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Antipsychotic-Induced Obesity: Histamine May Be the Key

Summary and Comment |
April 2, 2007

Antipsychotic-Induced Obesity: Histamine May Be the Key

  1. Jonathan Silver, MD

Results from an animal study

  1. Jonathan Silver, MD

Weight gain and onset of the metabolic syndrome associated with effective atypical antipsychotics (clozapine and olanzapine) are major clinical concerns and can lead to drug discontinuation or avoidance. The mechanism for these effects has not been clearly elucidated. Because hypothalamic AMP-kinase (AMPK) regulates food intake through the histamine H1 receptor, these researchers examined the effect of antipsychotics on this system in a series of mouse experiments.

In vitro, clozapine and olanzapine increased levels of phospho-AMPK, and quetiapine had similar effects. This effect was selective for the hypothalamus and was not seen with risperidone, ziprasidone, haloperidol, or aripiprazole. In intact mice, clozapine increased hypothalamic AMPK but did not have this effect in mice genetically engineered for deletion of histamine H1 receptors. The researchers measured H1-receptor binding in the presence of several antipsychotics and found that the potencies of the atypicals in H1-receptor blocking correlated with their appetite-enhancing potencies, as reported in other studies.

Comment

The authors demonstrate that clozapine and olanzapine selectively and potently stimulate hypothalamic AMPK. Although some evidence exists for the role of other neurotransmitters (serotonin, dopamine, and norepinephrine) in obesity and weight gain from these medications, these results clearly connect the problem to the H1 receptor. An editorialist observes that some reports have linked weight gain with clinical response. If we understand the mechanism of weight gain, the avenue is open for the development of potential treatment or prophylaxis.

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