One personal copy may be printed Mechanisms of Weight Gain Induced by Antipsychotic Drugs

Sir: Casey and Zorn recently published an excellent review article on the mechanisms of body weight gain induced by antipsychotic drugs. It is a timely topic, given the growing concern of the psychiatric community about the risk of obesity and non–insulin dependent diabetes mellitus during treatment with antipsychotics, particularly with some of the new atypical agents. Surprisingly, the authors did not mention a considerable body of research on the subject, conducted at our laboratory at Los Andes University Medical School in Merida, Venezuela, in collaboration with the National Institute of Mental Health, Bethesda, Md. , and Princeton University, Princeton, N.J. We have studied the effects of the antipsychotic sulpiride on body weight gain and feeding regulation in rats and humans, and, in fact, our research is the only published animal model of antipsychotic-induced obesity. I would like to summarize our findings within a chronological perspective, so that your readers may use them to complement the information provided by Casey and Zorn. When we first tested in Wistar rats the effects of most available antipsychotics in the 1980s, one striking finding was that significant body weight gain was observed only in females and prepuberal males. This sex-dependent effect was replicated by other authors and has also been reported with risperidone. Even though significant body weight gain was observed after administration of haloperidol, trifluoperazine, and thioridazine in female rats, the effect was more robust with racemic sulpiride, a D2-D3 dopamine receptor antagonist. Hence, we used this agent for additional experiments. Body weight gain during sulpiride administration was dose dependent, required increased food intake in order to be observed, and was prevented by bromocriptine. As sulpiride injections in the lateralperifornical hypothalamus induced strong feeding and drinking in satiated rats, we suggested that blockade of D2 receptors in that brain area might mediate antipsychotic effects on feeding. This proposal was contradicted for 2 main reasons: (1) the strong sex-dependent effect observed in rats in the absence of evidence of gender-related hypothalamic mechanisms for feeding regulation and (2) systemic sulpiride did not counteract the anorexia induced by local hypothalamic injections of amphetamine in rats. The role of dopamine in feeding regulation was also challenged by Silverstone et al., because pimozide did not prevent amphetamine anorexia in healthy people. In 1995, Parada et al. showed that rats self-inject sulpiride in the lateral-perifornical hypothalamus. In addition, these injections induce dopamine release in the nucleus accumbens, suggesting it might be an important pathway for food reward related to D2-D3 receptors in the lateral-perifornical hypothalamus. In 1989, Parada et al. proposed that antipsychoticinduced body weight changes in rats might be mediated by hyperprolactinemia-induced hypogonadism. It could explain sulpiride-induced body weight gain and permanent diestrous in females and body weight loss in males treated with some antipsychotics. In support of their proposal, we showed that estradiol and tamoxifen (an agonist of estradiol in relation to food intake in rodents) prevented sulpiride-induced body weight gain in female rats. In addition, ovariectomized rats (which display obesity after ovary removal) did not gain additional body weight after sulpiride administration. Our research group has also studied the role of hypogonadism in antipsychotic-induced body weight gain in people during treatment with typical antipsychotics. Sulpiride, phenothiazines, and haloperidol induce a strong reduction in the serum levels of estradiol and progesterone after short-term treatment. However, after prolonged administration, estradiol (but not progesterone) levels normalize. Hence, hypoestrogenemia might be involved in the initial events leading to body weight gain; low progesterone levels might promote abdominal obesity, as suggested by Björntorp. Low serum testosterone levels in men, which promote adiposity, have been observed after short-term administration of phenothiazines and haloperidol (but not sulpiride). That hormone has not been explored following prolonged antipsychotic administration. An important unresolved issue is that low gonadal steroid levels in people with schizophrenia may be relatively independent of antipsychotic administration. An additional role for hyperprolactinemia may be the modulation of insulin sensitivity, which is a very important issue, given the propensity of antipsychotics to induce glucose intolerance and non–insulin dependent diabetes mellitus. Female rats with sulpiride-induced body weight gain display other interesting features: they have normal or low glucose and insulin levels and normal leptin levels. This endocrine/ metabolic profile differs considerably from that reported in obese people after treatment with typical or atypical antipsychotics, who display the expected high levels of glucose, insulin, and leptin. Interestingly enough, male Wistar rats treated with sulpiride for 21 days did not gain body weight (as expected) and had significantly high levels of glucose and insulin after a glucose overload. This suggests insulin resistance (which may prevent body weight gain) and is in clear contrast to the metabolic profile observed in females. Finally, sulpirideinduced body weight gain in rats was not counteracted by pharmacologic doses of amantadine or naltrexone. In summary, the interaction of antipsychotics with dopamine receptors in the lateral-perifornical hypothalamus may stimulate appetite. This effect is perhaps balanced by the blockade of dopamine receptors in the limbic system, which, rather, decreases feeding. However, the interaction of antipsychotics with lateral-perifornical hypothalamus neurons may play a role in the voracious appetite observed in some patients shortly after antipsychotic administration. An insufficient number of D2 striatal receptors may be involved in primary obesity. This might be mimicked by antipsychotic-induced blockade of these receptors.