Differential Effects of Various Typical and Atypical Antipsychotics on Plasma Glu- cose and Insulin Levels in the Mouse: Evidence for the Involvement of Sympathetic Regulation

Atypical antipsychotic treatment has beenassociatedwith se-riousmetabolic adverse events, such as glucose dysregulation and development of type 2 diabetes. As part of our studies on possible underlying mechanisms, we investigated the acute effects of various typical and atypical antipsychotics on plasma glucose and insulin in FVB/N mice, a strain that showed amore pronounced hyperglycemic response to cloza-pine than C57BL/6 and CD-1 mice. Acute administration of high doses of clozapine, olanzapine, quetiapine, perphena-zine, or chlorpromazine significantly increased plasma glu-cose by 100%–140 % above basal levels without significant effects on insulin levels. In contrast, risperidone reduced plasma glucose (230%) and markedly enhanced plasma in-sulin levels.Doses of ziprasidone that gave 50-fold higher free plasma concentrations than therapeutic plasma levels, aswell as high doses of aripiprazole and haloperidol, did not signif-icantly alter either glucose or insulin levels. Clozapine- and olanzapine-induced hyperglycemia occurred at free plasma concentrations that were within, or one order of magnitude above, the range of therapeutic plasma levels. Pretreatment with either the ganglionic blocker hexamethonium, or the a2 adrenergic receptor antagonist yohimbine, blocked the clozapine- and chlorpromazine-induced increase in glucose levels. Taken together, these results suggest that typical and atypical antipsychotics with known metabolic liability produce acute hyperglycemia in mice and that this effect is likely driven by activation of the sympathetic autonomic ner-vous system via a central mechanism. Key words: antipsychotic/hyperglycemia/insulin/mous