Avoiding a Weighty Side Effect
By Constance Holden, Science NOW Daily News
13 February 2007

Weight gain can be a serious problem for patients taking antipsychotic drugs for schizophrenia--not only do the drugs have a sedative effect that slows people down, but they also stimulate the appetite, a combination that can mean a big weight gain. It so happens that this is also what certain antihistamines, which counter allergic reactions, do. Now scientists say they have identified a common mechanism: Both types of drugs act on the same histamine receptor in the brain. The knowledge should help drug makers avoid this side effect in the next generation of antipsychotics and other drugs.

Previous research had already suggested that the actions of a particular enzyme, AMP kinase (AMPK), are directly related to appetite control, apparently through action on the H1 histamine receptor. To see if antipsychotic drugs cause excess production of the enzyme, researchers led by neuroscientist Solomon Snyder of Johns Hopkins University in Baltimore, Maryland, injected mice with clozapine, a commonly prescribed antipsychotic drug. The injection resulted in quadrupled AMPK activity in the mice's brains. The researchers then gave the mice leptin, an appetite-suppressing hormone, and saw the AMPK levels go down.

The scientists then established the histamine link by giving clozapine to mice bred to lack H1 receptors. In this case, the mice failed to react with raised levels of AMPK, showing that the stimulation of the enzyme by the drug depends on the stimulation of the H1 histamine receptor, the researchers report online this week in the Proceedings of the National Academy of Sciences. "We've now connected a whole class of antipsychotics to natural brain chemicals that trigger appetite," said Snyder.

The first antipsychotic, chlorpromazine, was originally intended as an antihistamine when it was invented in the early 1950s, notes neuropsychopharmacologist Bryan Roth of the University of North Carolina, Chapel Hill. Roth's earlier research showed that many antipsychotics, in addition to targeting neurotransmitters linked to schizophrenia, appear to activate the signaling pathway mediated by H1 receptors. But now, he says, the mechanism has been definitively nailed down. He says, "I think this will go a long way towards convincing pharmaceutical companies and regulatory agencies that with drugs taken by humans we need to avoid hitting this receptor to avoid weight gain."