Second-generation (atypical) antipsychotics and metabolic effects: A comprehensive literature review

Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an ef