DIETING
February 14, 2007

Cause of Antipsychotic Weight Gain Found

Scientists have finally found out how and why some powerful drugs used for treating mental illnesses cause people to gain dramatic amounts of weight.

"We've now connected a whole class of antipsychotics to natural brain chemicals that trigger appetite," says Solomon H. Snyder, M.D., professor of neuroscience at the Johns Hopkins School of Medicine. "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."

Previous research already had fingered increased levels and actions of one particular enzyme, AMPK, in brain cells as a control lever for appetite in mice and presumably humans.

Suspecting that antipsychotic drugs might cause AMPK in the brain to overact, the Johns Hopkins team injected mice with clozapine (Clozaril), which, with olanzapine (Zyprexa) and risperidone (Risperdal), is commonly prescribed for schizophrenia and bipolar disorder in people who do poorly on conventional drugs.

Mice given clozapine showed quadrupled AMPK activity compared to activity measured pre-drug. The researchers then gave the mice leptin, a hormone that suppresses appetite; as suspected, this lowered AMPK levels.

Looking further into what controls AMPK and its boost of hunger, Sangwon Kim, Ph.D., lead author of the study, "rounded up the usual suspects, brain proteins known to relay communication from cell to cell."

Systematically manipulating these cell-signaling proteins, the research team found that blocking one in particular, a receptor site for histamine, the substance that triggers classic allergy symptoms, activates AMPK to the same extent as clozapine.

"Histamine also has a long history as a suspect in weight control, but no one ever could put a finger on the exact link," says Snyder. "The connection we've made between its receptor and appetite control is incredibly intriguing and opens new avenues for research on weight control, possibly including drugs that suppress appetite safely."

The study will be published in mid-Februry 2007, online, at the Proceedings of the National Academy of Sciences.
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