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Multiple Genetic Factors in Olanzapine-Induced Weight Gain in Schizophrenia Patients: A Cohort Study

Hiroshi Ujike, M.D., Ph.D.; Akira Nomura, M.D., Ph.D.; Yukitaka Morita, M.D., Ph.D.; Akiko Morio, M.D.; Yuko Okahisa, M.D.; Tatsuya Kotaka, M.D.; Masafumi Kodama, M.D., Ph.D.; Takeshi Ishihara, M.D., Ph.D.; and Shigetoshi Kuroda, M.D., Ph.D.

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% BMI increase.

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.

(J Clin Psychiatry 2008;69:1416-1422. Online Ahead of Print July 15, 2008.)

Received Sept. 12, 2007; accepted Feb. 28, 2008. From the Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

Dr. Ujike currently receives grant/research support from the Zikei Psychiatric Institute (Okayama, Japan) and the Research Group for Schizophrenia, Japan (Tokyo, Japan). Dr. Nomura has received grant/research support from the Kobayashi-Magobei Medicine Foundation (Okayama, Japan). Drs. Morita, Morio, Okahisa, Kotaka, Kodama, Ishihara, and Kuroda report no financial or other relationship relevant to the subject of this article.

Corresponding author and reprints: Hiroshi Ujike, M.D., Ph.D., Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan (e-mail: