Pharmacological Treatment of Obesity in Schizophrenia

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The literature thus far suggests that some of the novel antipsychotic medications cause less weight gain than others; thus it may be possible to switch patients on agents associated with the most weight gain to those with lower weight gain liability (Allison et al. 1999a; Wirshing et al. 1999); however, prior to switching, it is important to recall that the most difficult symptoms to control are those of psychosis. A switch of antipsychotic medication makes sense particularly if the patient is nonresponsive to the current antipsychotic. As discussed, weight gain can be a significant cause of nonadherence with a medication regimen; thus, in cases where a patient refuses to take medication due to weight gain concerns, a switch is advisable (Bernstein 1988; Silverstone et al. 1988). A switch study sponsored by Pfizer demonstrated that subjects switched from olanzapine to ziprasidone lost a statistically significant 2.2 kg on average over 6 weeks (Kingsbury et al. 2001). Moreover, recent preliminary data from a Janssen-sponsored study suggest improvements in both weight and markers of glucose tolerance in patients switched from olanzapine to risperidone (Berry and Mahmoud 2001). There is no current evidence that medications other than clozapine are highly effective in treatment-refractory patients, so caution must be exercised in deciding to switch a patient from clozapine.

There have been few studies involving the administration of weight loss agents to psychotic patients. The National Institutes of Health (NIH) guidelines allow the use of weight loss agents for patients with a BMI >27 kg/m2 and obesity-related complications. Weight loss agents can also be administered to patients with BMI >30 kg/m2 who do not have obesity-related complications (Aronne 2001). Amantadine, fenfluramine, and chlorphen-termine have been used with moderate success (Correa et al. 1987; Kolokowska et al. 1987), although there are concerns that these drugs may worsen psychotic symptoms, and fenfluramine is no longer available on the market due to complications of cardiac valve dysfunction and pulmonary hypertension.

Medications that have been recently indicated for weight loss such as sibutramine and orlistat (Cerulli et al. 1998) have not been methodically tried or reported in this patient population. Sibutramine is a serotonin and norepinephrine reuptake inhibitor that was originally developed as an antidepressant, but was instead approved by the FDA as a treatment for obesity (Luque and Rey 1999). Orlistat is an inhibitor of gastric and pancreatic lipases that decreases dietary fat absorption, resulting in lowering of body weight and plasma cholesterol (Cerulli et al. 1998). Orlistat is difficult to administer, requiring three-times-daily dosing and fat-soluble vitamin supplementation, and thus may be difficult to use in psychiatric populations; however, because it does not have CNS effects it may be useful in this population (Hilgar et al. 2002).

Unapproved options for obesity treatment that may be of benefit include topiramate, histamine H2 antagonists, and metformin. Topiramate, a new anticonvulsant that is being tested for its safety and efficacy in the treatment of bipolar disorder, causes a decrease in appetite and sustained weight loss in obese individuals. It has not been systematically studied as primarily a weight loss agent but has demonstrated weight loss in patients with epilepsy and bipolar disorders (McElroy et al. 2000; Norton et al. 1997; Rosenfeld et al. 1997) and is being tested in binge-eating disorder (Yanovski and Yanovski 2002). The use of H2 antagonists for weight loss has been suggested in the literature, with speculation that H2 antagonism may affect weight either by decreasing appetite via increases in cholecystokinin, a hormone that may signal satiety to the brain, or through the suppression of gastric acid secretion, which may decrease appetite (Sacchetti et al. 2000). Nizatidine, a histamine H2 blocking agent, was recently compared with placebo as an adjunct to olanzapine treatment, and modest reductions in weight gain were seen in patients receiving 300 mg of nizatidine versus placebo; however, weight gain still occurred in these olanzapine-treated patients (Werneke et al. 2002). Metformin, an oral hypoglycemic agent utilized for treatment of type II diabetes that increases insulin sensitivity in insulin-resistant patients, may also be useful as a weight loss agent (Baptista et al. 2001; DeFronzo and Goodman 1995; Fontbonne et al. 1996; Morrison et al. 2002). Of course, caution must temper enthusiasm for the results from these small studies, and more prospective, better-powered intervention studies are desperately needed.

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