Schizophrenia Daily News Blog

How Antipsychotic Drugs Cause Weight Gain

John Hopkins University Researchers Uncover Cause of Antipsychotic-related Drug Weight Gain

Johns Hopkins University brain scientists have announced that they understand how and why some of the antipsychotic drugs used for treating schizophrenia cause patients to frequently gain significant weight which may lead to life-threatening complications such as diabetes and heart disease.

In a press release from John Hopkins University it states: "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."

Covering this new research, The Wall Street Journal (WSJ) reported that "the brain has more than 50 neurotransmitter receptors, and Dr. Snyder says his team "squandered $10,000 on experiments" trying to pinpoint the right one. He then came across past studies that showed how antipsychotics can block the histamine H1 receptor, although none had shown the specific connection with weight gain, he says. The Johns Hopkins team now had a possible explanation: the role of AMPK."

Suspecting that antipsychotic drugs might increase AMPK in the brain, the Johns Hopkins researchers tested the theory by injecting the mice with clozapine (Clozaril), which, with olanzapine (Zyprexa) and risperidone (Risperdal), are some of the most commonly prescribed medications for schizophrenia.

Mice given clozapine showed quadrupled AMPK activity compared to activity measured pre-drug, and increased significantly with the other drugs also.

The researchers then gave the mice leptin, a hormone that suppresses appetite, and as suspected, saw lowered AMPK levels.

Looking into what controls AMPK and its boost of hunger, Sangwon Kim, Ph.D., a research associate and 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, Snyder's team found that blocking one in particular, a receptor site for histamine, a well-known player in triggering classic allergy symptoms, activates AMPK to the same extent as clozapine. To confirm that the histamine receptor connects the drug, AMPK activity and appetite, the team gave clozapine to mice genetically engineered without a histamine receptor.

"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 Wall Street Journal also noted in their story on this new development, that in November, 2006 the National Institutes of Health initiated a 300-patient trial to understand the effect of the schizophrenia drug aripiprazole (marketed as Abilify by Bristol-Myers Squibb) on metabolic changes, including weight gain and cholesterol levels.

The initial John Hopkins antipsychotic weight gain study will be published this week in the Proceedings of the National Academy of Sciences.

The research was funded by the U.S. Public Health Service, Canadian Institute of Health Research, National Institutes of Health and National Multiple Sclerosis Society.

Authors on the paper are Sangwon Kim, Alex Huang, Adele Snowman and Solomon H. Snyder of John Hopkins, and Cory Teuscher of the University of Vermont College of Medicine.

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