Second-Generation Antipsychotics and Metabolic Side Effects: A Systematic Review of Population-Based Studies

Drug Saf. 2017 Sep;40(9):771-781. doi: 10.1007/s40264-017-0543-0.


Introduction: There is strong evidence from randomized controlled trials (RCTs) that second-generation antipsychotic (SGA) medications are associated with metabolic adverse events. However, with the recent increases in the use of SGAs worldwide and frequent off-label use, it is unclear whether these associations are generalizable to populations beyond those included in RCTs.

Objectives: This review aims to characterize the impact of SGAs on the population through a systematic review of population-based studies of SGA users. Studies could examine the use of any SGA medication and any comparator group. Studies also needed to include at least one metabolic outcome such as type 2 diabetes mellitus, dyslipidemia, obesity, hypertension, or metabolic syndrome.

Methods: A systematic search process was used to identify studies for inclusion in this review. Included studies had to be population-based studies of users of any SGA medication with at least one reported metabolic outcome. Study quality was also assessed using the AMSTAR tool, and evidence was synthesized by both metabolic outcome and specific SGA medication.

Results: In total, 15 studies were included in this review. Type 2 diabetes mellitus was the most frequently reported outcome; clozapine and olanzapine were most strongly associated with type 2 diabetes mellitus. Evidence was mixed for a moderate association between type 2 diabetes mellitus and risperidone or quetiapine. Few studies examined other metabolic outcomes, and therefore it is difficult to estimate the true effect in the population.

Discussion: Population-based evidence for other SGAs and metabolic outcomes was limited. However, clozapine and olanzapine were consistently more strongly associated with metabolic adverse events than were other SGAs currently available.

Publication types

  • Comparative Study
  • Review
  • Systematic Review

MeSH terms

  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / adverse effects*
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / adverse effects
  • Clozapine / administration & dosage
  • Clozapine / adverse effects
  • Humans
  • Metabolic Diseases / chemically induced*
  • Metabolic Diseases / epidemiology
  • Metabolic Diseases / physiopathology
  • Olanzapine
  • Randomized Controlled Trials as Topic
  • Research Design*


  • Antipsychotic Agents
  • Benzodiazepines
  • Clozapine
  • Olanzapine