Avoiding weight gain from antipsychotic medications
For nearly 40 per cent of people taking one of a commonly prescribed group of antipsychotic drugs, the medication comes with serious side effects: significant weight gain and higher risks for obesity, diabetes and heart problems associated with a shortened life span.
CAMH’s Dr. Daniel Mueller believes the key to avoid antipsychotic-induced weight gain (AIWG) lies in our genes. Research by Dr. Mueller and collaborators suggests that a few gene variants can have large effects on medication-induced side effects. And he’s shown this to be the case in AIWG – in earlier research, Dr. Mueller identified a series of genetic variations that pinpoint at-risk individuals.
In a new, five-year study funded by the Canadian Institutes of Health Research (CIHR), he’s setting his sights on novel areas with the goal of developing a robust genetic model that could help individuals and their doctors find the right medication at the right dose as quickly as possible, eliminating or minimizing the risks of weight-gain side effects.
Reasons for concern
“With antipsychotic medications, there is great variability among people and their response to medications,” says Dr. Mueller, Clinician-Scientist in the Campbell Family Mental Health Research Institute and Head of the Pharmacogenetics Research Clinic at CAMH. “We’re still in the trial-and-error stages of prescribing these medications, and we need to do better.”
Weight gain occurs in many individuals taking newer (also known as second-generation) antipsychotic medications, such as olanzapine, risperidone and clozapine. Children and adolescents are at greater risk for substantial weight gain from antipsychotic medications, frequently leading to obesity in earlier life, an issue of particular concern. People may take these medications to treat schizophrenia, and, increasingly, neurodevelopment-related behavioural disorders, depression, anxiety, bipolar disorder, post-traumatic stress disorder (PTSD) or other mental illnesses.
In an earlier study, Dr. Mueller found that some people taking these medications gained as much as 8 kg (18 lbs.) in a 12-week trial. This weight gain may increase risk for obesity, which “may reduce people’s life expectancy by as much as 13 years, almost as much as smoking does,” according to other research, says Dr. Mueller.
A preliminary genetic model
“Our individual genetic makeup contributes to a large extent on how we metabolize medications and how they work on us,” explains Dr. Mueller.
Since he joined CAMH in 2008, Dr. Mueller and his team have identified new gene variants associated with antipsychotic-induced weight gain. These genetic markers are part of a new, enhanced version of Assurex Health’s GeneSight panel that the company and CAMH are now testing for clinical applicability in a $6-million clinical trial supported by Genome Canada.
The hope is that, in the near future, this screening tool, which uses a saliva sample, will make personalized medicine a reality in treating mental health, enabling doctors to match an individual with the right medication based on their genetic makeup.
Broadening the scope
In his new study, funded by the Canadian Institutes of Health Research, Dr. Mueller and his team are seeking new genetic variants involved in antipsychotic-induced weight gain using two innovative strategies: conducting a large genome-wide association study and sequencing the DNA of mitochondria.
In the genome-wide association study, Dr. Mueller’s team will screen the complete DNA, including all human genes, to search for gene variations that occur more frequently in people who experience antipsychotic-induced weight gain than in people without these side effects. Dr. Mueller will partner with more than 10 groups of international collaborators to cross-evaluate their findings and pool their data across a larger population sample.
Mitochondria are the parts of cells in the human body responsible for energy production. They represent an interesting area to investigate because CAMH researchers have already linked mitochondria to mental illness and metabolic dysfunctions. Mitochondria are also the only parts of our cells that possess their own unique DNA. Sequencing this DNA to look for variations that may contribute to antipsychotic-induced weight gain “is a novel approach,” says Dr. Mueller.
As another element, the researchers will look at health-care usage data from the Institute for Clinical Evaluative Sciences. More specifically, the team will look at health-care services used by two groups of individuals taking antipsychotic medications: people who have a high genetic risk for AIWG and people who have low genetic risk. If the research shows that the high-risk group uses a greater share of health-care services, this could point to a cost-saving benefit of genetic testing to avoid these weight-gain risks.
“We’re buoyed by the fact that our earlier research is entering the clinical arena, resulting in important, positive outcomes for individuals,” says Dr. Mueller. “Our goal is to further evaluate and optimize a genetic risk model and to facilitate an excellent test for antipsychotic-induced weight gain.”