Hopkins scientists uncover cause of antipsychotic drug weight gain

Previous research had identified that increased levels and actions of the enzyme, AMPK, as a control lever for appetite.

Suspecting that antipsychotic drugs might spike AMPK in the brain to overact, the Johns Hopkins team injected mice with Clozaril, which, with Zyprexa and Risperdal, is commonly prescribed for schizophrenia and bipolar disorder.

Medicines such as Eli Lilly’s Zyprexa have faced concerns about weight gain that can often develop life-threatening complications such as diabetes and heart disease.

Mice given Clozaril showed quadrupled AMPK activity compared to activity measured pre-drug. The researchers then gave the mice leptin, a hormone that suppresses appetite, and saw lowered AMPK levels.

The researchers decided to manipulate cell-signaling proteins in the brain and found that blocking one in particular, a receptor site for histamine, activates AMPK to the same extent as Clozaril.

When the team gave Clozaril to mice genetically engineered without a histamine receptor, this resulted in no heightened activity.

“Our identification of the molecular players that link such drugs to increased food intake means there’s now hope for finding a newer generation of drugs without the weight-gain side effects,” said Solomon Snyder, professor of neuroscience at the Johns Hopkins School of Medicine.