Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study.
OBJECTIVE
One of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain.


METHODS
Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisome proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan.


RESULTS
BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p < .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase.


CONCLUSIONS
We identified genetic variants of 5-HT(2A) and 5-HT(2C) receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain.
Ujike
Hiroshi
H
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. hujike@cc.okayama-u.ac.jp
Nomura
Akira
A
Morita
Yukitaka
Y
Morio
Akiko
A
Okahisa
Yuko
Y
Kotaka
Tatsuya
T
Kodama
Masafumi
M
Ishihara
Takeshi
T
Kuroda
Shigetoshi
S
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000009:adverse effects* / Q000627:therapeutic use; D015992:Body Mass Index; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011110:Polymorphism, Genetic / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D011569:Psychiatric Status Rating Scales; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics*
D014150:Antipsychotic Agents; C454420:G-protein beta3 subunit; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D022702:Receptors, Adrenergic, beta-3; D001569:Benzodiazepines; D020962:Heterotrimeric GTP-Binding Proteins; D000077152:Olanzapine