because of trans- Two weeks later, he returned to the iatrogenic conditions.5 inpatient psychiatric service on an involun- aminitis. His olfactory hallucinations did One old study suggests that ol- not respond to these medication trials. tary hold for grave disability after repeatedly factory hallucinations in schizophrenia However, his thought process became more pressing his cell’s emergency call button and 6 linear and organized, and the intensity of his complaining of ‘‘terrible smells.’’ On read- are resistant to antipsychotic treatment. delusional beliefs about the source of the mission, he repeated his delusion that an Furthermore, reportedly successful treat- smells decreased. An electroencephalogram unidentified ‘‘they’’ continually sprayed his ment options for idiopathic olfactory hal- (EEG) performed shortly after his first room with fecal and fungal smells. He lucinations include surgical extirpation of hospitalization revealed no epileptiform ac- blamed staff for ‘‘spraying smells’’ in his the olfactory epithelium and olfactory tivity. However, there was no note of whether bulb ablation. Majumdar et al5 reported he had experienced hallucinations at the time cell. He was paranoid and angry and refused of the EEG study. medications. His speech was rapid and 2 cases of idiopathic olfactory hallucinations responsive to anticonvulsant On the current presentation, he reported pressured; his thoughts were tangential; and he was intrusive and difficult to redirect. therapy (sodium valproate and phenytoin). that the smells that officers were ‘‘throwing 3 at’’ him ‘‘expanded into (his) mouth’’ and A repeat EEG showed no epileptiform or Kopala et al noted that schizophrenic cell. The sensations of the olfactory halluci- interictal activity. Of note, there was no subjects with olfactory hallucinations nations were of ‘‘dog feces,’’ ‘‘fungus,’’ and/ record or whether he was experiencing described unpleasant odors such as ‘‘stale or ‘‘a wet dog.’’ They were intermittent, olfactory hallucinations at the time of the cigarettes’’ or ‘‘feces.’’ Meats7 observed

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors that olfactory hallucinations as the prima- the symptom’s correlation with struc- 12. Canive JM, Lewine JD, Edgar JC, et al. tural abnormalities, a complete neuro- Psychopharmacol Bull. 1996;32:741–750. ry complaint with secondary delusional 13. Llinas R, Urbano FJ, Leznik E, et al. interpretations may be a rare presentation logical evaluation (including EEG Rhythmic and dysrhythmic thalamocortical of late onset paranoid schizophrenia. studies to rule out seizure disorder) dynamics: GABA systems and the edge However, Meats7 also observed that, most should be performed in such a patient. effect. Trends Neurosci. 2005;28:325–333. commonly, olfactory hallucinations in Clinicians may try using an anticonvul- schizophrenia were ‘‘subordinate’’ to sant such as topiramate in such a case, other psychiatric symptoms. especially when olfactory hallucinations The Effects of It has been well established that are refractory to otherwise therapeutic olfactory dysfunctions of odor identifi- doses of antipsychotics. Topiramate Adjunctive cation, odor detection threshold sensitivity, and odor memory are present Treatment Added to 1 Joel Johnson, MD in schizophrenia. However, it is not James A. Bourgeois, OD, MD Antidepressants in clear that olfactory hallucinations are Cameron Quanbeck, MD necessarily related to this generalized Patients with Resistant Department of Psychiatry olfactory dysfunction. In particular, 2 and Behavioral Sciences studies3,4 have demonstrated no correla- Obsessive-compulsive University of California tion between the presence of olfactory Davis Medical Center Disorder hallucinations and olfactory dysfunction Sacramento, CA as identified the University of Pennsyl- [email protected] To the Editors: vania Smell Identification Test.8 There Obsessive-compulsive disorder are few studies that have implicated the (OCD) is a chronic disorder associated medial temporal structures in the patho- REFERENCES to substantial impact on the quality of genesis of olfactory dysfunction in life. Serotonin reuptake inhibitors (SRIs) 4 schizophrenia. Deep brain stimulation 1. Moberg PJ, Agin R, Gur RE, et al. Olfactory are considered first-line treatments for studies on epileptic patients showed that dysfunction in schizophrenia: a qualitative OCD with response rates ranging from and quantitative review. Neuropsychophar- olfactory hallucinations might be caused 1 9 macology. 1999;21:325–340. 42% to 53%. Many patients receive by left amygdala stimulation. More- 2. Mueser KT, Bellack AS, Brady EU. Halluci- some benefit but remain symptomatic over, of 13 patients with olfactory nations in schizophrenia. Acta Psychiatr Scand. despite an adequate SRI trial. Little epileptic auras, all showed epileptic foci 1989;82:26–29. practical advice is available to clinicians in the mesial-temporal region.10 3. Kopala LC, Good KP, Honer WG. Olfactory hallucinations and olfactory identification on next-step treatment strategies for Given no evidence of structural ability in patients with schizophrenia and other patients who have not responded to 2 or abnormality or epileptic focus and psychiatric disorders. Schizophr Res. 1993;12: more trials of SRIs. robust response to topiramate, we 205–211. Hollander et al1 list behavioral speculate, as did Majumdar et al,5 that 4. Stedman TJ, Clair AL. Neuropsychological, neurological and symptom correlates of im- therapy and a trial of clomipramine as there may be a focus of abnormal paired olfactory identification in schizophre- the 2 options most often used in the signal generation and reverberating nia. Schizophr Res. 1998;32:23–30. treatment of refractory OCD. The circuits possibly in the mesial-temporal 5. Majumdar S, Jones NS, McKerrow WS, et al. combination of SSRI with medications, region. Evidence has been growing for The management of idiopathic olfactory hallucinations: a study of two patients. Laryngo- such as risperidone, olanzapine, pindo- the involvement of such reverberating scope. 2003;113:879–881. lol, buspirone, lithium, morphine, and circuits resulting in neuropsychiatric 6. Goldberg SC, Klerman GL, Cole JO. Changes thyroid hormones, have been reported.2 11 symptoms. For example, Llinas et al in schizophrenic psychopathology and ward Efficacy has been found in double-blind used magnetoencephalography to dem- behavior as a function of phenothiazine treatment. Br J Psychiatry. 1965;11:120–133. studies using haloperidol, risperidone, onstrate abnormal low-frequency thala- 7. Meats P. Olfactory hallucinations. Br Med J quetiapine, and pindolol as augmenta- mocortical oscillatory activity in (Clin Res Ed). 1988;296:645. tion agents in treatment-resistant OCD. neuropsychiatric patients was recorded. 8. Doty RL, Shaman P, Dann M. Development of Case reports of significant response to the University of Pennsylvania Smell Identifi- Such persistent low-frequency thalamo- cation Test: a standardized microencapsulated carbamazepine and sodium valproate cortical dysrhythmia has been recorded test of olfactory function. Physiolog Behav. have also been reported.3 in patients with schizophrenia.12 More- 1984;32:489–502. Topiramate is an anticonvulsant 9. Gloor P, Olivier A, Quesney LF, et al. The role over; the postulated inhibitory effect of of the limbic system in experiential phenomena with a novel chemical structure. It has g-aminobutyric acid on these circuits13 of temporal lobe epilepsy. Ann Neurol. 1982; been used to treat bipolar disorder, binge- may explain why topiramate, which 12:129–144. eating disorder, alcohol dependence, and 10. Acharya V, Acharya J, Luders IL. Olfactory 4 enhances g-aminobutyric acid receptor epileptic auras. Neurology. 1998;51:56–61. impulse control disorders. Topiramate activity, was effective in our case. 11. Llinas RR, Ribary U, Jeanmonod D, et al. presents several mechanisms of action: Thalamocortical dysrhythmia: a neurological enhances the activity of g-aminobutyric A patient presenting to a psy- and neuropsychiatric syndrome character- chiatrist with olfactory hallucinations is ized by magnetoencephalography. Proc Natl acid at nonbenzodiazepine sites, blocks uncommon in clinical practice. Given Acad Sci U S A. 1999;96:15222–15227. voltage-gated sodium channels, weakly n 2006 Lippincott Williams & Wilkins 341

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 inhibits carbonic anhydrase isoenzymes 14 or more weeks of open flexible dose Functioning (GAF) Scale10 for measur- CAII and CAIV, and inhibits glutamate treatment of an SRI (fluoxetine 80 mg/d, ing social functioning. via alpha adenosine monophosphate/ paroxetine 60 mg/d, fluvoxamine 300 mg/d, Subjects were permitted to con- kainate.5,6 clomipramine 250 mg/d, sertraline tinue taking concurrent benzodiazepines Rosenberg et al7 by using single- 200 mg/d, citalopram 60 mg/d, or (n = 2) or antidepressant medications, venlafaxine 300 mg/d); and have not voxel proton magnetic resonance spec- provided that they have been on a stable responded or partially responded (Yale- troscopy reported abnormally high dose of these medications for at least Brown Obsessive-compulsive Scale [Y- glutamatergic concentrations in the cau- 8 weeks before entering the study and BOCS] <30% of baseline score). Ex- agreed not to change the dose of the date nuclei of children with OCD. After clusion criteria were the following: any concurrent medication over the course selective SRI (SSRI) treatment, a de- other primary Axis I psychiatric diag- of the study. crease in OCD symptoms severity was nosis; current DSM-IV eating disorder, Primary efficacy measurement was associated with a reduction in caudate body dysmorphic disorder, alcohol or defined as the number of responders with glutamatergic concentrations. Consider- substance abuse disorder, Axis II cluster Y-BOCS less than 30% of Y-BOCS– ing these results about an association B personality disorders (borderline or baseline score. For changes between between decreased caudate glutamater- antisocial), history of bipolar disorder, baseline and follow-up assessments, gic concentrations and a reduction in schizophrenia, delirium, dementia or Wilcoxon signed rank test was used OCD symptoms as well as topiramate other cognitive disorders, initiation of (Statistical Package for Social Sciences, psychotherapy within 4 months, seizure inhibitory effects on glutamate, we version 9.0; SPSS, Chicago, IL). disorders, history of kidney stones, and found of interest to investigate in this The sample included 7 men and 5 study the effects of adjunctive top- Y-BOCS–baseline score of 16 or lower. women who had a mean of 46.6 ± 7.7 iramate in treatment-resistant OCD. Topiramate was initially started at years, a mean age of OCD diagnoses Twelve consecutive subjects with 25 mg/d. The dose was increased by 30.3 ± 3.7. At baseline, the means of Y- Diagnostic and Statistical Manual of 25 mg the first week, then increased by BOCS and GAF scores were 28.3 ± 2.7 Mental Disorders, Fourth Edition 50 mg increments for the following and 47.3 ± 3.4, respectively. Patients (DSM-IV)–defined OCD for more than week, up to 100 mg/d at the end of week demographics, concurrent diagnoses, 3 years who had failed 2 or more 3. The dose was titrated upward until a treatment history, and response are listed adequate SRI trials were recruited. Top- clinical response was achieved. At the in Table 1. All patients completed the iramate therapy was added over 16 end of week 5, the topiramate dose could follow-up study. Ten patients were weeks. Patients were seen approximately be further increased by 50 mg/d each considered responders (83%). A signif- every 2 weeks. Inclusion criteria includ- week up to a maximum dose of 400 mg/d icant change was found from baseline ed the following: male or female; aged at week 9, if intolerance occurred the to end point in Y-BOCS (z = 3.063, À 18 to 65 years old; meet DSM-IV criteria dose was adjusted accordingly. All P = 0.002) and GAF scores (z = 3.064, À for OCD (by structured clinical inter- patients were rated by the treating P = 0.002). There were no correla- view [SCID]8); informed consent given clinician at 2 weeks intervals using the tions between doses of topiramate and by patients; received an adequate trial of Y-BOCS9 and the Global Assessment of changes in Y-BOCS and GAF ( f = 0.087,

TABLE 1. Clinical Characteristics of the Patients Age of Topiramate OCD Comorbid Antidepressant Dose Added Y-BOCS Y-BOCS GAF GAF Case Sex Age Diagnostic Diagnoses (mg/d) (mg/d) (Basal) (16 weeks) Basal (16 weeks) 1 M 50 28 None Venlafaxine (300) 250 23 16 43 68 2 M 47 32 PD Clomipramine (250), clonazepam (4) 250 25 12 48 75 3 M 45 30 SPh Fluoxetine (80), diazepam (10) 200 30 20 45 57 4 M 60 38 Dys Sertraline (200) 200 32 21 45 55 5 F 46 34 MDD Fluoxetine (80) 200 32 22 45 55 6 M 31 27 SPh Fluoxetine (80) 250 28 8 48 80 7 M 49 25 None Fluvoxamine (300) 225 28 22 48 58 8 F 53 31 PD, SPh Clomipramine (250) 250 28 14 50 65 9 F 39 33 Dys Fluoxetine (80) 300 30 25 45 50 10 M 43 29 GAD Fluvoxamine (300) 250 30 18 45 65 11 F 55 31 None Clomipramine (250) 225 28 15 51 69 12 F 41 26 Dys Clomipramine (250) 250 26 14 55 69 Dys indicates dysthimia; GAD, generalized anxiety disorder; MDD, major depressive disorder; PD, panic disorder; SPh, social phobia.

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P = 0.78; F = 0.138, P = 0.67). The mean mate receptors.14 In fact, nicotine 4. Arnone D. Review of the use of Topimate for time for responders to achieve a Y-BOC treatment of psychiatric disorders. Ann Gen withdrawal symptoms are reverted by Psychiatry. 2005;4:1–4. less than 30% was 9.5 ± 2.3 weeks. administration of glutamate receptor 5. White HS, Brown SD, Woodhead JH, et al. Compulsions improved first, and then antagonist.19 Therefore, it can be hy- Topiramate modulates GABA-evoked cur- obsessive thoughts benefited from ther- pothesized that glutamatergic dysfunc- rents in murine cortical neurons by non- apy later. During the second month of benzodiazepine mechanism. Epilepsia. 2000; tion could be involved on compulsive treatment, patients could resume work 41:S17–S20. 6. Gibbs JW, Sombati S, DeLorenzo RJ, et al. activities and also they commented on behaviors associated to OCD and on compulsive consumptions of addictive Cellular actions of topiramate: blockade of improvement social functioning. kainate-evoked inward currents in cultured The mean dose of topiramate at end disorders. In both cases, topiramate may hippocampal neurons. Epilepsia. 2002;41: point was 237.5 ± 29.1 mg/d (range, 200– represent a useful pharmacological strat- S10–S16. egy. In OCD, topiramate improves the 7. Rosenberg DR, MacMaster FP, Keshavan MS, 300). Most commonly reported side et al. Decrease in caudate glutamatergic con- effects included weight loss (3/12), seda- control of compulsive behaviors al- centrations in pediatric obsessive-compulsive tion (2/12), memory/word finding diffi- lowing patients to reduce obsessive disorder patients taking paroxetine. J Am culties (2/12), and paresthesia (2/12). thoughts, as behavioral therapies based Acad Child Adolesc Psychiatry. 2000;39: 20 1096–1103. This is the first study in which on response prevention techniques. 8. First MB, Spitzer RL, Gibbson M, et al. topiramate has been used in the treatment In conclusion, the results of this Structured Clinical Interview for DSM-IV of OCD. The results presented suggest study show that administration topira- Axis I Disorders-Clinician Version (SCIS- that this drug was well tolerated and may mate together to antidepressants signif- CV). Washington: American Psychiatric Press; result an effective strategy to treat 1997. icantly improved the symptoms of OCD 9. Goodman WK, Price LH, Rasmusen SA, et al. patients with OCD resistant to antide- patients resistant to antidepressant treat- The Yale-Brown obsessive-compulsive scale pressant therapy. Other anticonvulsants, ments. Main limitations of the study (Y-BOCS). Part 1: development, use and valproate and carbamazepine, have been are related to low number of patients reliability. Arch Gen Psychiatry. 1989;46: useful in the treatment of OCD associated included and because the open design. 1006–1011. to other psychiatric conditions.11 10. Endicott J, Spitzer RL, Fleiss JL, et al. The However, further well-designed studies global assessment scale: a procedure for A common model for addictive are needed to determine efficacy of this measuring overall severity of psychiatric behaviors (alcohol dependence) and strategy. disturbance. Arch Gen Psychiatry. 1976;33: OCD has been suggested.12 Craving 766–771. 11. Freeman MP, Freeman SA, McElroy SL. could represent obsessive thoughts, and Gabriel Rubio, MD, PhD* alcohol drinking could be a compulsive The comorbidity of bipolar and anxiety 12 Miguel A. Jimeńez-Arriero, MD, PhD disorders: prevalence, psychobiology and behavior. In fact, the obsessive- Isabel Martıńez-Gras, MD, PhD*y treatment issues. J Affect Disord. 2002; 68: compulsive drinking scale is being used 1–23. 13 Jorge Manzanares, PhD in studies on alcohol dependence. In z 12. Modell JG, Glaser BF, Cyr L, et al. Ob- a recent study, topiramate was better Toma´s Palomo, MD, PhD sessive and compulsive characteristics of y craving for alcohol in alcohol abuse and than placebo to decrease obsessive- *Mental Health Services of Retiro, Lope de 14 Rueda, Madrid, Spain, dependence. Alcohol Clin Exp Res. 1992;16: compulsive drinking scale scores. Fur- 272–274. Department of Psychiatry thermore, topiramate was useful in the y 13. Anton RF, Moak GH, Lathman PK. The treatment of cocaine15 or alcohol depen- Hospital Universitario 12 de Octubre obsessive compulsive drinking scale: a new dence16 and in other disorders with Madrid, Spain and method of assessing outcome in alcoholism Instituto de Neurociencias de Alicante treatment studies. Arch Gen Psychiatry. compulsive behaviors, such as binge z 1996;53:225–235. 17,18 Universidad Miguel Hernańdez-CSIC eating and compulsive gambling. 14. Johnson BA, Ait-Daoud B, Bowden CL, Sant Joan dÁlacant, Spain The precise neurochemical mech- et al. Oral topiramate in the treatment of [email protected] anism by which topiramate improved the alcohol dependence: a randomized controlled trial. Lancet. 2003;361:1677–1685. efficacy of the treatment in OCD patients 15. Kampman KM, Pettinati H, Lynch KG, et al. resistant to antidepressants remains to be A pilot trial of topiramate for the treatment elucidated. However, it is tempting to REFERENCES of cocaine dependence. Drug Alcohol De- speculate that modifications in glutama- 1. Hollander E, Bienstock CA, Koran LM, et al. pend. 2004;75:230–240. Refractory obsessive-compulsive disorder: 16. Rubio G, Manzanares J, Ponce G, et al. tergic function may be responsible, at state-of-the-art treatment. J Clin Psychiatry. Topiramate in the treatment of alcohol least in part, of the improved response of 2002;63(suppl 6):20–29. dependence: a case series. Pharmacopsy- topiramate. Glutamatergic dysfunction 2. Koran LM, Aboujaoude E, Bullock KD, chiatry. 2004; 37:37–40. was a common mechanism involved in et al. Double-blind treatment with oral 17. McElroy SL, Arnold LM, Shapira NA, et al. morphine in treatment-resistant obsessive- Topiramate in the treatment of binge eating both type of disorders, OCD and addic- compulsive disorder. J Clin Psychiatry. 2005; disorder associated with obesity: a random- tions. It has been suggested that efficacy 66:353–359. ized, placebo-controlled trial. Am J Psychi- of SSRIs and their actions in the 3. Hollander E, Pallanti S. Current and experi- atry. 2003;160:255–261. treatment of OCD could be associated mental therapeutics of OCD. In: Davis KL, 18. Danon PN, Lowengrub K, Gonopolski Y, with glutamate neurotransmission.7 In Charney D, Coyle JT, Nemeroff C, eds. et al. Topiramate versus fluvoxamine in the Neuropsychopharmacology: The Fifth Gener- treatment of pathological gambling. Clin addition, topiramate could decrease al- ation of Progress. Philadelphia: Lippincott Neuropharmacol. 2005;28:6–10. cohol drinking by antagonizing gluta- Williams & Wilkins; 2003:1647–1664. 19. Kenny PJ, Fabricio G, Markou A. Group II n 2006 Lippincott Williams & Wilkins 343

metabotropic and alpha-amino-3-hydroxy- are common. Lithium toxicity is serious DVP treatment for partial DVP respond- methyl-4-isoxazole propionate (AMPA)/ ers. In another subgroup of patients (n = Kainate glutamate receptors regulate the and a potentially lethal risk which is deficit in brain reward function associated greater in this population because of 17) already stabilized on the combina- with nicotine withdrawal in rats. J Pharma- difficulties with self-monitoring of fluid tion of lithium and DVP, we examined col Exp Ther. 2003;306:1068–1076. intake and illness reporting. Other lith- efficacy and safety of adding GP and 20. Baer L, Minichiello WE. Behavior therapy for gradually tapering off the lithium. Con- obsessive compulsive disorder. In: Burrows GD, ium side effects include cognitive slow- Noyes R, Roth M, eds. Handbook of Anxiety. ing and blurred vision, which persons comitant low-dose antipsychotic drug treatment was not an exclusion criterion, Amsterdam: Elsevier Science; 1990. 4. with MR may be unable to report. provided this was not begun in the month Glomerular damage and renal failure prior, and the dosage was held constant may result from chronic lithium treat- during the GP trial. Much Improved ment. Lithium may worsen seizure dis- Written informed consent for a orders, which are a common problem clinical trial of GP treatment was obtained Outcome With in this population. For these reasons, trial from the patient or guardian before Gabapentin-divalproex of an adjunctive antiseizure medication starting the medication. In each case, GP in place of lithium is warranted and may was gradually introduced, starting with Combination in Adults improve safety in this population. 100 mg at night for 3 to 7 days, then 100 Gabapentin, which was marketed mg BID for 3 to 7 days, then 100 mg TID With Bipolar Disorders with a therapeutic range of 100 to to continue. The slower weekly dosage and Developmental 1800 mg/d, is available in liquid form increase was used for patients with and has a better safety profile than lith- compromised motor function or gait Disabilities ium. Although GP is renally excreted like disturbance to avoid possible sedation, lithium, it has a higher therapeutic index. clumsiness, and falling. In most cases, the To the Editors: Thus, in the absence of renal failure, dose was then again gradually increased as above, stepwise to 300 mg TID as a Many preliminary reports sug- toxicity is less likely to be associated minimum therapeutic dose (see Table 1). gest that gabapentin (GP), the add-on with therapeutic doses. It does not bind A CGI6 was completed at baseline and significantly to plasma proteins nor does antiseizure medication, improves mood thereafter at each visit by the treating stabilization. Because persons with men- it interact with drug-metabolizing en- clinician (J.H.). tal retardation (MR) manifest more side zymes in the liver. This reasoning led to Lithium taper was attempted ex- effects of lithium, we studied GP as an the present trial of the newer antiseizure tremely gradually in those individuals in alternative add-on mood stabilizer to medication GP (Neurontin) in place of the subgroup of 17 patients receiving divalproex (DVP; Abbott Pharmaceuticals). lithium. Side effects of lethargy, seda- lithium-DVP combination, by 150 to Antiepilepticmood-stabilizingagents tion, ataxia, and dizziness occur in 10% 300 mg every 3 to 4 months. Gabapentin including DVP, may be more effective of patients receiving GP and are dose dose was increased further if a recur- than lithium for acute and maintenance related.4 Nausea, diarrhea, increased rence of clinically mild or moderate treatment of patients with mixed, chronic, appetite and weight gain, headache, symptoms of mood disorder or aggres- or rapid-cycling bipolar disorders.1 tremor, and nystagmus are less-frequent sion occurred. Lithium was again in- Combination treatment of DVP and creased in those patients who developed another mood stabilizer together with side effects which usually resolve after a few weeks of treatment.5 significant relapse in mood or aggres- low-dose antipsychotic drug may be sive symptoms, or reintroduced for Clinical chart data were reviewed required to achieve adequate stabiliza- those patients in whom it had been 2 tion in resistant cases. Patients with of 30 patients with MR diagnosed with discontinued. These were recorded as MR are more likely to present with bipolar mood disorder or schizoaffective failures of GP replacement of lithium. aggression and to experience chronic, disorder, bipolar type, who received GP Of the 30 adult patients in this mixed, or rapid cycling bipolar disorder as add-on treatment to DVP. All diag- series, 13 received GP as add-on to DVP. responsive to combination mood stabi- noses were made by the author and the 3 Twelve (92.3%) of the 13 were rated as lizers. Lithium treatment is commonly psychiatry resident in our University moderate problem or less and as much used for bipolar disorder; however, MR/Autism Psychiatric Adult Outpa- improved at 3 months and 1 year (see persons with MR often manifest several tient specialty clinic using Diagnostic Table 1). At 5.3 years mean duration of problematic side effects and risks of and Statistical Manual of Mental Dis- follow-up (range, 4–8 years), 9 (84.6%) lithium treatment. orders, Fourth Edition criteria. Treat- of the 11 continuing to follow up in our A prominent side effect produced ment success was defined as Clinical clinic remained a moderate problem or by lithium in this population is hand Global Impressions (CGI)–Severity of 4 less, and much improved on CGI. Two tremor, often marked and disabling. (moderate problem) or less and CGI- patients (numbers 9 and 10) were lost to Tremor worsens when lithium is Improvement of at least much improved. follow-up, one (patient 4) had ongoing combined with DVP and antipsychotic In one subgroup (n = 13), we examined partial seizures, mood lability, and bipo- drugs. Excessive drinking and enuresis treatment outcome after GP addition to lar symptoms, and one (patient 8) had

344 n 2006 Lippincott Williams & Wilkins

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors ongoing depressive cycles with psycho- and had significantly reduced tremor at curred during lithium taper, in one case motor retardation now showing prelimi- 3 months and also at 1 year (see Table 1). with associated long-standing compli- nary response to lamotrigine combined At 5.1 years mean duration (range, 2.5–7 ance issues that had already required with DVP and an antipsychotic. The me- years), all 8 patients continuing on the repeated hospitalizations. Another 3 dian GP dose in this subgroup was 1200 GP-DVP combination remained much patients relapsed after several months mg daily (range, 600–2100 mg daily). improved. One patient (no. 28) had been off lithium, requiring lithium to be Two patients in group 1 had partially started by his general practitioner on anti- reinstituted. Another subject who re- controlled epilepsy: patient 4, as men- Parkinson medication for the tremor, lapsed during lithium taper had associated tioned above, and patient 8. Three other despite our communications that it was renal failure attributed to the lithium. To patients had a remote history of seizures. more likely associated with lithium accommodate for this, her GP dose was In the other subgroup of 17 patients, together with DVP and antipsychotic relatively low at 400 mg/d. However, her replacement of lithium by GP in combi- drug. The tremor resolved after lithium blood level was in the therapeutic range nation with DVP was successfully was discontinued. Overall, 8 patients for seizures at 8.1 Ag/mL. Thus, 8 (47.1%) achieved in 9 patients (52.9%), all of (47.1%) failed conversion from lithium of the 17 patients were unable to maintain whom remained a moderate problem to GP because of relapsing bipolar improvement off lithium on GP and DVP, (CGI-S of 4 or less) and much improved symptoms. Three of these relapses oc- whereas success was achieved in 9 cases

TABLE 1. Outcome for GP Addition to DVP (Patients 1–13) and GP Replacement of Lithium in Combination With DVP (Patients 14–30) CGI-Severity Patient Starting GP Dose, DVP Dose, Antipsychotic No. AgeSex mg (Level) mg (Level) Dose, mg Baseline 3 mo 1 yr 5 yr 1 30 F 800 (3.1) 1000 (72) Risperidone 2 4 3 4 4 2 35 M 1800 (4.2) 1750 (77.0) Loxapine 5 5 4 4 3 3 36 M 600 (8.5) 1000 (58) Loxapine 2.5 5 4 3 4 4 27 M 900 (2.2) 1500 (95) — 5 4 4 6 Failed 5 43 M 1800 (NA) CBZ 400 (14.2) — Missing 4 4 4 6 45 F 1200 (1.3) 1000 (60.9) — 6 4 4 4 7 21 M 2100 (2.7) 1500 (101.3) — 5 4 4 4 8 41 F 1200 (5.5) 1500 Olanzapine 10 5 4 5 6 Failed 9 34 F 1800 (NA) 1750 (76.1) Risperidone 2 5 4 4 LTF 10 46 F 2000 (NA) 1750 (75) Risperidone 2 5 5 4 LTF 11 20 F 900 (1.7) 1500 (94) — 5 4 4 4 12 18 F 1200 (2) 1250 (98) — 5 4 4 4 13 26 F 2500 (3.9) 1250 (64.8) — 5 4 4 4 14 50 M 1500 (NA) 1750 (24.1) Loxapine 10 5 4 5 Failed 6 Failed 15 33 M 2400 (4.9) 2000 (90) Risperidone 1.5, trifluoperazine 20 4 4 4 4 16 28 M 1500 (4.9) 2000 (98) Risperidone 5 5 4 4 4 17 62 M 1200 (7.0) 12750 (72.4) Olanzapine 7.5 4 4 3 4 18 37 F 1200 (3.0) 2000 (57.6) — 4 3 4 4 19 20 M 900 (NA) 2250 (82) Risperidone 2 4 6 Failed 6 Failed LTF 20 26 M 1500 (0.7) 2250 (85) Risperidone 1.5 4 6 Failed 6 Failed 6 Failed 21 36 M 1500 (4.8) 750 (58.7) Risperidone 5 3 3 4 4 22 35 M 1200 (1.7) 2000 (64.6) — 5 3 3 6 Failed 23 20 M 1600 (2.5) 2250 (101.2) — 5 4 4 4 24 30 M 900 (NA) 1000 (52.7) Loxapine 5 3 6 Failed 6 Failed 6 Failed 25 26 F 900 (1.8) 2000 (65.5) Risperidone 2 4 6 6 6 Failed 26 40 F 900 (NA) 1000 (95) Thiothixene 3 4 4 4 LTF 27 37 M 900 (NA) CBZ 400 (8.9) Loxapine 10 4 3 LTF LTF 28 37 M 900 (8.1) 1000 (72.8) Loxapine 25 4 4 4 4 29 46 M 900 (NA) CBZ 500,300 (9.5) Risperidone 2 4 4 4 6 Failed 30 46 F 400 (8.1) 1500 (39) Risperidone 2, thioridazine 150 4 4 6 Failed 6 Failed GP levels are given in mcg/mL; DVP levels, mdg/mL; CBZ levels, mcg/mL; Lithium levels, meq/L. CBZ indicates carbamazepine; LTF, lost to follow-up; NA, not available. n 2006 Lippincott Williams & Wilkins 345

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 or 52.9%. The dose range in this group for 6. Guy W. ECDEU Assessment Manual for resonance imaging, electroencephalogra- Psychopharmacology. U.S. Dept. of Health, GP was 400 to 2400 mg/d, and median Education, and Welfare Publication (ADM). phy, electrocardiography, laboratory tests, dose was 1200 mg/d. Overall GP was well Rev ed. Rockville, MD: National Institute of and neurological examination revealed no tolerated in mostly low doses (median, Mental Health; 1976:76–338. pathological findings in both patients. 1200 mg/d; range, 400–2400 mg/d) as Also, psychiatric examination findings shown in Table 1 and with blood levels were returned to normal after successful in the lower part of the dosage range Combination Therapy psychopharmacological treatment. established for seizures (2.0–12.0 Ag/dL). of Lamotrigine and A 22-year-old woman, affected by This improvement also in side effect bipolar disorder type II, was admitted to profile has been sustained on longer-term Escitalopram May our inpatient unit because she developed follow-up. No patients in this subgroup the second depressive episode preceded had uncontrolled clinical comorbid sei- Cause Myoclonus by a short manic episode. She received zure disorders. The lower response rate in S-CT for treatment of depressive symp- this group may possibly be associated To the Editors: toms. The dosage of S-CT was continu- with more severe bipolar pathology, The term myoclonus refers to ously raised to 30 mg/d within 6 weeks although studies are needed to clarify brief, involuntary jerking of a muscle (serum level of S-CT, 68 ng/mL [in the this. GP showed preliminary efficacy and or a group of muscles. It is a symptom reference frame]). At 6 weeks after that safety as an add-on mood stabilizer to of various diseases including neurode- final dosage was reached, concomitant DVP in adults with MR and bipolar mood generative and systemic metabolic dis- treatment with LTG (25 mg/d, raising disorder or schizoaffective disorder, bi- orders. In addition, myoclonus has been 25 mg/d every 2 weeks) was started as polar type, and was potentially effective described as a side effect of several maintenance treatment of the bipolar II and safer than lithium. Double-blind drugs: it is well established that it can disorder. Another 8 weeks later, upon studies are warranted. be caused by levodopa, cyclic antide- remission of the depressive episode, the pressants, and bismuth salts, while patient noticed the onset of myoclonus there exist only very few studies re- by night and by day (S-CT, 30 mg/d; Jessica A. Hellings, MD LTG, 100 mg/d). Serum levels of both Department of Psychiatry and porting that selective serotonin receptor inhibitors (SSRIs) or newer anticonvul- pharmaceuticals were measured at an Behavioral Sciences interval of 2 weeks for 3 times after the University of Kansas Medical Center sants like lamotrigine (LTG) can induce myoclonus as well.1 onset of myoclonus (LTG, 6.5, 7.1, and Kansas City, KS 6.1 mg/L [reference value, 1–13 mg/L]; [email protected] Furthermore, the induction of myoclonus has been linked with calcium S-CT, 66, 76, and 71 ng/mL [in the channel-blocking drugs like verapamil.2 reference frame]). Myoclonus did not ACKNOWLEDGMENTS It is known that voltage-gated calcium stop during the following months under Dr Hellings is a consultant to channels can be inhibited by LTG. Janszky equal medical treatment conditions. Abbott Pharmaceuticals. Supported by et al3 reported that 2 patients with epi- Analysis of CYP2D6, CYPC19, and Abbott unrestricted $5000 grant; NIMH lepsy experienced disabling myoclonic CYP3A4 revealed normal enzymatic grant number MH01516-K08; and jerks during LTG treatment. activity, indicating the patient to be a NICHD grant numbers HD26927 and normal metabolizer. Interestingly, also SSRIs are able to HD02528. inhibit voltage-gated ion channels.4 The A 28-year-old woman, affected by epilepsy, was admitted to our neurolog- SSRI citalopram (CT) is metabolized ical inpatient unit because of a seizure REFERENCES mainly by cytochrome P450 (CYP)2D6 during treatment with LTG (200 mg/d; 1. Post RM, Ketter TA, Denicoff K, et al. The enzyme. Inhibition of CYP2D6 results in serum level, 5.5 mg/L). This was the fifth place of anticonvulsant therapy in bipolar increasing plasma levels of that antide- seizure in the last 5 years. Hence, LTG illness. Psychopharmacology (Berl). 1996; pressant. Spigset et al5 reported on 128:115–129. dosage was raised to 300 mg/d. Until 2. Keck PE Jr, Strakowski SM. Psychopharma- myoclonus associated with CT treatment now, 9 months later, no seizure occurred cological treatment of psychotic disorders in patients treated with an additional again. In addition, this patient suffers across the lifespan. In: McElroy SL, eds. CYP2D6-inhibitingdrug.CTisaracemic Psychopharmacology Across the Life Span, from generalized anxiety disorder. There- vol 16. Washington, DC: American Psychiat- mixture of R-CT and its pharmacologi- fore, we started psychopharmacological ric Press; 1997:31–85. cally active S-enantiomer escitalopram treatment with S-CT (starting dosage, 10 3. Hellings JA. Psychopharmacology of mood (S-CT). S-CT is metabolized by the en- mg/d). Two weeks later, after dosage of disorders in persons with mental retardation zymes CYP3A4, CYP2C19, and CYP2D6 S-CT was raised to 20 mg/d, that patient and autism. Ment Retard Dev Disabil Res 6 Rev. 1999;5:270–278. in equal shares. observed onset of myoclonus during 4. Physicians Desk Reference. Montvale, NY: Here, we report the development of nighttime and daytime. At that timepoint, Medical Economics Company, Inc; 2003. myoclonus in 2 patients during com- the serum LTG level was 7.1 mg/L and 5. Ramsay RE. Gabapentin: toxicity. In: Levy bination therapy with LTG (250 mg/d) RH, Matson RH, Meldrum BS, eds. Anti- the serum S-CT level was 40 ng/mL. The epileptic Drugs. 4th ed. New York: Raven and S-CT (30 mg/d). At the timepoint frequency of the myclonus did not alter Press; 1995:857–860. myoclonus occurred, cranial magnetic for 6 months but stopped 2 weeks after

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors discontinuation of the treatment with S- hypothesized in a previous study regard- metabolites in vitro: cytochromes mediating CT. We could not determine any changes ing LTG and sertraline are improbable, biotransformation, inhibitory effects, a com- in LTG serum levels after discontinuation parison to R-citalopram. Drug Metab Dispos. because LTG is primarily metabolized 2001;29:1102–1109. of S-CT treatment. through glucuronidation.12 Hence, im- 7. Boyer EW, Shannon M. The serotonin syn- These cases suggest that LTG paired enzyme activity caused by a drome. N Engl J Med. 2005;352:1112–1120. enhances the onset of myoclonus if genetic ‘‘poor metabolizer’’ polymor- 8. Staedt J, Stoppe G, Riemann H, et al. Lamotrigine in the treatment of nocturnal combined with S-CT. Myoclonus, a phism is unlikely to have large effects symptom of the serotonin syndrome,7 is myoclonus syndrome (NMS): two case reports. on net metabolic clearance of any of J Neural Transm. 1996;103:355–361. a known side effect of treatment the substances. 9. Russell HH, Svensson E, Dewael Y, et al. with SSRIs like S-CT. Interestingly, Clinicians treating their patients 5HT inhibits N-type but not L-type Ca 2+ LTG is also able to induce myoclonus— with a combination therapy of an SSRI channels via 5-HT1A receptors in lamprey provided that high LTG serum levels are spinal neurons. Eur J Neurosci. 2003;18: reached.3 Although the main property of and LTG should look out carefully for 2919–2924. LTG is the inhibition of glutamate symptoms of the serotonin syndrome. 10. Vinod KY, Subhash MN. Lamotrigine release, thereby combating epilepsy and We propose that LTG and SSRIs share induced selective changes in 5-HT1A recep- 8 at least a few serotonin receptor sub- tor mediated response in rat brain. Neuro- myoclonus, LTG is apparently able to chem Int. 2002;40:315–319. amplify the risk of developing myoclo- types. This particular variation of LTG 11. Erfurth A, Amann B, Grunze H. Female nus alone3 or in combination therapy may also account for its robust activity genital disorder as adverse symptom of with an SSRI. Chronic administration of against depression, whereas other anti- lamotrigine treatment. A serotonergic effect? LTG downregulates cortical 5-HT1A convulsants like carbamazepine and Neuropsychobiology. 1998;38(3):200–201. receptor density thereby sensitizing the valproate seem to exert stronger anti- 12. Kaufman KR, Gerner R. Lamotrigine toxicity 13 secondary to sertraline. Seizure. 1998;7: serotonergic system for incidence of manic effects. 163–165. serotonin syndrome caused by substan- For this study, written informed 13. Ernst CL, Goldberg JF. Antidepressant ces increasing the amount of serotonin in consent and human subjects research properties of anticonvulsant drugs for bipo- the synaptic cleft.9,10 Erfurth et al11 committee approval were obtained. lar disorder. J Clin Psychopharmacol. 2003;23:182–192. showed female genital disorder as adverse symptom of LTG treatment and Marcus C. Rosenhagen, MD suggest this to be a serotonergic side Ulrike Schmidt, MD effect induced by high doses of SSRI. Levetiracetam for the Therefore, we consider LTG and S-CT to Frank Weber, MD have additive or even synergistic effects Axel Steiger, MD Treatment of Alcohol on the 5-HT1A receptor and its linked Max Planck Institute of Psychiatry enzyme system (adenylyl cyclase). Munich, Germany Withdrawal Syndrome: [email protected] Another conceivable hypothesis is An Open-label a possible additive blocking effect of LTG and S-CT on voltage-gated calcium Pilot Trial REFERENCES channels. As already mentioned, LTG is 1. Jimenez-Jimenez FJ, Puertas I, de Toledo- To the Editors: known to block the N-type calcium Heras M. Drug-induced myoclonus: frequen- channel. Hahn et al4 showed an inhibi- Alcohol withdrawal syndrome cy, mechanisms and management. CNS (AWS) is a serious complication of tion of voltage-activated calcium chan- Drugs. 2004;18:93–104. alcohol dependence and often requires nels by the SSRI fluoxetine. Vadlamudi 2. Vadlamudi L, Wijdicks FM. Multifocal my- 2 an intensive medical treatment and et al reported on multifocal myoclonus oclonus due to verapamil overdose. Neurolo- gy. 2002;58:984–985. hospital admission. The most recom- caused by an intentional overdose of 3. Janszky J, Rasonyi G, Halasz P, et al. mended treatment regimen for AWS are the calcium channel blocker verapamil. Disabling erratic myoclonus during lamotri- benzodiazepines (BDZs). As an alterna- Vadlamudi et al also describe cases with gine therapy with high serum level—report of tive, antiepileptic drugs (AEDs) (eg, other calcium channel blockers, for two cases. Clin Neuropharmacol. 2000;23: carbamazepine and valproate) have been example, nifedipine. 86–89. 4. Hahn SJ, Choi J-S, Rhie D-J, et al. Inhibition shown to be efficacious in the treatment Taken these 2 hypotheses into by fluoxetine of voltage-activated ion chan- of AWS in several controlled trials.1 account, combination therapy with LTG nels in rat PC12 cells. Eur J Pharmacol. However, BDZs and most of the AEDs and SSRIs has the capability to trigger 1999;367:113–118. 5. Spigset O, Hedenmalm K, Dahl ML, et al. are limited by side effects, especially 2,3 the incidence of myoclonus. Seizures and myoclonus associated with liver toxicity. In contrast, the AED Myoclonus is a known side effect antidepressant treatment: assessment of po- levetiracetam, a pyrrolidine derivative, of valproic acid, carbamazepine, and tri- tential risk factors, including CYP2D6 and has a favorable safety profile, shown in cyclic antidepressants, whereas LTG and CYP2C19 polymorphisms, and treatment with placebo-controlled trials in epilepsy.4 SSRIs so far were not listed as substances CYP2D6 inhibitors. Acta Psychiatr Scand. 1997;96:379–384. Recently, levetiracetam has been shown inducing myoclonus. Interactions of met- 6. Von Moltke LL, Greenblatt DJ, Giancarlo to reduce AWS in alcohol-dependent 5 abolic enzymes of LTG and S-CT, as GM, et al. Escitalopram (S-citalopram) and its mice, suggesting that levetiracetam may n 2006 Lippincott Williams & Wilkins 347

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 represent an efficacious drug for the samples. The global a level was 0.05, One major requirement for the treatment of AWS in humans. We Bonferroni correction was applied for treatment of AWS is an alternative to therefore initiated an open-label pilot multiple testing (n = 3), and the P level BDZ medication for patients with or- trial to evaluate the efficacy and safety of was adjusted to less than 0.016. ganic risk factors. The use of BDZs in levetiracetam for the treatment of AWS All patients successfully complet- AWS is based on their rapid sedation, in patients with severe alcoholism. ed the alcohol withdrawal treatment. anxiolytic effects, and antiepileptic pro- Overall, 15 patients (3 women Eight (53.3%) of the 15 patients could perties, but they may cause the risk of and 12 men) of central European origin be treated with levetiracetam as mono- abuse, intoxication with respiratory in- with a mean age of 40.5 years (SD, 10.2 therapy. The mean of maximal AWS sufficiency, and cognitive impairment.8 years; range, 22–53 years) who were Scale scores on day 1 was 6.6 (SD, 2.2; Although BDZs and some AEDs (eg, voluntarily seeking treatment for alco- range, 2–9). The mean scores of the carbamazepine and valproate) are rela- hol detoxification were included in this AWS Scale decreased significantly tively contraindicated in patients with trial. All patients fulfilled Diagnostic from 4.6 (SD, 1.7) on day 1 to 1.9 liver diseases,2,3 alternative treatment and Statistical Manual of Mental Dis- (SD, 1.5) on day 3 to 0.5 (SD, 0.7) on strategies for patients with somatic com- orders, Fourth Edition criteria for day 7 (day 1 vs 3: t = 4.84, P < 0.001; plications of chronic alcoholism are alcohol dependence and had an immi- day 1 vs 7: t = 9.66, P < .001). Within needed. In contrast, levetiracetam has a nent moderate to severe AWS with the 3 days, most of the patients recovered high tolerability in patients with hepatic need of medical treatment. Three of the from AWS. Seven patients (46.7%) re- diseases,9,10 as well as advantageous 15 patients had an untreated comorbid ceived an add-on medication with diaz- pharmacokinetics and no risk of drug major depression. Exclusion criteria epam (n = 2), clonidine (n = 3), or a interaction.4 Moreover, levetiracetam were alcohol withdrawal delirium, illicit combination of both (n = 2). The mean seems to have only a limited risk of drug use in the 30 days before admis- diazepam dose for those patients was intoxication or respiratory insufficiency sion, last alcohol beverage intake more 3.8 mg/d (SD, 1.4 mg/d; range, 1.4–10.8 in combination with alcohol due to its than 72 hours before admission, current mg/d) and overall 26.3 mg in 7 days lack of GABAergic properties.4 How- use of anticonvulsive medication or (SD, 32.5 mg; range, 10–75 mg). The ever, the mechanism by which levetir- BDZs, pregnancy, and serious medical mean clonidine dose was 10.7 Ag (SD, acetam exerts its therapeutic effects in conditions. The trial was approved by 49.3 Ag; range, 10.7–117.9 Ag) per day AWS is still unclear. Levetiracetam the local ethics committee. After a and overall 345.0 Ag in 7 days (SD, reduces BDZ11 as well as alcohol with- complete description of the study to 293.4 Ag; range, 75–825 Ag). Whereas 3 drawal syndrome5 in mice and was the subjects, fully informed written patients received diazepam 5 to 10 mg/d shown to have antikindling effects.12 consent was obtained. as single dose in the evening because of Kindling is a model for understanding The severity of AWS was as- insomnia, only 1 patient received diaz- AWS: repeated episodes of alcohol 6 sessed using the AWS Scale, a vali- epam up to 20 mg/d because of ongoing withdrawal may kindle over time, in- dated reliable measure of mental and moderate withdrawal symptoms. Four of creasing neuronal excitability, leading somatic symptoms of the current sever- the 15 patients complained about adverse to progressively severe alcohol with- ity of alcohol withdrawal consisting of events such as mild sedation (n = 3) or drawal including delirium and seiz- 10 items (blood pressure, pulse rate, mild pruritus (n = 1), which were judged ures.13 Due to its sedative effects4 breathing rate, sweating, tremor, agita- as possibly related to treatment with similar to BDZs, levetiracetam may also tion, contact, orientation, hallucinations, levetiracetam. None of these symptoms decrease irritability and agitation in the and anxiety), scored from 0 (no with- caused permanent or transient discontin- first days of AWS. Levetiracetam does drawal) to 32 (maximum withdrawal uation of treatment. No major complica- not appear to have significant activity severity). The AWS Scale was ad- tions, such as seizures or deliria, could be against other drug targets of AEDs4; ministered at least 4 times a day during observed. moreover, there was no indication of the study period. Levetiracetam was giv- Overall, treatment with levetira- direct effects on GABAergic mecha- en in a fixed-schedule regimen (Table 1) cetam resulted in a rapid clinical nisms.14 Levetiracetam reduces currents in 500-mg tablets during 6 days between improvement of AWS in all patients; through high-voltage–activated calcium 500 and 2000 mg/d. Treatment was two thirds of the patients recovered channels, interacts with a unique bind- started with 1000 mg/d, which was given from AWS within 3 days. In all of the ing site,15 and has high affinity to the to the patients immediately after admis- patients, a positive outcome and a com- SV2A protein16 that is involved in sion, independently from blood alcohol pletion of levetiracetam treatment were synaptic vesicle function and calcium- concentration. Clonidine 75 Ag/d up to a achieved. No severe adverse events or dependent regulation of neurotransmitter 17 maximum of 400 Ag/d was given in case complications according to AWS oc- release during repetitive stimulation. of hypertonia. Diazepam 5 mg/d up to a curred. Only one patient had to be treat- Thus, levetiracetam might reduce exces- maximum of 30 mg/d was administered ed with additional diazepam because of sive neuronal activity and thereby seiz- as needed according to persistent with- withdrawal symptoms, whereas patients ures and may also exert protective effects drawal symptoms or moderate to severe in other alcohol detoxification trials re- regarding the kindling effect of AWS.17 insomnia. Statistical analyses were per- ceived daily diazepam dosages between The results of this open-label pilot formed using t tests for dependent 10 and 90 mg during the first 4 days.7 trial are preliminary and have to be

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TABLE 1. Levetiracetam Dose-Escalation Schedule alcohol-withdrawal syndrome (AWS Scale). Alcohol Alcohol. 1997;32:753–760. Day Morning Dose Evening Dose Total Daily Dose 7. Lucht M, Kuehn KU, Armbruster J, et al. Alcohol withdrawal treatment in intoxicated 1 500 500 1000 vs non-intoxicated patients: a controlled open-label study with tiapride/carbamazepine, 2 1000 1000 2000 clomethiazole and diazepam. Alcohol Alco- 3 1000 1000 2000 hol. 2003;38:168–175. 4 500 1000 1500 8. Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. 5 500 500 1000 J Clin Psychiatry.2004;65(suppl5):7–12. 6 0 500 500 9. Chabolla DR, Harnois DM, Meschia JF. 70 0 0Levetiracetam monotherapy for liver transplant patients with seizures. Transplant Proc. 2003;35:1480–1481. 10. Paul F, Meencke HJ. Levetiracetam in focal epilepsy and hepatic porphyria: a case interpreted with caution because of the Berlin, Charite´ Campus Mitte report. Epilepsia. 2004;45:559–560. small number of patients and the lack of Berlin, Germany and 11. Lamberty Y, Gower AJ, Klitgaard H. The a control group, so further controlled Department of Psychiatry and new antiepileptic drug levetiracetam normal- trials with larger samples are needed. Psychotherapy,y Kliniken-Essen Mitte, Ev ises chlordiazepoxide withdrawal–induced anxiety in mice. Eur J Pharmacol. 2002; Nevertheless, these preliminary data Huyssenstift, Essen, Germany 439:101–106. provide evidence that levetiracetam is [email protected] 12. Loscher W, Honack D, Rundfeldt C. safe and efficacious in the treatment of Antiepileptogenic effects of the novel acute AWS. The use of modern AEDs anticonvulsant levetiracetam (ucb L059) in not affecting the liver such as levetir- the kindling model of temporal lobe REFERENCES epilepsy. J Pharmacol Exp Ther. 1998; acetam may be an important strategy for 284:474–479. the treatment of AWS in the future. 1. Kosten TR, O’Connor PG. Management of 13. De Witte P, Pinto E, Ansseau M, et al. drug and alcohol withdrawal. N Engl J Med. Alcohol and withdrawal: from animal re- ACKNOWLEDGMENT 2003;348:1786–1795. search to clinical issues. Neurosci Biobehav 2. Peppers MP. Benzodiazepines for alcohol Rev. 2003;27:189–197. The data were presented in part at withdrawal in the elderly and in patients with 14. Margineanu DG, Klitgaard H. Levetiracetam the 17th ECNP Congress in Stockholm liver disease. Pharmacotherapy. 1996;16: has no significant gamma-aminobutyric 2004, October 9th–13th and the 8th 49–57. acid–related effect on paired-pulse interac- WCBP Congress in Vienna 2005, June 3. Malcolm R, Myrick H, Brady KT, et al. tion in the dentate gyrus of rats. Eur J Update on anticonvulsants for the treatment Pharmacol. 2003;466:255–261. 28th–July 3rd. of alcohol withdrawal. Am J Addict. 2001;10 15. Niespodziany I, Klitgaard H, Margineanu (suppl):16–23. DG. Levetiracetam inhibits the high-voltage– Michael Krebs, MD* 4. LaRoche SM, Helmers SL. The new anti- activated Ca(2+) current in pyramidal neuro- epileptic drugs: scientific review. JAMA. nes of rat hippocampal slices. Neurosci Lett. Karolina Leopold, MD* 2004;291:605–614. 2001;306:5–8. Christoph Richter, MD* 5. Bennett B, Lamberty Y, Bizot JC, et al. 16. Lynch BA, Lambeng N, Nocka K, et al. Thorsten Kienast, MD* Levetiracetam prevents signs of alcohol The synaptic vesicle protein SV2A is the withdrawal in mice. New Research Program binding site for the antiepileptic drug Axel Hinzpeter, MD* and Abstracts of the 156th Annual Meeting levetiracetam. Proc Natl Acad Sci U S A. Andreas Heinz, MD* of the American Psychiatric Association; May 2004;101:9861–9866. Martin Schaefer, MD* 21, 2003; San Francisco [Abstract NR689]. 17. Stahl SM. Psychopharmacology of anticon- y 2003:258. vulsants: levetiracetam as a synaptic vesicle *Department of Psychiatry and 6. Wetterling T, Kanitz RD, Besters B, et al. A protein modulator. J Clin Psychiatry. 2004; Psychotherapy, Charite´-Universita¨tsmedizin new rating scale for the assessment of the 65:1162–1163.

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