Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome

Harv Rev Psychiatry. May-Jun 2006;14(3):152-64. doi: 10.1080/10673220600748486.


In this article we examine the two major classes of side effects with atypical antipsychotics: extrapyramidal symptoms (EPS) and the metabolic syndrome (the triad of diabetes, dyslipidemia, and hypertension, with associated obesity). We conclude that atypical antipsychotics continue to have notable risks of EPS, particularly akathisia, and that these agents also appear to increase the risk of the metabolic syndrome, though this effect seems most marked with clozapine and olanzapine. Novel conclusions based on this review are as follows: we provide a classification scheme based on low versus high D2 binding affinity (which is, to our knowledge, a new means of classifying atypical antipsychotics); we emphasize that the akathisia risk is likely equal among agents and that tardive dyskinesia is an early, and not late, risk in treatment (a common misconception); we make the methodological point that in randomized clinical trials, there is a high risk of false-negatives regarding side effects; we raise the issue of confounding bias in epidemiological studies of metabolic syndrome; and we stress the need to compare side effects in the same studies and not different studies. Future prospective observational cohort studies must target side effects and be designed to collect and analyze data on confounding factors.

Publication types

  • Review

MeSH terms

  • Acute Disease
  • Akathisia, Drug-Induced / etiology
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / classification
  • Antipsychotic Agents / metabolism
  • Basal Ganglia Diseases / chemically induced*
  • Diabetes Mellitus / chemically induced
  • Dyskinesias / etiology
  • Dyslipidemias / chemically induced
  • Dystonia / chemically induced
  • Humans
  • Metabolic Syndrome / chemically induced*
  • Observation
  • Parkinson Disease, Secondary / chemically induced
  • Randomized Controlled Trials as Topic
  • Weight Gain


  • Antipsychotic Agents