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Journal of Clinical Psychopharmacology

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FIGURE 1. Time course of delirium and the period of administration of medications in the case. Ris indicates risperidone; Bu, bupropion.

combination of risperidone and bupropion may elevate the serum level of hydroxybupropion and consequently contribute to more severe adverse reactions to bupropion, such as delirium. Nevertheless, the findings in other animal systems may not always be the same in human model systems.6,7 Measuring risperidone, bupropion, and hydroxybupropion plasma concentration could support our hypothesis, but these assays are not routinely clinically performed for the therapeutic drug monitoring, and it is limitedly available. It is our limitation. Despite the possibility of a drug-drug interaction between bupropion and risperidone, serious adverse effects of coadministration have not been previously reported. Ten cases of bupropion-induced delirium have been reported to date,8 and through assessment of those symptomatic patients, several possible risk factors for the development of bupropion-induced delirium have been proposed. These include a history of nicotine abuse/dependence, polysubstance abuse, concomitant use of a cytochrome P450 2D6 inhibitor or dopaminergic agent, psychotic episodes, and advanced age.8 It has been speculated that the central nervous system toxicity occurring in bupropion treatment was related to an increased plasma level of the parent agent or its metabolites.9 In our patient, a history of alcohol abuse, psychotic episodes, and older age, or a combination of these factors may have increased his vulnerability to the development of delirium related to bupropion. Therefore, augmentation with risperidone was sufficient to induce delirium resembling that ascribed to bupropion. Multiple combinations of psychotropic substances to treat bipolar depression are routine10; however, for most combinations, drug-drug interactions have not been studied and are underrecognized. Clinicians must keep in mind that early recognition of their signs and symptoms is crucial to managing these adverse reactions. Finally, there is a great need for

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improved understanding of these potential interactions in clinical practice.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Yuan-Yuan Lu, MD Department of Psychiatry China Medical University Hospital and China Medical University Taichung, Taiwan

Jung-Hua Hsueh, MD Department of Plastic Surgery Kaohsiung Veterans General Hospital Kaohsiung, Taiwan

I-Hua Wei, PhD Department of Anatomy China Medical University Taichung, Taiwan

Chih-Chia Huang, MD, PhD Department of Psychiatry China Medical University Hospital and Department of Psychiatry and Graduate Institute of Clinical Medical Science China Medical University Taichung, Taiwan [email protected]

5. Wang JS, DeVane CL, Gibson BB, et al. Population pharmacokinetic analysis of drug-drug interactions among risperidone, bupropion, and sertraline in CF1 mice. Psychopharmacology (Berl). 2006;183: 490Y499. 6. Zanger UM, Vilbois F, Hardwick JP, et al. Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry. 1988;27: 5447Y5454. 7. Rodrigues AD. Use of in vitro human metabolism studies in drug development. An industrial perspective. Biochem Pharmacol. 1994;48: 2147Y2156. 8. Mack DR, Barbarello-Andrews L, Liu MT. Agitated delirium associated with therapeutic doses of sustained-release bupropion. Int J Clin Pharm. 2012;34:9Y12. 9. Preskorn SH. Should bupropion dosage be adjusted based upon therapeutic drug monitoring? Psychopharmacol Bull. 1991; 27:637Y643. 10. Haeberle A, Greil W, Russmann S, et al. Mono- and combination drug therapies in hospitalized patients with bipolar depression. Data from the European drug surveillance program AMSP. BMC Psychiatry. 2012; 12:153.

REFERENCES 1. Golden RN, Rudorfer MV, Sherer MA, et al. Bupropion in depression. I. Biochemical effects and clinical response. Arch Gen Psychiatry. 1988;45:139Y143. 2. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55:391Y393. 3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 4. Mrazek DA. The Cytochrome P450 2D6 Gene In: Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010:31Y53.

The Genetic Association of FTO Variants With Metabolic Traits in Patients With Schizophrenia May Be Modified by Antipsychotics To the Editors: he mechanism underlying the enhanced risk of metabolic abnormalities in patients with schizophrenia is not entirely clear. Different antipsychotics have distinct propensities to induce metabolic

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an antipsychotic medication.7 These observations suggest the pharmacogenetic significance of the development of metabolic disturbances. Therefore, we aimed to investigate the associations of FTO variants with metabolic traits and the potential genotype-antipsychotic interactions of the associations in a large sample of patients with schizophrenia. We recruited 764 patients with schizophrenia, aged 20 to 65 years, and assessed their metabolic profiles including blood pressure, waist circumference, fasting plasma glucose (FPG), triglyceride (TG), high-density

rs9939609 and antipsychotic-induced body weight gain.4,5 Only one marker (rs9939609) was tested, and the limited sample size may have hindered the optimal power to detect significant associations. One recent study showed that the effect of methylenetetrahydrofolate reductase (MTHFR) gene variants on the risk of MetS was greater in patients treated with clozapine or olanzapine than those treated with other antipsychotics.6 Another follow-up study showed that latent metabolic vulnerability of subjects carrying the risk genotype was expressed after challenge with

problems, with clozapine having the strongest effect followed by olanzapine.1 However, patients taking these agents have interindividual variations in the likelihood of developing metabolic abnormalities, suggesting an underlying genetic contribution. Variants of the fat mass and obesityassociated gene (FTO) have been suggested to confer a genetic susceptibility to obesity or the development of metabolic syndrome (MetS).2,3 To date, 2 reports have examined the role of FTO variants in patients with schizophrenia, neither of which showed significant associations between FTO

TABLE 1. Association* of FTO Variants and Metabolic Parameters in Clozapine/Olanzapine Group rs1421085 QTL Metabolic Parameters† BMI Overweight Obesity BP SBP DBP WC FPG‡ TG‡ HDL-C‡ Insulin‡ HOMA-IR‡

rs1421092 Binary

A

P

j0.94

0.047A

P

OR

0.44R 0.16L 0.52R 0.58L 0.13L 0.06L 0.11L 0.12L

A

0.90 0.71 0.64 0.59

0.62A 0.24D 0.052L 0.02L

0.68

0.11L

BMI overweight obesity BP SBP DBP WC FPG‡ TG‡ HDL-C‡ Insulin‡ HOMA-IR‡

QTL A

1.25 1.19 0.66 0.47R 0.04R 0.13R 0.57R 0.005D 0.32D 0.64A 0.73L

j0.42

OR

P

D

0.35D 0.31L 0.24R 0.09D 0.007D 0.30D 0.29R 0.36R

A j1.07

0.40

0.26 0.89 0.87 1.43 j0.90 3.09 0.02 0.07 j0.01 j0.08 j0.08

A

P 0.30R

0.43D 0.28A 0.08D

1.37 1.04 0.52 0.85

0.20R 0.87L 0.007D 0.51R

0.83

0.51R

QTL

j1.90 j1.73 j4.25 j0.06 j0.10 0.03 j0.19 j0.27

0.12L 0.04L 0.09R 0.007R 0.06R 0.008R 0.01R 0.002R

0.02

OR

0.91 0.84 0.45 0.77

0.83R 0.48D 0.14R 0.15L

0.39

0.11R

1.10 j1.24 j0.82 j0.01 j0.05 0.04 j0.06 j0.06

A

P

j0.99 0.53 0.52 1.81

0.53D 0.24L 0.50L 0.66L 0.052L 0.01L 0.12L 0.14L

P

0.71 0.77 0.71

0.18D 0.20A 0.048L

0.55 1.53 0.58 0.77

0.18R 0.07D 0.29L 0.12L

0.47

0.22R

QTL

A

0.08R 0.54A 0.46L

OR

rs8050136 Binary

P

Binary

j1.05

rs9939609 Binary

P

P

OR

0.03A 0.03D 0.15R j1.20 j2.41 2.07 j0.02 j0.07 0.01 j0.01 j0.01

QTL

0.24A

rs9930506 Metabolic Parameters†

Binary P

0.37 0.56 0.53 2.60

3.39 j1.47 2.30 j0.01 j0.04 0.03 j0.06 j0.07

QTL

rs1588413

Binary P

0.91 0.78 0.59 0.55

0.66L 0.39D 0.02L 0.009L

0.61

0.051L

P

0.61 0.53 2.33

0.07A 0.02A 0.22R

0.91 0.70 0.62 0.58

0.66L 0.23D 0.04L 0.02L

0.65

0.08L

0.04

0.02A 0.01A 0.37R 1.26 j0.99 j0.75 j0.01 j0.05 0.04 j0.07 j0.06

OR A

0.40A 0.35L 0.54L 0.59L 0.09L 0.01L 0.16L 0.17L

*The smallest P value, adjusted for sex, age, and BMI, was selected from 4 models (A, additive; L, allelic; D, dominant; R, recessive) by quantitative (QTL) and binary analyses. Values in bold represent with a P value e 0.01. † Diagnosis threshold for clinical characteristics: HOMA-IR, Q2.5 HIU/mL for insulin resistance; 24 e BMI G 27 and BMI Q27 kg/m2 for overweight and obesity, respectively; Q90 cm (male) and Q80 cm (female) for waist; SBP, Q130 or DBP, Q85 mm Hg for hypertension; FPG, Q100 mg/dL for hyperglycemia; TG, Q150 mg/dL for hypertriglyceridemia; and G40 mg/dL (male) and G50 mg/dL (female) for low HDL-C. ‡ Values were log transformed. BMI indicates body mass index; BP, blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment for insulin resistance; OR, odds ratio; SBP, systolic blood pressure; TG, triglyceride; WC, waist circumference.

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lipoprotein cholesterol, insulin, and body mass index. We divided the 724 patients, whose antipsychotic information was available, into those currently being treated with clozapine/ olanzapine (clozapine/olanzapine group, 392 subjects) and those being treated with other antipsychotics (nonclozapine/olanzapine group, 332 subjects). Metabolic syndrome, overweight or obesity, and homeostasis model assessment for insulin resistance (HOMA-IR) have been defined elsewhere.8 Six FTO markers, rs1421085, rs1421092, rs1588413, rs9930506, rs9939609, and rs8050136, were genotyped using the ABI StepONE Plus Software version 2.1 genotyping assay. We examined the associations of FTO variants with various metabolic traits by quantitative and binary analyses and whether or not there was a genotypeantipsychotic interaction in the association. Because the values of insulin, HOMA-IR, FPG, TG, and high-density lipoprotein cholesterol were not normally distributed, these values were logarithmically transformed in all analyses. P e 0.01 was set as the level for statistical significance. In the entire sample, the observed genotypes did not violate the Hardy-Weinberg equilibrium (P Q 0.05). The quantitative and binary analyses revealed significantly negative associations of the rs1588413 minor allele with FPG level (P = 0.0006) and hyperglycemia (P = 0.01). We found significant genotype-antipsychotic interactions of the FTO variants with blood pressure, lipid profiles, glucose homeostasis, and HOMAIR. In further stratified analysis, FTO variants (rs1421092, rs1588413, rs9930506, rs9939609, and rs8050136) were significantly associated with certain metabolic traits in the clozapine/olanzapine group (Table 1), whereas none of the FTO variants were associated with metabolic parameters in the nonclozapine/olanzapine group. The associations of the FTO variants and MetS status in the entire sample or the 2 subgroups were also nonsignificant. Overall, we observed significant associations of the FTO variants with metabolic parameters in the patients with schizophrenia. In particular, there was a significant genotype-antipsychotic-type interaction in the association, with a trend for greater genotype effects in the clozapine/olanzapine users. Consistent with our findings, an earlier report showed that the effect of MTHFR gene variants on metabolic abnormalities was considerably greater in patients treated with clozapine/olanzapine than in those treated with any other antipsychotic.6 Animal studies have also shown that olanzapine administration regulates orexigenic and anorexigenic neuropeptides in the hypothalamus,9 where FTO mRNA is highly expressed.10 It is possible that clozapine and olanzapine

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Journal of Clinical Psychopharmacology

treatment conveys a distinct risk for metabolic problems by modifying the genotypespecific FTO expressions. Contrary to the findings in the nonpsychiatric population in which subjects carrying FTO minor alleles generally have a higher risk of obesity,2,11 the minor alleles seemed to be protective against metabolic abnormalities in our patients, particularly for those taking clozapine or olanzapine (except for rs9930506 and TG levels). It has been found that first-episode patients with homozygous minor alleles of FTO rs9939609 have a higher body mass index before antipsychotic administration; however, a lower, though nonsignificant, body weight gain than those with other genotype counterparts after 1 year of antipsychotic treatment.5 Therefore, we speculate that antipsychotics may also affect the FTO genetic effect on metabolic features. The cross-sectional design and the lack of information regarding the duration of antipsychotic treatment are limitations to this study. In addition, we did not stratify the patients into individual antipsychotic medication owing to statistical power consideration. In conclusion, we suggest that the genetic effect of FTO on metabolic susceptibility may be modified by antipsychotic treatment. The exact role of individual antipsychotics in modulating the genetic association of FTO with metabolic parameters should be examined further. AUTHOR DISCLOSURE INFORMATION The authors received the following grants for this study: from the Taipei City Hospital (98001-62-014, 10001-62-006, 10101-62-032; MCH), the Taipei Medical University-Wan Fang Hospital (100WFEVA-09; CHC), the National Science Council, Taiwan (NSC100-2314-B-532-002, NSC972314-B-038-009-MY3, NSC99-2314-B-038020-MY3, and NSC100-2314-B-038-040; MCH, CHC, and MLL), and the National Health Research Institute, Taiwan (NHRIEX99-9741PI; MLL). The authors declare no conflicts of interest. Ming-Chyi Huang, MD, PhD Department of Psychiatry Taipei City Psychiatric Center Taipei City Hospital and Department of Psychiatry School of Medicine Taipei Medical University Taipei, Taiwan

Chung-Feng Kao, PhD Department of Public Health & Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei, Taiwan

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Volume 34, Number 1, February 2014

Chih-Chiang Chiu, MD, PhD Department of Psychiatry Taipei City Psychiatric Center Taipei City Hospital and Department of Psychiatry School of Medicine Taipei Medical University Taipei, Taiwan

Po-Hsiu Kuo, PhD Department of Public Health & Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University and Research Center for Genes Environment and Human Health National Taiwan University Taipei, Taiwan

Po-Yu Chen, MD, MS Department of Psychiatry Taipei City Psychiatric Center Taipei City Hospital Taipei, Taiwan

Mong-Liang Lu, MD, MS Department of Psychiatry School of Medicine and Department of Psychiatry Wan Fang Hospital Taipei Medical University Taipei, Taiwan

Chun-Hsin Chen, MD, MS Department of Psychiatry School of Medicine and Department of Psychiatry Wan Fang Hospital Taipei Medical University Taipei, Taiwan [email protected]

REFERENCES 1. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686Y1696. 2. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889Y894. 3. Sjogren M, Lyssenko V, Jonsson A, et al. The search for putative unifying genetic factors for components of the metabolic syndrome. Diabetologia. 2008;51:2242Y2251. 4. Jassim G, Ferno J, Theisen FM, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15Y20. 5. Perez-Iglesias R, Mata I, Amado JA, et al. Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. J Clin Psychopharmacol. 2010;30:661Y666.

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6. van Winkel R, Rutten BP, Peerbooms O, et al. MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010;121:193Y198. 7. van Winkel R, Moons T, Peerbooms O, et al. MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study. Int Clin Psychopharmacol. 2010;25:270Y276. 8. Chen PY, Huang MC, Chiu CC, et al. Association of plasma retinol-binding protein-4, adiponectin, and high molecular weight adiponectin with metabolic adversities in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1927Y1932. 9. Ferno J, Varela L, Skrede S, et al. Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. PLoS One. 2011;6:e20571. 10. Gerken T, Girard CA, Tung YC, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318: 1469Y1472. 11. Liu Y, Liu Z, Song Y, et al. Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. Obesity (Silver Spring). 2010;18:1619Y1624.

Clozapine-Associated Asterixis Case Report To the Editors: lthough schizophrenia is one of the most disabling psychiatric conditions affecting young adults, the prevalence and impact in the elderly are also considerable.1 Antipsychotic agents are the standard treatment of this disorder. However, typical antipsychotics have a high risk for central nervous system adverse effects in the elderly with schizophrenia. Clozapine is an atypical antipsychotic drug that is useful for treatment-resistant schizophrenia. The efficacy of this drug exceeds that of typical antipsychotics.2 Despite the usefulness in refractory schizophrenia, its extensive use is limited by serious adverse effects such as agranulocytosis, myocarditis, and seizures. In addition to seizures, clozapine has also been reported to induce several movement adverse effects, including akathisia,3 neuroleptic malignant syndrome,4 and myoclonus.5,6 Myoclonus can occur either as jerky muscle contraction

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(positive myoclonus) or a brief lapse of muscle activity (negative myoclonus or asterixis). Most reported cases of clozapineassociated myoclonus are positive myoclonus, whereas asterixis is rarely reported.7,8 Herein, we present a case of clozapineassociated asterixis and briefly review the symptoms.

CASE REPORT A 68-year-old woman with a 40-year history of schizophrenia was admitted to the inpatient cognitive behavior unit because of gradual decline of cognitive functions. The family reported no prior history of physical illness or substance abuse. Her medications at admission to our unit were clozapine 200 mg per os (po) daily, zolpidem 12.5 mg po daily, lorazepam 1 mg po daily, and amitriptyline hydrochloride 10 mg po daily since 3 years ago before her admission to the hospital. Review of medical records revealed previous unsuccessful treatment with risperidone, haloperidol, and quetiapine for psychotic symptoms despite good compliance of these medications. Psychotic symptoms and agitation have significantly improved since commencing clozapine therapy 3 years ago. During examination upon admission, the patient was noted to be restlessly wandering while experiencing paranoid delusions and misidentification syndromes. Vital signs were stable, and there was no evidence of focal neurologic deficit. Cognitive dysfunctions (Mini-Mental State Examination score, 20/30; Clinical Dementia Rating score, 1/5) were evident upon neurocognitive function testing. Magnetic resonance imaging revealed mild cerebral atrophy of the brain. Electroencephalographic (EEG) tracing in awake state with eyes closed showed mild slow background activity. Laboratory investigation results including complete hemogram, liver and renal function test, fasting blood glucose level, lipid profile, and urine analysis were within reference range. After admission, she was severely delusional and agitated, necessitating an increase in clozapine dosage from 200 mg/d to 275 mg/d, which resulted in clinical remission. After 2 weeks of treatment with 275 mg of clozapine, she had a viral upper respiratory tract infection (URTI) with fever (38.5-C), and she was treated with oral antibiotics (amoxicillin). Three days after developing URTI, sudden onset of knee buckling accompanied by dropping objects was noted and appeared every 10 to 30 minutes in clusters except during sleeping time. Furthermore, she was disoriented to time, place, and person and was unable to perform daily activities. Her clozapine

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and norclozapine levels were 1096.1 Hg/L and 501.71 Hg/L, respectivelyVlevels generally considered to be supratherapeutic for patients with clozapine medication. Other laboratory examination including ammonia level revealed no significant abnormalities. The EEG showed generalized rhythmical 5 and C slowings (Fig. 1). Follow-up brain computed tomographic scan excluded any abnormalities. Clozapine therapy was immediately discontinued, and clonazepam was used for severe agitation, with gradual resolution of her asterixis in 4 days. After resolution of asterixis, risperidone was started and titrated to 1.5 mg po daily for her psychotic symptoms and agitation. However, risperidone treatment did not alleviate psychotic symptoms and agitation. Meanwhile, prominent tremor and ataxia were evident and newly presented. Therefore, the clinical decision was made to decrease risperidone therapy to 0.5 mg po daily and reintroduce clozapine, with gradual increases up to 150 mg po daily. Both psychotic and extrapyramidal symptoms improved after low-dose risperidone and clozapine combination therapy. There was no recurrence of asterixis over the next 3 months.

DISCUSSION In 1949, Adams and Foley9 first reported asterixis in patients experiencing advanced hepatic encephalopathy. Asterixis is a motor control disorder because of brief lapse of posture and clinically characterized by brief, arrhythmic interruptions of sustained voluntary muscle contraction. This symptom is observed in various clinical conditions ranging from epilepsy to toxic-metabolic encephalopathy because of drug intoxication.10 Myoclonus has been reported to be a dose-dependent adverse effect of clozapine.6,11,12 Most reported cases of clozapine-associated myoclonus were positive myoclonus, and asterixis has been reported as a rare adverse effect of clozapine.7,8 Although the exact mechanisms of underlying asterixis system are not fully known, several neurotransmitters have been implicated in the pathophysiology. Certain neurochemical imbalances might cause episodic dysfunction of neural circuits concerned with the maintenance of sustained muscle contraction.13 Because myoclonus can be induced by imbalanced serotonergic transmission, and clozapine influences multiple effects upon serotonergic neurotransmission, serotonin is a strongly suggested putative neurotransmitter in clozapine-associated asterixis.14,15 This patient’s case demonstrates asterixis associated with clozapine after developing URTI. The serum concentrations www.psychopharmacology.com

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The genetic association of FTO variants with metabolic traits in patients with schizophrenia may be modified by antipsychotics.

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