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
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
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 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.”
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 treatment.
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. Müller and Kennedy, and
conducted by PhD student Nabilah Chowdhury. They 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,” says Dr. Müller. “We need further studies to
validate this result and eventually turn this into a clinical application.”
The CAMH researchers were supported by a
Canadian Institutes of Health Research (CIHR) grant and a NARSAD grant from the
U.S. Brain and Behavior Fund.
Media Contact: Michael Torres, Media
Relations, CAMH; 416-595-6015
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
CAMH is fully affiliated with the University of Toronto, and is a Pan American Health
Organization/World Health Organization Collaborating Centre.