Figure 31 Relationship between histamine Ht receptor affinity and adjusted weight gain among antipsychotics

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Source. Reprinted from Wirshing D, Wirshing W, Kysar L, et al.: "Novel Antipsychotics: Comparison of Weight Gain Liabilities." Journal of Clinical Psychiatry 60:358-363, 1999. Used with permission.

5-HT2C receptor was knocked out. As these mice age, they become obese, and also develop type II diabetes mellitus (Tecott et al. 1995). Although most of the novel antipsychotic medications are indeed 5-HT2C antagonists, the propensity for weight gain best correlates not with the rank order of 5-HT2C antagonism, but with the potency of histamine H1 antagonism.

Another mechanism by which novel antipsychotics may have an impact on weight is via effects on peptide hormones. Leptin is a hormone produced by adipose tissue that is thought to signal the size of the pool of adiposity to the brain and thereby decrease feeding behavior. In humans, circulating leptin correlates closely with BMI (Kraus et al. 1999). Mice and humans deficient in leptin are obese, whereas parenteral administration of exogenous leptin reverses the abnormalities in food intake and weight in leptin-deficient individuals (Pelleymounter et al. 1995). An early paper examining clozapine-treated patients found increases in both adipose tissue and circulating levels of leptin (Bromel et al. 1998). In a subsequent study which found that leptin was increased in patients treated with clozapine or olanzapine but not with haloperidol, the investigators speculated that the normal hormonal feedback mechanism was impaired in patients taking those novel antipsychotic medications (i.e., they continue to overeat despite high circulating leptin levels) (Kraus et al. 1999). Moreover, an 8-week study found significant increases in body weight, serum leptin levels, and percentage of body fat in patients treated with olanzapine, but not in the drug-free comparison group (Eder et al. 2001).

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