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 anti-psychotic 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 anti-psychotic medications. Thus, the results of that survey reflect obesity in a population of schizophrenic patients medicated with conventional anti-psychotic 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, que-tiapine, 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 ris-peridone and ziprasidone show lower weight gain propensities, and conflicting data exist regarding quetiapine. Mean increases reported during the first year of therapy are 5.3-6.3 kg for clozapine and 6.8-11.8 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). Package insert information on olanzapine reports that over 50% of patients treated in long-term studies gained more than 7% of their initial body weight. Although risperidone and quetiapine have more weight gain propensity than that associated with a high-potency agent such as haloperidol, their reported mean gains of 2.0-2.3 kg and 2.77-5.60 kg, respectively, over 12 months compare favorably with clozapine, olanzapine, and low-potency typical antipsychotics (Jones et al. 2000; Marder 1997; Taylor and McAskill 2000); however, recent long-term data from Canada showed weight gain related to quetiapine therapy of 7.6 kg, much closer to that seen with olanzapine and clozapine (Mclntyre et al. 2001). Interestingly, retrospective data published by Reinstein found that quetiapine, when added to patients' clozapine regimen after clozapine dose reduction, resulted in weight loss. However, it is difficult to know if co-treatment with quetiapine or the dosage reduction of clozapine was responsible for the weight loss observed (Reinstein et al. 1999). Ziprasidone was released in the United States in 2001, and long-term studies show a mean gain of 0.23 kg at 6 months, with 14.0% gaining >7% of their baseline weight at 10.5 months (Pfizer 2000).

The relative propensity for weight gain with atypical antipsychotic medications is reflected in the manufacturers' package inserts, which must include FDA-mandated data on the percentage of patients who gained >7% of their initial body weight during short-term premarketing clinical trials. The reported percentages are as follows: olanzapine 29%, quetia-pine 23%, risperidone 18%, and ziprasidone 10% (Zyprexa 2000; Seroquel 2000; Risperdal 1999; Geodon 2001, respectively).

The time course in the progression of weight increase varies with the potential of each individual agent to cause weight gain. For those atypicals associated with greater weight gain, namely olanzapine and clozapine, a plateau appears between 39 and 52 weeks of therapy, although patients on clozapine may continue to gain approximately 4 pounds per year through the fourth year of treatment (Henderson et al. 2000; Kinon et al. 2001). In patients receiving ziprasidone, risperidone, or quetiapine, the plateau occurs much earlier, typically during the first few months of treatment (Brecher and Melvin 2001; Green et al. 2000; Taylor and McAskill 2000). Wirshing and colleagues also noted in their retrospective study that patients treated with clozapine and olanzapine had weight gain over longer periods of time compared with risperidone- and haloperidol-treated patients (Wirshing et al. 1999). They observed that patients gained weight over at least 20 weeks on clozapine and olanzapine, compared with approximately 10 weeks during treatment with risperidone.

The literature on weight gain with novel antipsychotic medications indicates that certain groups of patients, such as adolescents, may be particularly susceptible to this problem. In a retrospective study, Theisen and colleagues reported that the prevalence of obesity in adolescent patients was 64% on clozapine (n =69) and 56% on other atypicals (olanzapine, sulpiride, and risperidone) (n=27), compared with 30% for adolescent patients on conventional antipsychotic medications (n=20) and 28% for patients on no medications (n=25) (Theisen et al. 2001).

In an attempt to understand patient characteristics that may be predictors of weight gain on atypical antipsychotics, several retrospective studies have examined correlations between clinical response and weight gain. There are several conflicting reports about the relationship between weight gain and clinical improvement on atypical antipsychotic medications (Gupta et al. 1999; Leadbetter et al. 1992; Umbricht et al. 1994). Investigators from Eli Lilly, Inc., retrospectively analyzed their data from olanzapine trials and concluded that patients who were thinnest gained the most weight (Basson et al. 2001) and that there was a correlation between clinical improvement and weight gain. No relationship between either olanzapine dose or quetiapine dose and weight gain has been established (Brecher and Melvin 2001). Prospective research to determine which patient population or patient characteristics increase vulnerability to weight gain is still sorely needed.

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