Trazodone for the treatment of neuroleptic-induced acute akathisia: a placebo-controlled, double-blind, crossover study

Clin Neuropharmacol. Sep-Oct 2010;33(5):219-22. doi: 10.1097/WNF.0b013e3181ee7f63.


Introduction: Neuroleptic-induced acute akathisia (NIA) is a common and distressing extrapyramidal symptom usually resulting from the use of antipsychotic medication.Despite its high incidence (20%-45%), the underlying mechanism of NIA has not yet been adequately explained. Although treatment strategies for NIA have traditionally included anticholinergic agents, γ-aminobutyric acid agents, dopamine enhancers, and the β-adrenergic antagonists, many patients fail to respond. Trazodone (Trz) is an antidepressant agent demonstrating prominent serotonergic antagonistic properties. In a recent pilot open-label trial, Trz demonstrated to be strongly effective in the treatment of NIA in 9 female schizophrenic patients.

Objective: On the basis of the results of this pilot study, we investigate further the efficacy of Trz in the treatment of NIA in a double-blind, placebo (Pla)-controlled, crossover design.

Methods: Thirteen inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia or schizo-affective disorder and with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition NIA with a severity of at least mild akathisia according to the Barnes Akathisia Rating Scale participated in the study. Patients were randomly assigned to either the order Trz-Pla or the order Pla-Trz in the treatment periods. Each period lasted for 3 consecutive days (days 1-3 and 4-6). Eight patients were treated with the Trz-Pla order (100 mg/d before bedtime); and 5, with the opposite order (Pla-Trz).

Results: Statistically significant improvement in most symptoms of NIA, as measured by the Barnes Akathisia Rating Scale, was detected with Trz compared with Pla treatment.

Conclusions: The findings of this double-blind, placebo-controlled, crossover study indicate the efficacy of Trz in the management of NIA, corroborating the results of a preliminary pilot study. We suggest that Trz's property of serotonin 2A postsynaptic receptor antagonism may be its principal mechanism for the improvement of NIA.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Akathisia, Drug-Induced / drug therapy*
  • Akathisia, Drug-Induced / etiology
  • Akathisia, Drug-Induced / physiopathology
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Antipsychotic Agents / adverse effects*
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Psychotic Disorders / drug therapy*
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Trazodone / therapeutic use*
  • Treatment Outcome


  • Antidepressive Agents, Second-Generation
  • Antipsychotic Agents
  • Serotonin Uptake Inhibitors
  • Trazodone