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Association of a Functional Polymorphism in Neuropeptide Y With Antipsychotic-Induced Weight Gain in Schizophrenia Patients

Tiwari, Arun K. PhD*; Brandl, Eva J. MD*; Weber, Caroline MD; Likhodi, Olga MSc*; Zai, Clement C. PhD*; Hahn, Margaret K. MD; Lieberman, Jeffrey A. MD§; Meltzer, Herbert Y. MD; Kennedy, James L. MD*; Müller, Daniel J. MD, PhD*‡

Journal of Clinical Psychopharmacology: February 2013 - Volume 33 - Issue 1 - p 11–17
doi: 10.1097/JCP.0b013e31827d145a
Original Contributions

Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG.

We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates.

In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (P corrected = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (P corrected = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (P corrected = 0.011).

Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.

Supplemental digital content is available in the text.

From the *Neurogenetics Section, Neuroscience Department, Centre forAddiction and Mental Health & Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; †Department of Internal Medicine, Oberhavel Kliniken, Hennigsdorf, Germany; ‡Schizophrenia Program, Centre for Addiction and Mental Health & Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; §Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY; and ∥Psychiatric Hospital, Vanderbilt University, Nashville, TN.

Received November 18, 2011; accepted after revision June 15, 2012.

Reprints: Daniel J. Müller, MD, PhD, Department of Psychiatry, University of Toronto, Pharmacogenetics Research Clinic, Neurogenetics Section, Centre for Addiction and Mental Health, 250 College St, R30, Toronto, Ontario, Canada M5T 1R8 (e-mail:

A.K.T. is a recipient of a NARSAD 2010 young investigator award. D.J.M. has received a CIHR operating grant (Genetics of Antipsychotics-Induced Metabolic Syndrome, MOP 89853), a NARSAD Young Investigator Award, a CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia, and an OMHF New Investigator Fellowship. J.L.K. is a recipient of a CIHR operating grant. M.K.H. is supported by the Bebensee Fellowship Program and the Ontario Graduate Scholarship.

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© 2013 Lippincott Williams & Wilkins, Inc.