Multiple Genetic Factors in Olanzapine-Induced Weight Gain in Schizophrenia Patients: A Cohort Study
J Clin Psychiatry 2008;69(9):1416-1422
© Copyright 2016 Physicians Postgraduate Press, Inc.
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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.
Method: 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%
Conclusions: We identified genetic variants of 5-HT2A
and 5-HT2C 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.