Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies

Am J Psychiatry. 2004 Mar;161(3):414-25. doi: 10.1176/appi.ajp.161.3.414.


Objective: Based on lower rates of acute extrapyramidal side effects associated with second-generation antipsychotics, compared to first-generation antipsychotics, and based on preliminary data, second-generation antipsychotics are expected to cause less tardive dyskinesia than first-generation antipsychotics. This hypothesis was examined in a systematic review of studies involving open or controlled treatment with any second-generation antipsychotic.

Method: Studies of treatment with second-generation antipsychotics lasting > or =1 year and reporting on new cases of tardive dyskinesia or dyskinesia were systematically reviewed.

Results: In 11 studies, 2,769 patients received treatment with risperidone (five studies, N=1,235), olanzapine (two studies, N=610), quetiapine (two studies, N=386), amisulpride (one study, N=331), or ziprasidone (one study, N=207) for a weighted mean and median duration of 263 and 306 days, respectively. Study designs were double blind and randomized (N=3); open-label extensions of double-blind, randomized trials (N=4); and open label (N=4). Of the four trials that had a comparator (all involving adults with schizophrenia spectrum disorders), three used haloperidol (N=408) and one used placebo (N=71). Studied populations included children (N=77), adults (N=1,419), adults and elderly persons (N=794), and exclusively patients age 54 years or older (N=479). The weighted mean annual incidence of tardive dyskinesia for second-generation antipsychotics was 0% in the children, 0.8% (range=0.0%-1.5%) in the adults, 6.8% in the mixed adult and elderly population, and 5.3% (range=0.0%-13.4%) in the patients age 54 years and older, compared to 5.4% (range=4.1%-7.4%) in adults treated with haloperidol.

Conclusions: Results from 11 long-term studies support the idea that second-generation antipsychotics have a reduced risk for tardive dyskinesia, compared to first-generation antipsychotics, although the doses of haloperidol used in the comparator studies were relatively high. More carefully designed studies, ideally lasting beyond 1 year and comparing the effects of different second-generation antipsychotics in patients who have never taken first-generation antipsychotics, are needed to estimate the true risk. It would not appear premature for clinicians to consider these findings in making long-term treatment decisions.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amisulpride
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use
  • Benzodiazepines / adverse effects
  • Benzodiazepines / therapeutic use
  • Child
  • Dibenzothiazepines / adverse effects
  • Dibenzothiazepines / therapeutic use
  • Double-Blind Method
  • Dyskinesia, Drug-Induced / diagnosis
  • Dyskinesia, Drug-Induced / etiology*
  • Haloperidol / adverse effects
  • Haloperidol / therapeutic use
  • Humans
  • Middle Aged
  • Neurologic Examination / drug effects
  • Olanzapine
  • Piperazines / adverse effects
  • Piperazines / therapeutic use
  • Quetiapine Fumarate
  • Randomized Controlled Trials as Topic
  • Risk
  • Sulpiride / adverse effects
  • Sulpiride / analogs & derivatives*
  • Sulpiride / therapeutic use
  • Thiazoles / adverse effects
  • Thiazoles / therapeutic use


  • Antipsychotic Agents
  • Dibenzothiazepines
  • Piperazines
  • Thiazoles
  • Benzodiazepines
  • Quetiapine Fumarate
  • ziprasidone
  • Sulpiride
  • Amisulpride
  • Haloperidol
  • Olanzapine