- Background: Piracetam is a potent antioxidant, a cerebral neuroprotector, a neuronal metabolic enhancer, and a brain integrative agent. More than 20 years ago, an intravenous preparation of piracetam demonstrated an improvement in the symptoms of tardive dyskinesia. The aim of our study was to reexamine the efficacy of piracetam in the treatment of tardive dyskinesia using an oral preparation. Method: The study was conducted at the Be'er Sheva Mental Health Center from May 2003 to December 2004 and involved a 9-week, double-blind, crossover, placebo-controlled trial assessing 40 DSM-IV schizophrenic and schizo-affective patients with DSM-IV-TR tardive dyskinesia. All study subjects received their usual antipsychotic treatment. Initially, subjects were randomly assigned to receive 4 weeks of treatment with either piracetam (4800 mg/day) or placebo. Thereafter, following a washout period of I week, they entered the crossover phase of the study for a further 4 weeks. The change in score of the Extrapyramidal Symptom Rating Scale from baseline to the study endpoint was the primary outcome measure. Results: The mean decrease in score from baseline to endpoint in the clinical global impression subscale in patients treated with piracetam was 1.1 points compared to 0.1 points in the placebo group (p =.004). The mean decrease in the tardive parkinsonism subscale was 8.7 points in patients treated with piracetam and 0.6 points in those on placebo (p =.00 1). The mean decrease in the tardive dyskinesia subscale was 3.0 points in the piracetam group in contrast to deterioration of condition in the placebo group by -0.2 points (p =.003). Conclusion: Piracetam appears to be effective in reducing symptoms of tardive dyskinesia. The specific mechanism by which piracetam may attenuate symptoms of tardive dyskinesia needs to be further evaluated. Clinical Trials Registration: ClinicalTrials.gov identifier NCT00 190008.