Investigation of melanocortin system gene variants in antipsychotic-induced weight gain

Abstract

Objectives. The use of second-generation antipsychotic medications may result in substantial weight gain in a subset of schizophrenia patients. Distinct populations of neurons expressed in the hypothalamus, including the cocaine- and amphetamine-regulated transcript (CART), the polypeptide pro-opiomelanocortin (POMC) and the agouti-related protein (AGRP), have regulatory roles in weight control and energy homeostasis. Thus, we investigated the potential role of CART, POMC and AGRP genetic variants in antipsychotic-induced weight gain (AIWG). Methods. Five CART single nucleotide polymorphisms (SNPs) (rs10515115, rs3763153, rs3857384, rs11575893, rs16871471), three POMC SNPs (rs6713532, rs1047521, rs3754860) and one AGRP SNP (rs1338993), were genotyped in 218 patients treated with antipsychotics for chronic schizophrenia and evaluated for AIWG. We compared weight change (%) across genotypic groups using analysis of covariance. Results. None of the SNPs in POMC, CART, AGRP were significantly associated with AIWG in the refined samples stratified by ethnicity and medication treatment. Conclusions. In this exploratory study, we observed that POMC, CART and AGRP gene variants are not a major contributor to AIWG. However larger samples are required to completely rule out their effect on AIWG.

Key words::

• schizophrenia
• clozapine
• olanzapine
• melanocortin
• antipsychotics

Acknowledgements

Canadian Institutes of Health Research (CIHR) operating grant to JLK (MOP 115097). CIHR (Genetics of antipsychotics induced metabolic syndrome, MOP 89853), CIHR Michael Smith New Investigator Salary Prize for Research in Schizophrenia NARSAD Independent Investigator Award to DJM and AKT, to DJM, and an Early Researcher Award by the Ministry of Research and Innovation of Ontario (CIHR) postdoctoral fellowship to RPS. Ontario Mental Health Foundation (OMHF) New Investigator Fellowship to DJM; OMHF Research Studentship to NIC. We also thank the patients who agreed to participate in this study.

Statement of Interest

DJM/NIC/RPS/AKT/EJB/MS reported no competing interests. JLK has been a consultant to Eli Lilly, Roche and Novartis. HYM has received grants, or payment for lectures, or is or was a consultant to: Abbott Labs, ACADIA, Alkemes, Bristol Myers Squibb, DaiNippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, Novartis, Roche, Sunovion, TEVA and BiolineRx. HYM is a shareholder of ACADIA, Glaxo Smith Kline and Suregene. HYM is a board member of Acadia, and is an advisor to Centerstone Research Institute. JAL serves on the Advisory Board of Intracellular Therapies. He does not receive direct financial compensation or salary support for participation in research, consulting, or advisory board activities. He receives grant support from Allon, Biomarin, Genentech, GlaxoSmithKline, Eli Lilly, Novartis, Psychogenics, Sepracor (Sunovion) and Targacept; and he holds a patent from Repligen.

Supplementary material available online

Methods

Sample-A: Charité University Medicine (Berlin, Germany) (DJ Müller, n = 88).

Sample-B: Case Western Reserve University in Cleveland (Ohio, USA) (HY Meltzer, n = 73).

Sample-C: Hillside Hospital in Glen Oaks (New York, USA) (JA Lieberman, n = 48).