Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.

Objectives: To review current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and type 2 diabetes mellitus (T2DM) and to examine the relation of adiposity to medical risk. Methods:We identified relevant publications through a search of MEDLINE from the years 1975 to 2006, using the following primary search parameters: "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles were also reviewed. We summarized key studies in this emerging literature, including case reports, observational studies, retrospective database analyses, and controlled experimental studies.Results: Treatment with different antipsychotic medications is associated with variable effects on body weight, ranging from modest increases (for example, less than 2 kg) experienced with amisulpride, ziprasidone, and aripiprazole to larger increases during treatment with agents such as olanzapine and clozapine (for example, 4 to 10 kg). Substantial evidence indicates that increases in adiposity are associated with decreases in insulin sensitivity in individuals both with and without psychiatric disease. The effects of increasing adiposity, as well as other effects, may contribute to increases in plasma glucose and lipids observed during treatment with certain antipsychotics. Conclusion:Treatment with certain antipsychotic medications is associated with metabolic adverse events that can increase the risk for metabolic syndrome and related conditions such as prediabetes, T2DM, and cardiovascular disease. Limitations· Currently, knowledge of the cost-effectiveness of different interventions to lower metabolic risk is limited. · Questions remain concerning how to implement clinical strategies that would improve quality and disparities of care in mental illness. · Future studies are needed to identify the mechanisms that allow medications to cause adiposity and changes in insulin sensitivity.

Despite statistically significant improvements after the ADA guidelines were issued, monitoring for plasma lipids and glucose in this population remains low. Clinicians and administrators responsible for the health of at-risk populations should implement new approaches for effective monitoring of major modifiable risk factors for medical morbidity and mortality in patients taking second-generation antipsychotics.

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Alterations in plasma leptin have been reported in schizophrenia patients treated with antipsychotics, suggesting the hypothesis that impairments in leptin secretion or signaling might play a role in antipsychotic-induced weight gain. Plasma leptin was measured in 72 schizophrenia patients chronically treated with olanzapine (n ¼ 27), risperidone (n ¼ 24) or typical antipsychotics (n ¼ 21) and 124 healthy adult control subjects. ANCOVA was used to test effects of adiposity (body mass index kg/m 2 ; BMI), subject group (treated patients vs untreated controls), and treatment group (specific medication groups and untreated controls) on plasma leptin concentrations. Additional analyses were performed in a subset of patients and controls individually matched for BMI to further assess group differences in plasma leptin independent of adiposity. BMI strongly predicted plasma leptin concentrations in the overall sample. In addition, a significant three-way interaction between BMI, subject group, and gender was observed. In the individually BMI-matched sample, modestly reduced plasma leptin levels (effect size 0.4 SD) were observed in treated patients in comparison to the BMI-matched healthy controls, with both groups including males and females. However, no differences in plasma leptin levels were observed in the matched sample when separately comparing male patients vs untreated male controls and female patients vs untreated female controls. Plasma leptin in chronically treated patients with schizophrenia is strongly predicted by adiposity, similar to untreated healthy individuals despite adequate power to detect a difference. The results argue against a role for defective leptin secretion or sensitivity in the weight gain induced by antipsychotic medications.