Scripps Research scientists investigate how antipsychotic medications drive weight gain

December 14, 2018

LA JOLLA, CA – About three million Americans take antipsychotic medications for conditions such as bipolar disorder, PTSD and schizophrenia. These medications are vital for mental health, yet many people stop taking them because of the side effects of weight gain and associated metabolic diseases.

“On the surface, weight gain from these medications seems like a minor thing, but it’s not,” says Michael Petrascheck, PhD, an associate professor at Scripps Research. “These people have a 3 to 4 times greater risk of diabetes, and there have been cases where people gained up to 60 pounds in a year.”

In collaboration with the lab of Olivia Osborn, PhD, at the University of California, San Diego, Petrascheck’s lab wants to understand how antipsychotic medications cause increased eating and weight gain. In a recent study, published in the journal Nature Communications, Petrascheck and his colleagues found that the brain regulates normal eating and antipsychotic-induced overeating through distinct mechanisms. The scientists found that an FDA-approved medication called minocycline has the potential to counteract this overeating.

This discovery came about when the researchers did a screen of 192 FDA-approved medications, looking for one that could suppress antipsychotic-induced overeating in a worm species called Caenorhabditis elegans (C. elegans). The screen led them to minocycline, a medication most commonly used as an antibiotic. Further experiments in mice confirmed that minocycline significantly reduced antipsychotic-induced overeating without affecting the animal’s normal appetite.

Why would minocycline have this effect? The scientists found that antipsychotic-induced overeating is motivated by an increase in two molecules, called transcription factors, in an area of the brain called the hypothalamus. Minocycline blocks the activation of these molecules by antipsychotics in both C. elegans and mice.

Importantly, minocycline does not appear to affect how the antipsychotic works. This means weight gain is not intrinsically linked to an antipsychotic medication’s effectiveness, as some scientists had thought.

Although it is too early to know if minocycline could help human patients, Petrascheck says several small clinical trials are underway to study minocycline taken in conjunction with antipsychotics.

Petrascheck cautions that long-term use of antibiotics is not recommended, so he is looking forward to investigating other medications that could have the same effects as minocycline.

In fact, now that he knows worm eating behavior is affected by antipsychotic medications, Petrascheck hopes to use the same C. elegans model to study the metabolic side effects of all FDA-approved medications. “Side effects are unwanted, and we don’t know how they arise most of the time,” says Petrascheck. “The worm is a great discovery system.”

Additional authors of the study, “A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia,” include Anabel Perez-Gomez, Maria Carretero, Alan To, Viktoriya Titova and Gregory Solis of Scripps Research; and Natalie Weber, Veronika Peterka and Olivia Osborn of the University of California, San Diego.

The study was supported by the National Institutes of Health (grants R01DK117872, UL1TR001442 and DP2OD008398.

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