Antipsychotic Induced Weight Gain: Genetics, Epigenetics, and Biomarkers Reviewed

Abstract

Antipsychotic-induced weight gain (AIWG) is a prevalent side effect of antipsychotic treatment, particularly with second generation antipsychotics, such as clozapine and olanzapine. At this point, there is virtually nothing that can be done to predict who will be affected by AIWG. However, hope for the future of prediction lies with genetic risk factors. Many genes have been studied for their association with AIWG with a variety of promising findings. This review will focus on genetic findings in the last year and will discuss the first epigenetic and biomarker findings as well. Although there are significant findings in many other genes, the most consistently replicated findings are in the melanocortin 4 receptor (MC4R), the serotonin 2C receptor (HTR2C), the leptin, the neuropeptide Y (NPY) and the cannabinoid receptor 1 (CNR1) genes. The study of genetic risk variants poses great promise in creating predictive tools for side effects such as AIWG.

Antipsychotics-induced metabolic alterations: Focus on adipose tissue and molecular mechanisms

“…Moreover, past studies have found that several genes may be involved in the susceptibility to antipsychoticsinduced side effects, and the most consistent ones are those directly involved in the regulation of appetite and food intake. Namely, melanocortin 4 receptor (MC4R), cannabinoid receptor 1 (CNR1), 5-HT2C receptor, NPY and leptin genes (Shams and Muller, 2014). Therefore, antipsychoticsinduced weight gain can also develop from drug-geneenvironment interactions, which result in a net change of balance between peptides and hormones regulating food intake and energy homeostasis (De Kloet and Woods, 2010).…”

TOX and ADIPOQ Gene Polymorphisms Are Associated with Antipsychotic-Induced Weight Gain in Han Chinese

“…However, as yet no genetic tests for AIWG are endorsed for clinical application. Although there are significant findings for AIWG associations with many other genes, the most consistently replicated findings are with HTR2C, MC4R, and leptin genes2425. A recent meta-analysis reported that 11 SNPs from 8 genes were associated with weight or BMI change, and 4 SNPs from 2 genes were significantly related to categorical weight or BMI increase14.…”

The activity of the serotonin receptor 2C is regulated by alternative splicing

“…The understanding of 5HT2C’s role in appetite control resulted in the development of Lorcarserin, an approved drug for the short-term treatment of obesity, which enhances the activity of the 5HT2C receptor (Greenway et al 2016). A large number of antipsychotic drugs used to treat depression, anxiety, and schizophrenic disorders interact with the 5HT2C (Chagraoui et al 2016; Martin et al 2014), which contributes to the drug’s efficacy, but frequently causes weight gain as a major side effect (Shams and Muller 2014). Based upon its constitutive expression in motoneurons after spinal cord injury (Murray et al 2010), targeting the 5HT2C spinal cord system may hold great potential for combating uncontrolled muscle spasms.…”