Antipsychotics’ Link to Weight Gain FoundAntipsychotics’ Link to Weight Gain Found

While adverse effects and drugs often go hand in hand, some of the complications that can arise from medication use have remained a mystery.

“A really big challenge in pharmacology is to establish which action of a drug is responsible for its clinical effect, whether it is a therapeutic or adverse effect,” said Solomon Snyder, MD, of the Johns Hopkins School of Medicine, in Baltimore.

Snyder and colleagues have taken on the challenge of elucidating an important adverse effect—major weight gain—often caused by certain atypical antipsychotic drugs (AAPDs) used for the treatment of schizophrenia (Kim SF et al. Proc Natl Acad Sci U S A. doi:10.1073/pnas.0611417104 [published online February 20, 2007]).

The findings could be useful in the development of improved antipsychotic drugs and may lead to a better understanding of the brain's role in the regulation of food intake.

While the first antipsychotic drugs on the market were designed to block dopamine D2 receptors, researchers found that newer “atypical” drugs such as clozapine blocked a number of different receptors in the brain and were more effective in treating many of the symptoms of schizophrenia.

“Clinically, clozapine did wonderful things, but drug companies had no idea why,” said Snyder. Other AAPDs were subsequently manufactured that mimicked clozapine's beneficial properties, even though it was not clear which receptors being targeted were important for easing symptoms.

Unfortunately, clozapine and some of these other AAPDs, including olanzapine and quetiapine, also stimulate appetite and cause weight gain in patients. Weight gain elicited by AAPDs can be significant; one of Snyder's patients quickly gained 100 pounds when taking one of these drugs.

These so-called orexigenic properties of certain AAPDs appear to relate to stimulation of hypothalamic AMP-activated protein kinase (AMPK), an enzyme important for maintaining energy homeostasis that has been linked to the regulation of food intake (Kahn BB et al. Cell Metab. 2005;1:15-25). Snyder's team found that clozapine, olanzapine, and quetiapine all stimulated AMPK within brain tissue both in vitro and in vivo, while the less orexigenic AAPDs—risperidone, ziprasidone, and aripiprazole—did not.

To investigate the mechanism by which orexigenic AAPDs influence AMPK, the scientists assessed the drugs' effects on receptors in the brain. While these agents did not alter binding of molecules such as leptin that are involved in appetite regulation, the AAPDs did block the histamine H1 receptor, which mediates histamine's inflammatory effects during allergic responses. The investigators observed that, like clozapine—an H1 receptor antagonist stimulated AMPK—histamine decreased AMPK stimulation, an effect that could be reversed by clozapine. Furthermore, AMPK activity quadrupled in mice given clozapine, but the drug had no effect on AMPK in knockout mice lacking the H1 receptor.

Although a number of studies have suggested some role for serotonin, norepinephrine, and dopamine in the development of obesity in patients taking medications for psychiatric conditions, the new findings establish that orexigenic AAPDs act via histamine H1 receptors and AMPK, the authors wrote.

Fortunately, AAPDs' weight gain effects are not related to their therapeutic effects and researchers are optimistic that they will find ways to get around the drugs' propensity to stimulate appetite. The drug recognition sites of dopamine and histamine receptors are different, so developing new antipsychotic drugs that do not block H1 receptors is one option. Another potential strategy could involve giving a drug that mimics histamine and stimulates the receptors as an adjunct or antidote, said Snyder. Yet another approach is targeting other molecules that affect histamine production while simultaneously administering antipsychotics. Pharmaceutical companies are looking into these various strategies, said Snyder.

The study's findings may have implications for other classes of drugs that can cause significant weight gain, such as antidepressants. One obvious question that arises from the study, said Snyder, is the effect on weight of allergy drugs taken specifically to block the histamine receptors. People who take certain antihistamines for a long period do often gain weight, but most individuals only take small doses of these drugs for short periods, he explained.

In future studies, Snyder and colleagues plan to continue exploring drug-related weight gain in animal models and to further investigate AMPK's role in regulating appetite.