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Why Atypical Antipsychotics Cause Weight Gain
BALTIMORE—Atypical antipsychotic drugs (AAPDs) have greatly improved management of schizophrenia, but their use is complicated by major weight gain in many patients. A new study reported in Proceedings of the National Academy of Sciences shows that orexigenic AAPDs cause weight gain by histamine H1 receptor–linked activation of hypothalamic AMP-kinase (AMPK) and that the weight-gain effects of some AAPDs occur via mechanisms different from those that produce therapeutic antipsychotic effects.
“Our findings establish definitively the way in which AAPDs increase appetite, which is clearly different from how they exert antipsychotic actions,” senior author Solomon H. Snyder, MD, told NeuroPsychiatry Reviews. “Accordingly, the two effects can be separated clinically. One can now readily screen for drugs that won’t stimulate appetite, by monitoring effects of candidates at histamine H1 receptors that are readily monitored in test tube systems such that a thousand compounds could be screened in a day.”
The researchers used hypothalamic slices taken from 8- to 10-week-old mice and dispersed in artificial CSF buffer to test the effects of clozapine, olanzapine, quetiapine, risperidone, ziprasidone, haloperidol, and aripiprazole on AMPK phosphorylation.
Good Old H1 Receptors Hold the Key
“Numerous ‘exotic’ neurotransmitter peptides in the hypothalamus regulate appetite and were the focus of our attention for many months and at great expense,” said Dr. Snyder. “Finally, it dawned on us to study histamine H1 receptors, which are simple to evaluate and which had been first identified in our laboratory some 30 years ago.”
In the hypothalamic slices, clozapine, olanzapine, and quetiapine (all of which are orexigenic) increased phospho-AMPK levels. The less appetite-stimulating drugs risperidone, ziprasidone, haloperidol, and aripiprazole did not increase AMPK phosphorylation.
The researchers concluded, “We now show that orexigenic AAPDs selectively and potently stimulate hypothalamic AMPK, which has been linked to the regulation of food intake, and reverse the actions of the anorexigenic hormone leptin. This action involves the histamine H1 receptor, because clozapine augmentation of AMPK is abolished in histamine H1 receptor–knockout mice, and orexigenic potencies of neuroleptics correlate with their affinities for the histamine H1 receptor.”
What Tips the Scale?
However, Dr. Snyder pointed out that important questions about antipsychotic drugs and weight gain remain unanswered. “For instance, weight gain might involve metabolic effects of the drugs outside of the brain in addition to stimulation of appetite. The propensity of the drugs to promote diabetes may or may not be a product of the weight-gain effects. We are examining whether antidepressants that cause weight gain also act via histamine H1 receptors and AMPK,” he said.
Even without the answers to these questions, the study has important implications for treatment of patients taking AAPDs.
“Clinicians should remember that antipsychotic drugs act potently on multiple receptors. Besides histamine H1 sites and dopamine D2 receptors (whereby they exert antipsychotic effects), the drugs also influence a-adrenergic receptors (which may contribute to hypotension) and several types of serotonin receptors. Clinicians should note that some AAPDs, such as ziprasidone and aripiprazole, do not block histamine H1 receptors and don’t provoke weight gain,” Dr. Snyder said.
The researchers suggest that testing candidate AAPDs for their effects on the H1 receptor and on hypothalamic AMPK might be a useful screening tool for developing agents associated with fewer adverse effects.
—Janis Kelly
Suggested Reading
Kim SF, Huang AS, Snowman AM, et al. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A. 2007 Feb 12; [Epub ahead of print].
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