Scientists have discovered two genetic variants associated with substantial, rapid weight gain occurring in nearly half of patients treated with antipsychotic medications.
The results from two studies from the Centre for Addiction and Mental Health in Canada could eventually be used to identify which patients have the variations, enabling doctors to choose strategies to prevent this serious side effect and offer more personalized treatment, the researchers note.
“Weight gain occurs in up to 40 percent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,” said Dr. James Kennedy, senior author of the study.
The weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span, he noted.
“Identifying genetic risks leading to these side effects will help us prescribe more effectively,” said Kennedy. Currently, the center screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the latest study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics.
The study had four patient groups: Two from the U.S., one in Germany, and one from a larger European study. Three of the four groups had never taken atypical antipsychotics.
Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed, the researchers said. Weight and other metabolic-related measures were taken at the start and during treatment.
“The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behavior or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,” noted researcher Dr. Daniel Müller.
“The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.”
The gene’s role in antipsychotic-induced weight gain was identified in a study published earlier this year in The Pharmacogenomics Journal. Researchers
found a different variation on MC4R that was linked to the side effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene — known as single nucleotide polymorphisms (SNPs) — related to the drug-induced weight gain side effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. “We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,” said Müller. “We need further studies to validate this result and eventually turn this into a clinical application.”
The recent study is published online in the Archives of General Psychiatry.