In the pre-antipsychotic era, Kraepelin noted that some patients with schizophrenia exhibited bizarre eating habits, and not uncommonly were obese. “The taking of food fluctuates from complete refusal to the greatest voracity. The body weight usually falls at first often to a considerable degree. . . . [L]ater, on the contrary we see the weight not infrequently rise quickly in the most extraordinary way, so that the patients in a short time acquire an uncommonly well-nourished turgid appearance” (Kraepelin 1919, p. 125).

It is worth noting that this tendency to weight loss during more active phases of the illness has been borne out by results from a recent meta-analysis of multiple antipsychotic drug trials, which noted that placebo-treated patients on average lost weight (Allison et al. 1999a). Nevertheless, there are a number of reasons that patients with schizophrenia might be prone to obesity, including the effect of symptoms such as paranoia and negative symptoms such as apathy and social withdrawal, which may independently contribute to schizophrenic patients’ lack of adherence to proper diet and their overall sedentary lifestyle (Davidson et al. 2001).

Moreover, the economic conditions of chronically mentally ill individuals also contribute to poor dietary habits. One theory about the major vector of the obesity epidemic in this country and abroad correlates obesity trends with the growth of the fast-food industry (Schlosser 2001). Fast food is an affordable option for those on limited budgets, yet unfortunately is often very high in saturated fat and total calories.

The Effects of Antipsychotic Medications on Weight

Antipsychotic medications have been the mainstay of treatment for schizophrenia for over half a century. A link between weight gain and treatment with chlorpromazine and other low-potency conventional antipsychotic agents, such as thioridazine, was noted in early studies of the metabolic effects of these agents. (Bernstein 1988; Rockwell et al. 1983). A recent study by Allison et al. (1999b) based on 1989 National Health Interview Survey data revealed that a significantly greater proportion of female patients with schizophrenia had BMI distributions in the overweight and obese spectrum compared with their counterparts in the general medical population, with a trend toward greater BMI seen among male schizophrenic patients.

This study is notable because the data are based on survey material collected in 1989, before the advent of the novel antipsychotic medications. Thus, the results of that survey reflect obesity in a population of schizophrenic patients medicated with conventional antipsychotic medications. In general, treatment with lower-potency conventional antipsychotics was associated with greater weight gain than treatment with higher-potency agents. Over 10 weeks of treatment with conventional agents, mean gains of 2.65 kg were seen with chlorpromazine and 3.19 kg with thioridazine, compared with only 1.1 kg with the high-potency agent haloperidol (Allison et al. 1999a). The pharmacology of obesity will be discussed later in this chapter, but the greater propensity for histamine H1 antagonism is thought to be the primary reason that lower-potency agents were associated with greater weight gain than higher-potency drugs such as haloperidol or fluphenazine. Since the late 1980s a number of novel antipsychotic medications have been developed and released for clinical use worldwide. Unlike typical antipsychotics, the novel agents clozapine, risperidone, olanzapine, quetiapine, and ziprasidone are weaker dopamine D2 antagonists, and therefore have very favorable extrapyramidal side-effect profiles compared with conventional antipsychotic agents.

Unfortunately, some of the novel agents appear to have significant liabilities in terms of weight gain, especially compared with high-potency conventional drugs such as haloperidol. Wirshing and colleagues published a retrospective study of 122 clinical records of 92 outpatients involved in long-term clinical trials and found that clozapine therapy was associated with the most weight gain (6.9 ± 0.8 kg) among the novel antipsychotic medications examined (controlling for patient age and treatment duration), followed by olanzapine (6.8 ± 1.0 kg), risperidone (5.0 ± 0.6 kg), and the conventional agent haloperidol (3.7 ± 0.6 kg) (Wirshing et al. 1999). Allison and colleagues’ comprehensive meta-analysis of 81 clinical trials with data on antipsychotic-induced weight gain (Allison et al. 1999a) found that the dibenzodiazepine-derived novel antipsychotics clozapine and olanzapine demonstrated weight gain at 10 weeks of therapy exceeding even that seen with thioridazine (clozapine 4.45 kg, olanzapine 4.15 kg); lesser gains were seen with risperidone (2.1 kg) and ziprasidone (0.04 kg).

Ten-week data were not available for quetiapine. Long-term data with clozapine- and olanzapine-treated patients also document weight gain far in excess of that seen with the low-potency typical antipsychotics such as chlorpromazine or thioridazine, whereas risperidone and ziprasidone show lower weight gain propensities, and conflicting data exist regarding quetiapine. Mean increases reported during the first year of therapy are 5.3­6.3 kg for clozapine and 6.8­11.8 kg for olanzapine, with substantial proportions in each group gaining more than 20% of their initial body weight in this time frame (Bustillo et al. 1996; Henderson et al. 2000; Kinon et al. 2001; Nemeroff 1997).