How antipsychotic drugs can cause weight gain

A study of mice has identified a biological mechanism by which certain psychiatric medications cause people to gain weight.

Researchers linked the appetite-increasing effects of three such drugs—the so-called atypical antipsychotics clozapine (Clozaril), olanzapine (Zyprexa), and risperidone (Risperdal)—to their capacity to neutralize the protein histamine, just as the antihistamine drugs that are used to treat allergies do.

“Histamine also has a long history as a suspect in weight control,” says neuroscientist Solomon Snyder of the Johns Hopkins School of Medicine in Baltimore. “The connection we’ve made … opens new avenues for research on weight control, possibly including drugs that suppress appetite safely.”

The new finding might also lead to safer treatments for schizophrenia and other manifestations of psychosis, Snyder and his colleagues say.

The researchers injected the drugs into mice and found that they quadrupled the activity of AMP kinase, an enzyme previously shown to increase appetite. They then gave the mice leptin, an appetite-suppressing hormone, and found that AMP kinase concentrations dropped back toward normal.

Mice that lacked sensitivity to histamine experienced no increase in AMP kinase when given the drugs. That result suggests that atypical antipsychotic drugs block histamine activity and thereby increase AMP kinase, the researchers say.

Their results appear in the Feb. 27 Proceedings of the National Academy of Sciences.