Are atypical antipsychotics associated with an increased risk of diabetes, and is this associated with weight gain?

Although the methodology of many of the studies in this area has been criticized, there are consistent trends with the evidence to date suggesting a hierarchy of diabetic association with atypical antipsychotic treatment. Clozapine and olanzapine appear the most likely to be associated with new-onset diabetes (generally type 2) and worsening of pre-existing diabetes (type 1 and type 2). Of the conventional antipsychotics, chlorpromazine appears to have the greatest propensity for inducing and exacerbating diabetes. If anything, the studies to date likely underestimate the true prevalence of antipsychotic-associated diabetes; however, given the problems associated with obtaining accurate fasting blood data in this population, large prospective incidence studies are difficult to complete. Nonetheless, studies report significantly greater impairment on indices of insulin resistance and glucose regulation with olanzapine and clozapine than with quetiapine, risperidone and ziprasidone.

The cause of these effects is complex and likely to be multifactorial, with different factors important for different drugs, and influenced by the relation between diabetes and schizophrenia; the prevalence of diabetes was first reported to be higher in patients with schizophrenia in the 1920s, and with the advent of chlorpromazine, the prevalence increased 4-fold. The risk of antipsychotic-associated diabetes appears to overlap with a number of risk factors for insulin resistance, including smoking, inactivity, family history of diabetes, older age and increased body mass index.

Insulin resistance, a recently recognized metabolic syndrome, is characterized by hyperinsulinemia, hyperglycemia and intra-abdominal adiposity. Thus, the mechanisms of antipsychotic-associated diabetes appear to be related to particular patterns of CNS receptor blockade, metabolic effects on systemic organs and indirect effects via weight gain. In animal and cellular models, dopamine and norepinephrine induce hyperglycemia, whereas serotonin induces hypoglycemia. However, the overall effect also depends on relative selectivity and activity at particular receptor subtype(s).

There is an association between diabetes and weight gain, and it is likely mediated through the development of insulin resistance. An increase in the calculated homeostatic model assessment index of insulin resistance (HOMA-IR) correlates with weight gain but can occur even before weight change with olanzapine and clozapine. Leptin is an adipocyte-derived hormone that mediates insulin sensitivity and regulates adiposity. Significant changes in leptin levels are observed early in treatment with clozapine and olanzapine. In addition, tumour necrosis factor-α and neuropeptide Y have been linked with clozapine-associated changes in weight and appetite regulation.

Because insulin resistance is associated with a cluster of significant cardiovascular risk factors (i.e., obesity, hypertension, dyslipidemia and type 2 diabetes), it is recommended that patients receiving atypical antipsychotics — particularly those with identified risk factors and being treated with the more diabetogenic drugs — should have weight, blood pressure, fasting glucose and lipids monitored regularly. Given the long-term health implications, appropriate management strategies should be initiated early if metabolic changes occur.