A Common Polymorphism in the Cannabinoid Receptor 1 (CNR1) Gene is Associated with Antipsychotic-Induced Weight Gain in Schizophrenia

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT + TT) gained more weight (5.96%), than the CC carriers (2.76%, p = 0.008, FDR q-value = 0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT + TT, 2.21 +/- 4.51 vs 4.33 +/- 3.89 kg; p = 0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p = 0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets. Neuropsychopharmacology (2010) 35, 1315-1324; doi: 10.1038/npp.2009.235; published online 27 January 2010