Weight gain is an unfortunate side effect of many antipsychotic drugs like olanzapine. It’s important to help patients manage these unwanted complications, especially to improve their quality of life but also because the weight gain comes with health problems. There is some good news on that front; researchers have identified a serotonin receptor that’s responsible for the weight gain that often accompanies these drugs. The work, performed by researchers at the University of Texas Southwestern Medical Center, was published in the Journal of Clinical Investigation and is outlined in the following video.
"Atypical antipsychotics are essential medications for millions of schizophrenia patients worldwide and they are increasingly being prescribed for bipolar disorder, major depressive disorder, and autism," commented Dr. Chen Liu, an Assistant Professor of Internal Medicine and Neuroscience.
"Most members of this class of antipsychotics are linked to a drug-induced metabolic syndrome characterized by excessive weight gain, blood fat abnormalities, and type 2 diabetes. Obesity and diabetes often develop shortly after treatment begins."
When the investigators exposed mice to the drug olanzapine over a period of six weeks, the drug caused the mice to gain weight. That weight gain was especially pronounced in female mice, who gained additional body fat.
"Similar to treatment in humans, mice given olanzapine showed significant weight gain, higher food intake, and metabolic changes associated with insulin resistance and diabetes," explained Dr. Caleb Lord, who worked as a postdoctoral researcher in the Division of Hypothalamic Research.
However, mice that were genetically modified so they would not have a serotonin 2c receptor did not exhibit weight gain after drug exposure, nor did they have an increase in blood sugar. That showed the receptor was important to the mechanism by which these drugs cause weight gain.
"Our study directly demonstrates in a mouse model that this interaction with the serotonin 2c receptor is a major cause of olanzapine's metabolic side effects," Liu explained.
"This finding is clinically significant because of an FDA-approved weight loss drug called lorcaserin, which in contrast to olanzapine, activates the serotonin 2c receptor. Based on the opposite effects of lorcaserin and olanzapine on the serotonin 2c receptor, we wanted to test whether lorcaserin treatment could counteract the metabolic effects of olanzapine,” Liu continued.
The findings were encouraging. “Co-treating with lorcaserin prevented weight gain and significantly improved the metabolic profile of mice treated with olanzapine,” noted Liu.
While it remains to be seen whether these results will hold true for people, it is an important step toward relieving patients suffering from depression and schizophrenia of these side effects.
Other factors may also be at play as well, the researchers noted. While expected drug effects were reduced in the mice without the serotonin receptor, energy expenditure and physical activity was still low, and not ameliorated by the gene edit. The investigators noted that the suggests that other molecules or receptors are an influence.
“This study suggests that by preventing the interaction between antipsychotic drugs and the serotonin 2c receptor we might be able to eliminate many of the metabolic side effects without interfering with the psychiatric effects. We plan to continue working to understand the mechanisms involved,” Liu concluded.