Since their introduction, the atypical antipsychotics clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon) have been widely prescribed for the management of patients with schizophrenia and other psychotic disorders or severe behavioral disturbances. This is, in part, due to emerging evidence suggesting beneficial effects on positive symptoms, negative symptoms and cognition in schizophrenia, combined with the lower propensity of the atypical antipsychotics for extrapyramidal symptoms or tardive dyskinesia than conventional antipsychotics. However, there have been case reports, retrospective studies and recently published epidemiological data suggesting that certain of these newer agents may be associated with metabolic abnormalities, including significant weight gain, hypertriglyceridemia, and new-onset type 2 diabetes mellitus (DM) or diabetic ketoacidosis (DKA).
As the proportion of patients with psychosis and other disorders using atypical antipsychotics continues to grow, these potential metabolic adverse effects are a focus of interest, not only because of the resultant medical complications--including mortality--but also the greater cost of care exacted for the evaluation and treatment of metabolic complications and their sequelae. The concern about medication-related DM is heightened in patients with schizophrenia due to the twofold greater prevalence of type 2 DM in this group compared to the general population (Dixon et al., 2000). Moreover, the possibility that DKA may arise at times as the first presentation of DM is alarming, as this is a serious acute medical condition with significant morbidity and mortality.
Findings From Case Series
Since the first atypical antipsychotic was introduced in 1987, numerous single cases or case series have reported the potential association between atypical agents and new-onset DM or exacerbation of pre-existing DM. Early last year, we reported data based on an analysis of 45 published cases (clozapine [20 cases], olanzapine [19 cases], quetiapine [three cases] and risperidone [three cases]) with sufficient documentation to make an association between the use of an atypical antipsychotic and the development of new-onset DM (Jin et al., 2002). The mean age was 40.3 years (range=16 to 56), 87% were male, and 47% were African-American. At time of diagnosis, 63% had blood glucose values greater than 500 mg/dL, and 50% manifested no weight gain at time of presentation with DM. It should be noted that at baseline, 84% were >5% over ideal body weight, and 42% of these new-onset diabetes cases initially presented with DKA. The mean duration of atypical antipsychotic exposure prior to the development of DM or DKA was 19 weeks (range=two weeks to 124 weeks), with 14% developing DM or DKA within a month after starting the atypical antipsychotic.
Over the past two years, Elizabeth Koller, M.D., of the U.S. Food and Drug Administration, and colleagues have used data from the FDA MedWatch surveillance program pooled with published cases and abstracts to examine the association between atypical antipsychotic therapy and DM, hyperglycemia or DKA. The data for clozapine and olanzapine have been published (Koller and Doraiswamy, 2002; Koller et al., 2001), while preliminary findings for risperidone were presented at a meeting (Koller et al., 2002). Koller and colleagues identified 753 cases having DM, of which 384 cases were treated with clozapine, 237 with olanzapine and 132 with risperidone. Furthermore, among the new-onset DM patients, DKA was reported in 80 of both the olanzapine and clozapine cases and in 36 risperidone cases. Of particular concern were the reported deaths: 25 for clozapine, 15 for olanzapine and five for risperidone. Among patients who developed hyperglycemia or DM on clozapine or olanzapine, more than 60% of cases were noted within six months after starting atypical antipsychotic therapy. Although the number of individuals exposed to risperidone is significantly greater than those exposed to olanzapine, the retrospective and unsystematic nature of case reporting does not permit calculation of relative risk between agents.
Since 2001, several large retrospective studies have examined the relative risk of DM associated with different antipsychotics, primarily in patients with schizophrenia. Comparing 552 patients with schizophrenia on clozapine and 2,461 on typical agents in the Iowa Medicaid database, researchers found a relative risk of developing DM of 2.5 only among those on clozapine ages 20 to 34, but not for the cohort as a whole (Lund et al., 2001). A case control study of older diabetics (mean age=63.6 ±18.3) and controls (mean age=61.9 ±17.5) examined the odds of developing DM related to clozapine exposure (Wang et al., 2002). In this group of primarily nonpsychotic patients (only 40.3% had a psychotic disorder), neither clozapine dose nor duration of exposure (up to 176 days) was associated with increased odds of developing DM.