Weight Gain From Antipsychotics Traced to Appetite-Regulating Enzyme, Receptor

A likely mechanism by which antipsychotic medications trigger weight gain — with its attendant risks of heart disease, diabetes and treatment non-adherence — has been unraveled in mice by NIMH-funded scientists. They demonstrated that an antipsychotic boosted activity of an appetite-inducing enzyme four-fold in a brain region that regulates eating, by blocking a receptor. A promising strategy for eliminating the side effect would be to engineer medications that don’t interact with the receptor, say the researchers.

A scientific team led by NIMH grantee Dr. Solomon Snyder, Johns Hopkins University, reported on their discovery online February 9, 2006 in the Proceedings of the National Academy of Sciences.

In 2003, NIMH grantee Dr. Bryan Roth, now at the University of North Carolina, and colleagues, reported that an antipsychotic’s propensity to activate a receptor for the messenger chemical histamine predicted the drug’s weight gain risk. However, the mechanism by which this interaction might induce weight gain remained a mystery.

In the new study, Snyder and colleagues picked up on recent evidence implicating an enzyme, AMPK, in regulating eating. AMPK increased four times more than normal in hypothalamus regions controlling feeding when the researchers gave mice the atypical antipsychotic clozapine. In untreated mice, AMPK was reduced after the animals were given the appetite suppressant leptin. However, when given the antipsychotic clozapine, AMPK increased even in the presence of leptin. There were hints that an intermediary mechanism was also involved, and the Hopkins team eventually followed-up on the earlier clues pointing to the histamine receptor.

Blocking the histamine receptor mimicked clozapine’s effect, boosting AMPK activation. Mice genetically engineered to lack the histamine receptor showed no increase in AMPK in response to clozapine. This confirmed that the receptor is likely the important link in the appetite-stimulating effect of atypical antipsychotic medications.

In addition to the implications for design of newer antipsychotics, the findings may also lead to new strategies in weight and appetite control research generally, add the researchers.

Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. PNAS Early Edition, 2/9/07.