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Explaining the Link Between an Antipsychotic Medication and Excessive Weight Gain

Researchers have identified a receptor (cell-surface protein) in the mouse brain responsible for the metabolic syndrome caused by an antipsychotic medication, as well as a therapy that may prevent this side effect. Olanzapine is part of a drug family called the “atypical antipsychotics” (AATPs). AATPs can be effective treatments for disorders such as schizophrenia, bipolar disorder, and depression. However, AATPs can also cause side effects like food cravings and binge eating that can lead to obesity and type 2 diabetes within months of starting treatment. AATPs have been known to interact with multiple receptors in the brain, including HTR2C, which helps regulate food intake, body weight, and glucose metabolism. Blocking HTR2C signaling in mice was known to cause overeating and obesity, which resembled side effects induced by AATPs. Moreover, many AATPs, including olanzapine, interfere with HTR2C function, which led researchers to suggest that it was olanzapine’s block of HTR2C function that was causing the metabolic syndrome.

To test this hypothesis, researchers fed mice the drug to reproduce the olanzapine blood concentrations seen during human olanzapine therapy. This mouse model was then used to investigate how olanzapine causes weight gain. Female mice fed olanzapine ate more and moved less, leading to excessive weight gain and other indications of metabolic syndrome similar to that seen in humans. Overeating was less prominent in male mice fed olanzapine than in female mice, and the male mice gained less weight, though the reason for the difference between the males’ and females’ responses was unclear. This result, compared with that of other experiments, suggested that, at least in mice, the main contributor to olanzapine-induced weight gain was overeating.

The researchers performed further experiments with genetically modified mice to identify factors responsible for olanzapine-induced metabolic syndrome. Mice who were fed olanzapine but also lacked the HTR2C protein did not overeat, develop altered glucose metabolism or insulin levels, or gain weight, indicating that HTR2C is important for these side effects. The researchers then asked: if olanzapine’s metabolic side effects are mediated by its blockage of HTR2C function, then could the side effects be alleviated by activating HTR2C? To test this, they fed mice olanzapine and treated the mice with an FDA-approved weight-loss drug called lorcaserin, which activates HTR2C. Lorcaserin blocked olanzapine’s overeating, weight gain, and metabolic syndrome side effects.

Since other existing anti-obesity and anti-diabetic medications have limited effectiveness against AATP-induced metabolic syndrome, this work offers hope that HTR2C activators like lorcaserin may be useful tools to prevent these side effects.

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