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

Abstract

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 ¼ 0.008, FDR q-value ¼ 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 ¼ 0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p ¼ 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.

The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data

“…CNR1 is located on chromosome 6q14-15 14 and is expressed widely in the central nervous system. 15 Polymorphisms in this gene have been associated with schizophrenia 16 and comorbid substance abuse, 17 as well as with antipsychotic response 18 and adverse effects 19 ; however, other studies have reported negative findings, 20,21 and these associations remain inconclusive.…”

“…The authors concluded that CNR1 may be associated with antipsychotic-induced weight gain in patients with chronic schizophrenia, but these results still need to be replicated in larger sample sets. 19 Another study, conducted in Korea with a small sample (n=78), found no significant association between CNR1 polymorphisms (rs1049353, rs806368, and rs4707436) and olanzapine-induced weight gain in patients with chronic schizophrenia. 32 Likewise, an Italian study found no association between CNR1 polymorphism rs1049353 and antipsychotic-induced weight gain.…”

“…Three of these investigated treatment response, and only one observed a significant effect. 18 Three studies investigated antipsychotic-induced weight gain, and Tiwari et al 19 reported a positive association between rs806378 and weight gain in a subsample of patients of European ancestry treated with clozapine or olanzapine. 19 Finally, one study investigated the association of CNR1 SNPs with MetS, and another investigated its association with TD; both reported significant results.…”

“…Considering that CNR1 has been implicated in the regulation of feeding behavior and body weight, 49 Tiwari et al 19 investigated the possible association of CNR1 polymorphisms with antipsychotic-induced weight gain. This study analyzed 20 SNPs of the CNR1 gene in a sample of 183 patients from three different sites in Germany and the U.S.…”

Mechanisms of development of antipsychotic-induced metabolic disorders: pharmacogenetic aspect

“…Более того, появляются све-дения, что прием атипичных антипсихотиков может спровоцировать лептинорезистентность по аналогии с инсулиновой резистентностью [23]. Показано, что изменения пищевой регуля-ции и метаболизма при приеме атипичных антип-сихотиков происходят через адренорецепторы и белки, связывающие стериновый регуляторный ýлемент (SPERBs) [24].…”