Hyperglycemic Clamp Assessment of Insulin Secretory Responses in Normal Subjects Treated with Olanzapine, Risperidone, or Placebo

Abstract

The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.

Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

“…In contrast to previous reports (Sowell et al, 2002(Sowell et al, , 2003 our clamp experiments show that there is a significant decrease (po0.001) in whole body insulin sensitivity in response to hyperinsulinemic euglycemic challenge in healthy subjects (baseline: 5.7±0.4 ml/h/kg, mean ± SM) following oral intake of 10 mg/day olanzapine (4.7 ± 0.3 ml/h/kg, mean ± SM, Figure 1). Whereas Sowell et al reported an increased total insulin response for olanzapine, they attributed those changes to the antipsychotic-induced weight gain and concluded that the observed changes were insignificant (Sowell et al, 2002).…”

“…Sowell et al (2002) performed hyperglycemic clamps in healthy subjects before and after 3 weeks of oral intake of olanzapine, risperidone or placebo. Despite their finding of substantial weight gain that was reported for olanzapine and risperidone (B1.5 kg), they did not find the observed changes in whole body insulin sensitivity to be significant.…”

“…Despite the welldescribed effects of adiposity on glucose metabolism in the general population (Welch et al, 1990;Karter et al, 1996;Macor et al, 1997;Mayer-Davis et al, 1997), the underlying mechanisms for potential adiposity-independent effects of atypical antipsychotics on insulin sensitivity have not been identified yet. While most studies report an increased risk for the development of metabolic abnormalities like glucose intolerance, insulin-resistance, and consequentially DM2 in rodent (Houseknecht et al, 2005) or dog studies as well as in patients with schizophrenia (Hedenmalm et al, 2002;Koller and Doraiswamy, 2002;Newcomer et al, 2002;Sernyak et al, 2002;Wilson et al, 2003;Kane et al, 2004;Simpson et al, 2004;Henderson et al, 2005, 2006, Haupt et al, 2007, patients with schizoaffective disorder (Wilson et al, 2003;Simpson et al, 2004) or patients with mood disorder (Gianfrancesco et al, 2003) treated with atypical antipsychotics, other studies fail to confirm these correlations for healthy subjects (Sowell et al, 2002(Sowell et al, , 2003 or patients with schizophrenia (Kinon et al, 2001).…”

Antipsychotic drugs and diabetes—an application of the Austin Bradford Hill criteria

“…Where a change in insulin resistance has been observed in humans, this has been entirely explicable by a change in body weight [69,70]. However, studies in myotubes have shown that olanzapine inhibits insulin signalling [71].…”

“…Experiments in islet cell cultures have shown that clozapine and olanzapine, but not quetiapine, risperidone and ziprasidone, increase insulin release [75]. It is unclear how these findings are to be interpreted during normal physiology as no change in beta cell function has been observed in humans [70]. Nevertheless there are case reports of diabetic ketoacidosis in patients receiving antipsychotics [67].…”