Early research demonstrated that chlorpromazine induces a state similar to hibernation in experimental animals, with lowered overall metabolism and a shift from glycolysis to increased use of fatty acids and ketones for energy. Dr. Dwyer believes that a triad of antipsychotic-induced changes in humans---weight gain, hyperglycemia, and possible ketoacidosis--- may be analogous, and reflect findings observed in the 1950s during initial investigation of phenothiazines as tranquilizing agents.

Using a rat neuron cell line developed for examination of glucose uptake by neurons and characterization of changes produced by the newer, atypical antipsychotic agents, Dr. Dwyer and his colleagues found that antipsychotic drugs produce a dose-dependent, dopamine-independent inhibiting effect on glucose transport.

By comparing minimal drug concentrations that inhibit glucose transport in vitro with plasma levels observed during naturalistic treatment, Dr. Dwyer and his colleagues found that clinically relevant clozapine plasma levels do not inhibit glucose transport. However, plasma levels of clozapine's active metabolites do approach threshold level for inhibition of glucose transport, and the summed parent drug-metabolite plasma concentration is even higher.

Comparison of the molecular shape of the transmembrane glucose carrier GLUT 3 with chemical structures of drugs and active metabolites is beginning to enable researchers to hypothesize about potential drug-transport carrier interactions that may result in inhibition of glucose uptake. That kind of analysis may explain the relatively high affinity of clozapine for the carrier, as well as the even higher affinity of one metabolite and the lower affinity of another.

Comparing published antipsychotic drug studies with findings from his experimental model, Dr. Dwyer found, that of all of the atypical antipsychotics, clozapine and olanzapine were associated with the highest rates of hyperglycemia and diabetes. Both clozapine and olanzapine inhibited glucose uptake in his in vitro model, as did risperidone, quetiapine, and loxapine (each associated in the clinical literature with diabetes, but to a lesser degree than clozapine and olanzapine).

Dr. Dwyer concluded by reminding the audience about the historical association of antipsychotic agents and metabolic change, as well as our growing understanding of the molecular basis for the kinds of metabolic changes associated with antipsychotic agents. Enhanced understanding of the molecular mechanisms mediating both antipsychotic effects and inhibition of glucose transport may lead to development of antipsychotic agents with lower risks of metabolic adverse effects.