The Melanocortin 4 Receptor (MC4R) is a receptor found in the hypothalamus and involved in the regulation of satiety, food intake, and energy expenditure. Specifically, two main signals from the body are propagated via MC4R: anorexigenic signals and orexigenic signals. Anorexigenic signals promote satiety, resulting in decreased food intake and increased energy expenditure, while orexigenic signals promote energy intake and storage. Gene variations in MC4R may cause receptor desensitization and have been associated with leptin resistance, insulin resistance, binge eating, food-seeking behavior, excessive hunger, and obesity.
Genome-wide association studies (GWAS) have identified a significant association between the minor (A) allele and increased risk for antipsychotic induced weight gain (AIWG). One of these studies included a pharmacogenetic association analysis of their discovery patient cohort, and found that patients with the homozygote risk genotype (A/A) gained significantly more weight over a 12-week trial of various second generation antipsychotics than either heterozygotes (C/A) or common allele homozygotes (C/C). The latter two groups did not significantly differ from one another. The authors of this study then repeated this analysis across three additional independent cohorts and replicated their initial results, indicating a marked increase of AIWG in A/A homozygotes.
Adapted from Malhotra et al (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry.
Consideration of the metabolic consequences of second generation antipsychotics is important, as they are associated with decreased compliance and long-term morbidity from conditions such as obesity, dyslipidemia, diabetes and cardiovascular disease. Second generation antipsychotics can be stratified according to their metabolic risk.
- High risk: olanzapine and clozapine
- Medium risk: aripiprazole, brexpiprazole, iloperidone, paliperidone, quetiapine, and risperidone
- Lower risk: asenapine, cariprazine, lurasidone, and ziprasidone
For patients with a homozygote risk MC4R genotype (A/A), consideration of lower weight gain risk treatment options may be considered. This pharmacogenetic information may also prompt a clinician to consider weight gain mitigation options such as metformin (if clinically appropriate).
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