We’ve known for some time now that clozapine and Zyprexa (olanzapine) cause the most weight gain of any antipsychotic, but we didn’t know the actual mechanism – until now. Researchers from Johns Hopkins and the University of Vermont found that both clozapine and Zyprexa increase levels of a specific enzyme in the hypothalamus that boosts the appetite. The enzyme, AMPK (AMP-protein kinase), is one of the brain's major fuel-sensors, and leads to various biochemical reactions that eventually cause weight gain and metabolic abnormalities. Atypical antipsy- chotics that cause little weight gain, such as Risperdal, Abilify, and Geodon, increase AMPK levels only minimally. Interestingly, the way clozapine and Zyprexa stimulate AMPK appears to be via histamine-1 receptor antagonism, a neurotransmitter pathway that has long been a prime suspect as a mediator of weight gain (Kim SF et al., Proc Nat Acad Sci 2007:104(9): 3456-3459).

TCPR’s Take: It’s rare to find a clear molecular explanation for anything in psychiatry, so this finding is intriguing for that reason alone. Are there any clinical implications? Not really, since we already knew which antipsychotics caused the most weight gain. But researchers will use these findings to develop more targeted medica- tions, both to prevent and to treat obesity in our psychotic patients.