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Gene Variants Implicated in Extreme Weight Gain Associated with Antipsychotics

Science Update

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Source: Jupiter

Extreme weight gain associated with taking an antipsychotic medication may be linked to certain genetic variants, according to a study published in the September 2012 issue of the Archives of General Psychiatry.


Antipsychotic medications, especially those known as “second generation” or “atypical” antipsychotics, generally are the first-line of treatment for schizophrenia and other serious mental disorders. They are effective in treating psychotic symptoms, but they are also associated with serious metabolic side effects that can result in substantial weight gain, and other cardiovascular problems.

Some people appear to be more susceptible to severe weight gain than others, but it is difficult to predict who is most at risk. To date, there have been few genetic studies of weight gain associated with antipsychotics, in part because it is difficult to control such variables as prior exposure to the medications, and because patients often stop taking the medications prematurely.

Anil Malhotra M.D., of the Feinstein Institute for Medical Research, and colleagues set out to identify any common gene variants associated with antipsychotic-induced weight gain in a group of patients who had never taken the medications before and who were carefully monitored to ensure they continued to take the medication over the study period. The initial study included a cohort of 139 pediatric patients who were prescribed a second-generation antipsychotic. Patients were examined over a period of 12 weeks to assess weight and metabolic effects of the medications.

To compare and confirm their results, the researchers also conducted similar assessments of three small cohorts with adult patients taking second generation antipsychotics.

Results of the Study

The researchers found markers in a gene called the melanocortin 4 receptor (MC4R) that were associated with severe weight gain in people taking second generation antipsychotics. The MC4R region overlaps somewhat with another region previously identified as being associated with obesity in the general population. In addition, the results were replicated in the three independent cohorts.


In many genetic studies involving obesity, thousands of participants are needed to achieve statistically significant results and to overcome the many environmental factors that can influence a person’s weight. In this study, the critical environmental factor predisposing patients to weight gain was only antipsychotic medication use over a short period of time, thus allowing more control over other variables that could have confounded results. Therefore, even though the study only included 139 individuals, the researchers were able to detect results that implicated specific gene variants.

The results also have potential clinical implications. Patients with the identified gene variants that would predispose them to severe weight gain while taking an antipsychotic could be directed to alternative treatments, especially those who do not have a psychotic disorder.

What’s Next

Although particular gene variants were implicated, the study’s sample size was small. Further research with larger samples is needed to extend the findings.


Malhotra A, et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen. Psychiatry. 2012 Sep. 69(9):904-912.