Novel antipsychotic medications and conventional antipsychotic medications affect a number of central neurotransmitter systems that may have an impact on satiety and feeding behavior. Many of the receptor systems blocked by antipsychotic medications are those that are stimulated by medications that promote weight loss.

For example, all antipsychotic medications block dopamine D2 and noradrenergic 1 receptors, the same sites stimulated by amphetamines and sympathomimetic amine drugs used to promote weight loss. Additionally, psychotropic drugs influence serotonin (5-HT) and histamine H1 neurotransmission, both of which have been reported to affect food intake and cause fluctuations in weight. In examining the binding profiles of antipsychotic agents, the receptor affinity characteristic most closely correlated with weight gain among novel antipsychotic medications was H1 antagonism (Wirshing et al. 1999) (see Figure 3­1). Although H1 blockade also causes sedation, the mechanism by which H1 receptor antagonism may increase weight is peripheral interference with normal satiety signals from the gut, resulting in overeating (Knight 1985; Rockwell et al. 1983).

Both low-potency conventional agents and those novel antipsychotic medications with higher weight gain potential have substantial affinity for this receptor (Schotte et al. 1993); however, what may contribute to the greater weight gain seen with some of the novel antipsychotics is the additional effect of 5-HT_2C antagonism. Since the advent of clozapine, novel antipsychotics have been designed primarily to be both relatively weak D2 antagonists and potent antagonists at 5-HT2A receptors, yet these agents also have substantial affinity for the closely related 5-HT_2C receptor.

It is known that compounds that stimulate 5-HT transmission reduce food consumption and cause weight loss (e.g., m-chlorphenylpiperazine, fenfluramine, sibutramine) whereas drugs that decrease 5-HT transmission increase food intake and are associated with weight gain (Goodall et al. 1988; Samanin and Garattini 1990). It is unclear which 5-HT receptor type is responsible for stimulating food intake and weight gain (Aulakh et al. 1992), but data implicate antagonism of 5-HT_2C receptors as a possible site where novel antipsychotics might have an impact on weight (Tecott et al. 1995).

Evidence for this assertion comes from two types of data. Drugs such as fenfluramine are thought to suppress appetite via 5-HT_2C agonism (Garattini et al. 1989); moreover, Tecott and colleagues developed a strain of mice in which the gene coding for the 5-HT_2C receptor was knocked out.

Figure 3­1. Relationship between histamine H1 receptor affinity and adjusted weight gain among antipsychotics.
Source. Reprinted from Wirshing D, Wirshing W, Kysar L, et al.: “Novel Antipsychotics: Comparison of Weight Gain Liabilities.” Journal of Clinical Psychiatry 60:358­363, 1999. Used with permission.

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-HT_2C antagonists, the propensity for weight gain best correlates not with the rank order of 5-HT_2C 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).

Donna A. Wirshing, M.D.
Jonathan M. Meyer, M.D.

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