Scientists at a prestigious US medical institute believe that they have uncovered the reasons why antipsychotic drugs cause patients to gain so much weight that they often develop life-threatening complications such as diabetes and heart disease.

Professor Solomon Snyder of the Johns Hopkins School of Medicine and one of the authors of the study, which will be published online next week at the Proceedings of the National Academy of Sciences, said: “We have now connected a whole class of antipsychotics to natural brain chemicals that trigger appetite.”

According to the report, previous research has already noted increased levels and actions of one particular enzyme, AMPK, in brain cells as a control lever for appetite in mice “and presumably humans.” Therefore, suspecting that antipsychotic drugs might spike AMPK in the brain to overact, the Johns Hopkins team injected mice with Novartis’ Clozaril (clozapine) which, with Lilly’s Zyprexa (olanzapine) and Johnson & Johnson’s Risperdal (risperidone), is commonly prescribed for schizophrenia and bipolar disorder in people who do poorly on conventional drugs.

Quadrupled AMPK activity

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

Looking further into what controls AMPK and its boost of hunger, Sangwon Kim, another author of the study, “rounded up the usual suspects, brain proteins known to relay communication from cell to cell.” Systematically manipulating these cell-signalling proteins, the 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, which resulted in no heightened AMPK activity.

“Histamine also has a long history as a suspect in weight control, but no one ever could put a finger on the exact link,” said Prof 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 research was funded by the US Public Health Service, the Canadian Institute of Health Research, the National Institutes of Health and the National Multiple Sclerosis Society.