Concerns about the metabolic side effects of widely used atypical antipsychotic drugs (AAPDs) have grown in recent years, but the complex pharmacological activities of AAPDs have made it particularly difficult to determine the underlying mechanisms. This has hindered the development of new drugs without these side effects. Reporting in PNAS, Snyder and colleagues now shed light on this mystery by showing that histamine 1 receptor (H1R) antagonism and activation of the appetite-stimulating enzyme AMP-protein kinase (AMPK) in the hypothalamus underlie the orexigenic effects of the AAPDs clozapine and olanzapine.

AMPK is a central regulator of energy homeostasis; it acts as a fuel sensor inhibiting ATP-consuming pathways and activating ATP-generating catabolic pathways. Pharmacological activation of AMPK in the hypothalamus, the appetite-control centre of the brain, has previously been shown to increase food intake and body weight. In their study, Snyder and colleagues observed that the administration of clozapine increased the levels of phospho-AMPK and AMPK activity in intact mice more than threefold. This effect was specific for the hypothalamus as levels in the cerebellum, cortex and liver remained unchanged.

The orexigenic effects of various AAPDs were found to correlate with their affinity for H1R. Clozapine and olanzapine, which have been observed to have the most marked effects on weight gain in clinical use, have the strongest affinity for H1R. Although the H1R antagonist triprolidine mimicked the effect of clozapine in both hypothalamic slices and in intact animals, histamine reduced the effects of the drug on AMPK activation. More importantly, in mice with H1R knocked out, administration of clozapine had no effect on hypothalamic AMPK.

The precise mechanism through which H1R modulates AMPK remains unclear, but the results of this study suggest that assessing H1R binding and hypothalamic AMPK activity could be a valuable and straightforward strategy to guide the development of novel antipsychotic drugs with fewer metabolic side effects. Furthermore, these findings help to explain why using antihistamines can lead to weight gain, and highlight H1R as a potential target for the treatment of obesity.

ORIGINAL RESEARCH PAPER

1. Kim, S. F. et al. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc. Natl Acad. Sci. USA 104, 3456–3459 (2007) | Article | PubMed |

FURTHER READING

1. Meltzer, H. Y. Illuminating the molecular basis for some antipsychotic drug-induced metabolic burden. Proc. Natl Acad. Sci. USA 104, 3019–3020 (2007) | Article | PubMed |
2. Stroup, T. S. et al. Clinical trials for antipsychotic drugs: design conventions, dilemmas and innovations. Nature Rev. Drug Discov. 5, 133–146 (2006) | Article |