Antagonism of the serotonin (5-HT)-2 receptor and insulin sensitivity: implications for atypical antipsychotics

Both conventional and second-generation antipsychotics have been associated with an increased risk for impaired glucose tolerance and diabetes mellitus. Though this has been largely attributed to weight gain, there may also be a direct, receptor-mediated effect of antipsychotics on glucose tolerance. We tested the hypothesis that antagonism of the serotonin (5-HT)-2 receptor impairs insulin sensitivity.

Ten healthy male volunteers were included in a double-blind, placebo-controlled crossover study of a single dose of 40 mg of the 5-HT2 antagonist ketanserin versus placebo. Insulin sensitivity was measured by means of the euglycemic-hyperinsulinemic clamp technique. Subjects were treated with the alpha-1 adrenergic antagonist phenoxybenzamine in both parts of the study to control for ketanserin's effects at the level of this receptor.

Compared with the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4 +/- 3.6 mg/kg/min; ketanserin: 7.7 +/- 2.1 mg/kg/min; p = .047).

The selective 5-HT2 antagonist ketanserin impaired insulin sensitivity. This effect was possibly mediated by suppression of 5-HT(2A) receptor mediated glucose uptake in skeletal muscle.