Genetic link to rapid weight gain from antipsychotics discovered
TORONTO, July 17, 2012 /PRNewswire/ – Scientists have discovered two genetic
variants associated with the substantial, rapid weight gain occurring
in nearly half the patients treated with antipsychotic medications,
according to two studies involving the Centre for Addiction and Mental
These results could eventually be used to identify which patients have
the variations, enabling clinicians to choose strategies to prevent
this serious side-effect and offer more personalized treatment.
“Weight gain occurs in up to 40 per cent of patients taking medications
called second-generation or atypical antipsychotics, which are used
because they’re effective in controlling the major symptoms of
schizophrenia,” says CAMH Scientist Dr. James Kennedy, senior author on
the most recent study published online in the Archives of General Psychiatry.
This weight gain can lead to obesity, type 2 diabetes, heart problems
and a shortened life span. “Identifying genetic risks leading to these
side-effects will help us prescribe more effectively,” says Dr.
Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which
is part of CAMH’s Campbell Family Mental Health Research Institute.
Currently, CAMH 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 Archives of General Psychiatry 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 difference was
approximately 6 kg versus 2 kg.) The study had four patient groups: two
from the U.S., one in Germany and one from a larger European study.
“The weight gain was associated with this genetic variation in all these
groups, which included pediatric patients with severe behaviour or mood
problems, and patients with schizophrenia experiencing a first episode
or who did not respond to other antipsychotic treatments,” says CAMH
Scientist Dr. Daniel MÃ¼ller. “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
Three of the four groups had never previously 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. Weight and other
metabolic-related measures were taken at the start and during
A genome-wide association study was conducted on pediatric patients by
the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside
Hospital in Glen Oaks, NY. In this type of study, variations are sought
across a person’s entire set of genes to identify those associated with
a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been
identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. MÃ¼ller and Kennedy, and conducted by PhD student Nabilah
Chowdhury. They found a different variation on MC4R that was linked to
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,” says Dr. MÃ¼ller. “We need further studies to
validate this result and eventually turn this into a clinical
The CAMH researchers were supported by a Canadian Institutes of Health
Research (CIHR) grant and a NARSAD grant from the U.S. Brain and
The Centre for Addiction and Mental Health (CAMH) is Canada’s largest
mental health and addiction teaching hospital, as well as one of the
world’s leading research centres in the area of addiction and mental
health. CAMH combines clinical care, research, education, policy
development and health promotion to help transform the lives of people
affected by mental health and addiction issues.
CAMH is fully affiliated with the University of Toronto, and is a Pan
American Health Organization/World Health Organization Collaborating
SOURCE Centre for Addiction and Mental Health