Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: A cohort study

Hiroshi Ujike, Akira Nomura, Yukitaka Morita, Akiko Morio, Yuko Okahisa, Tatsuya Kotaka, Masafumi Kodama, Takeshi Ishihara, Shigetoshi Kuroda

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Abstract

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.

Original languageEnglish
Pages (from-to)1416-1422
Number of pages7
JournalJournal of Clinical Psychiatry
Volume69
Issue number9
Publication statusPublished - Sep 2008

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olanzapine
Weight Gain
Schizophrenia
Cohort Studies
Body Mass Index
Alleles
Adrenergic beta-3 Receptors
Receptor, Serotonin, 5-HT2C
Histamine Receptors
Ghrelin

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Ujike, H., Nomura, A., Morita, Y., Morio, A., Okahisa, Y., Kotaka, T., ... Kuroda, S. (2008). Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: A cohort study. Journal of Clinical Psychiatry, 69(9), 1416-1422.

Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients : A cohort study. / Ujike, Hiroshi; Nomura, Akira; Morita, Yukitaka; Morio, Akiko; Okahisa, Yuko; Kotaka, Tatsuya; Kodama, Masafumi; Ishihara, Takeshi; Kuroda, Shigetoshi.

In: Journal of Clinical Psychiatry, Vol. 69, No. 9, 09.2008, p. 1416-1422.

Research output: Contribution to journalArticle

Ujike, H, Nomura, A, Morita, Y, Morio, A, Okahisa, Y, Kotaka, T, Kodama, M, Ishihara, T & Kuroda, S 2008, 'Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: A cohort study', Journal of Clinical Psychiatry, vol. 69, no. 9, pp. 1416-1422.
Ujike, Hiroshi ; Nomura, Akira ; Morita, Yukitaka ; Morio, Akiko ; Okahisa, Yuko ; Kotaka, Tatsuya ; Kodama, Masafumi ; Ishihara, Takeshi ; Kuroda, Shigetoshi. / Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients : A cohort study. In: Journal of Clinical Psychiatry. 2008 ; Vol. 69, No. 9. pp. 1416-1422.
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abstract = "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.",
author = "Hiroshi Ujike and Akira Nomura and Yukitaka Morita and Akiko Morio and Yuko Okahisa and Tatsuya Kotaka and Masafumi Kodama and Takeshi Ishihara and Shigetoshi Kuroda",
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AU - Ujike, Hiroshi

AU - Nomura, Akira

AU - Morita, Yukitaka

AU - Morio, Akiko

AU - Okahisa, Yuko

AU - Kotaka, Tatsuya

AU - Kodama, Masafumi

AU - Ishihara, Takeshi

AU - Kuroda, Shigetoshi

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N2 - 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.

AB - 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.

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