Genetics of Antipsychotic-Induced Weight Gain: Update and Current Perspectives

Abstract

Antipsychotic medications are used to effectively treat various symptoms for different psychiatric conditions. Unfortunately, antipsychotic-induced weight gain (AIWG) is a common side effect that frequently results in obesity and secondary medical conditions. Twin and sibling studies have indicated that genetic factors are likely to be highly involved in AIWG. Over recent years, there has been considerable progress in this area, with several consistently replicated findings, as well as the identification of new genes and implicated pathways. Here, we will review the most recent genetic studies related to AIWG using the Medline database (PubMed) and Google Scholar. Among the steadiest findings associated with AIWG are serotonin 2C receptors (HTR2C) and leptin promoter gene variants, with more recent studies implicating MTHFR and, in particular, MC4R genes. Additional support was reported for the HRH1, BDNF, NPY, CNR1, GHRL, FTO and AMPK genes. Notably, some of the reported variants appear to have relatively large effect sizes. These findings have provided insights into the mechanisms involved in AIWG and will help to develop predictive genetic tests in the near future.

Diabetes mellitus and severe mental illness: mechanisms and clinical implications

“…One important example is the genetic influence on the degree of weight gain following antipsychotic treatment. 35 Polymorphisms in the promoter region of the genes that encode the 5 hydroxytryptamine (HT) 2C receptor and leptin have been consistently reported to convey a statistically sig nifi cant risk of weight gain after starting anti psychotic treatment. 35 Studies published in the past 5 years have also implicated the gene that encodes methylenetetra hydrofolate reductase (MTHFR) and the MC4R gene in altering the risk of antipsychoticinduced weight gain.…”

“…35 Polymorphisms in the promoter region of the genes that encode the 5 hydroxytryptamine (HT) 2C receptor and leptin have been consistently reported to convey a statistically sig nifi cant risk of weight gain after starting anti psychotic treatment. 35 Studies published in the past 5 years have also implicated the gene that encodes methylenetetra hydrofolate reductase (MTHFR) and the MC4R gene in altering the risk of antipsychoticinduced weight gain. 35 Other genetic polymorphisms that might convey a risk of antipsychoticinduced weight gain include those in the genes HRH1, BDNF, NPY, CNR1, GHRL, FTO and AMPK.…”

“…35 Studies published in the past 5 years have also implicated the gene that encodes methylenetetra hydrofolate reductase (MTHFR) and the MC4R gene in altering the risk of antipsychoticinduced weight gain. 35 Other genetic polymorphisms that might convey a risk of antipsychoticinduced weight gain include those in the genes HRH1, BDNF, NPY, CNR1, GHRL, FTO and AMPK.…”

Safety and Tolerability of Antipsychotics

“…The underlying pathophysiology for antipsychotics to cause weight gain is complex but thought to involve genetic variables that include the 5HT2C receptor system and leptin promoter gene variants MTHFR and MC4R genes. Additional factors reported were HRH1, BDNF, NPY, CNR1, GHRL, FTO, and the AMPK gene (Kao and Muller 2013 ). Further research remains underway to determine biological mechanisms that infl uence antipsychotic-induced weight gain.…”

Anti-Psychotic Medication and the Pattern of Cardiovascular Risk Factors: A Population Based Study (The Ayrshire Diabetes Follow-Up Cohort (ADOC) Study)

“…Various mechanisms beyond lifestyle and demographic characteristics have been proposed to explain the link. These include shared susceptibility genes between severe mental illness and type 2 diabetes [9], geneenvironment interactions [10], foetal development [11] and co-morbid problems such as low vitamin D [12,13].…”