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A Frequently Sampled Intravenous Glucose Tolerance Test and Minimal Model Analysis

David C. Henderson, MD; Enrico Cagliero, MD; Paul M. Copeland, MD; Christina P. Borba, BS, MPH; Eden Evins, MD; Doug Hayden, MA; Mary T. Weber, PhD, APRN, BC, PMHNP; Ellen J. Anderson, MS, RD, LDN; David B. Allison, PhD; Tara B. Daley, BS, MPH; David Schoenfeld, PhD; Donald C. Goff, MD

Arch Gen Psychiatry. 2005;62:19-28.

Background  While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.

Objective  To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.

Design  A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.

Setting  Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center.

Patients  Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis.

Main Outcome Measures  Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness.

Results  The mean ± SD duration of treatment with the identified atypical antipsychotic agent was 68.3 ± 28.9 months (clozapine), 29.5 ± 17.5 months (olanzapine), and 40.9 ± 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F₃₃ = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t₃₃ = 2.32; P = .03) and olanzapine and risperidone (t₃₃ = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F₃₃ = 10.66; P<.001) (clozapine<olanzapine<risperidone), with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone (clozapine vs risperidone, t₃₃ = –4.29; P<.001; olanzapine vs risperidone, t₃₃ = –3.62; P = .001 [P<.001]). The homeostasis model assessment of insulin resistance also differed significantly among groups (F₃₃ = 4.92; P = .01) (clozapine>olanzapine>risperidone) (clozapine vs risperidone, t₃₃ = 2.94; P = .006; olanzapine vs risperidone, t₃₃ = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F₃₀ = 4.18; P = .02) (clozapine<olanzapine<risperidone) with significant differences between clozapine and risperidone (t₃₀ = –2.59; P = .02) and olanzapine and risperidone (t₃₀ = –2.34, P = .03).

Conclusions  Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects. Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences.

Author Affiliations: Schizophrenia Program (Drs Henderson, Evins, and Goff and Mss Borba and Daley), Diabetes Research Center (Dr Cagliero), MGH Weight Center and Endocrine Unit (Dr Copeland), Mallinckrodt General Clinical Research Center (Drs Cagliero and Schoenfeld and Mr Hayden and Ms Anderson), Biostatistics Center (Dr Schoenfeld and Mr Hayden), Bionutrition Research (Ms Anderson), Massachusetts General Hospital, Boston; University of Texas at Arlington School of Nursing, Arlington (Dr Weber); Departments of Biostatistics and Nutrition Sciences, University of Alabama at Birmingham, Birmingham (Dr Allison); Harvard Medical School, Boston (Drs Henderson, Cagliero, Copeland, Evins, Schoenfeld, and Goff).