We commend Cohen et al. (1) on their report on hyperglycemia and diabetes in patients with schizophrenia and schizoaffective disorders. To our knowledge, this is the first large study of oral glucose tolerance tests in this population.
Cohen et al. found that the prevalence rate of diabetes was significantly higher in patients with schizophrenia and schizoaffective disorders than in the general population. They did not detect a differential effect of antipsychotic monotherapy in diabetogenic effects, and they consequently proposed a modification of the consensus statement on antipsychotic drugs, obesity, and diabetes, i.e., measurement of fasting glucose in all patients with schizophrenia irrespective of the prescribed antipsychotic drug. We argue that the differences in the metabolic effects of different antipsychotic agents are too clear in the literature to justify any notion that the antipsychotic agents are comparable in their metabolic effects.
Comparative studies of antipsychotic agents are limited in their scope by the difficulty in conducting randomized controlled trials of antipsychotic agents. For many patients, specific antipsychotic agents are indicated ahead of the others based on the information available at that time. For example, clozapine is difficult to study in comparative investigations because it is not recommended by most as a first-line treatment. A recent study (2) addressed this issue to some extent by conducting a randomized controlled trial of risperidone and olanzapine in dogs. The dogs who received olanzapine developed hepatic insulin resistance, whereas those who received risperidone did not. Furthermore, the usual compensatory increase in insulin secretion in response to insulin resistance was lacking in the olanzapine-fed dogs. Apart from the evidence of differential effects of the two agents, the results suggest that olanzapine may induce insulin resistance even in the absence of psychopathology. The lack of compensatory increase in insulin secretion suggests that olanzapine may also impair insulin secretion.
A recent correlational analysis (3) of receptor affinities of individual antipsychotic agents and their diabetogenic effects suggests that muscarinic M3 receptor affinity is the best predictor of risk for development of type 2 diabetes. The study was limited by its use of data from different laboratories, collected under different conditions. Nevertheless, the results are not surprising given the clinical knowledge that two of the antipsychotic agents with the most anticholinergic activity, clozapine and olanzapine, seem to present the greatest risk for development of type 2 diabetes. Among the first generation agents, there are reports (4) of diabetes in patients taking chlorpromazine, an agent with considerable anticholinergic activity. To our knowledge, however, there are no reports of diabetes in those taking haloperidol, an agent without significant anticholinergic activity. Muscarinic receptor affinity may also be the reason why a comparative study (5) of clozapine and chlorpromazine did not find a significant difference between treatments and their effects on weight or glucose metabolism. The study was cited by Cohen et al. (1) in support of their contention that all antipsychotic agents present risks of diabetes.
Taken together, these studies suggest that antipsychotic agents differ from one another in their effects on glucose metabolism. Until this issue is completely resolved, it would be prudent to monitor measurement of fasting glucose in all patients with schizophrenia, irrespective of the prescribed antipsychotic drug, with special attention provided to those taking olanzapine, clozapine, and chlorpromazine.
