OBJECTIVE: The aim of the present retrospective pilot study was to examine the clinical impact of the cytochrome P450 (CYP) enzyme CYP2D6 poor metabolizer (PM) genotype in patients taking antipsychotic medication. The impaired metabolic capacity of the PM genotype results in higher steady-state plasma concentrations at a given dose, thus increasing the risk of toxic effects from medication. METHODS: We identified 18 PM patients with a schizophrenia spectrum diagnosis from a clinical database covering all patients who have been analyzed in an ongoing standardized CYP2D6 screening program. Each PM patient was carefully matched on age, gender and diagnosis with an intermediate metabolizer (IM) and an extensive metabolizer (EM) from the same database to generate 18 triplets. Clinical data, primarily on side effects of treatment, were obtained from medical records by an experienced research and consultant psychiatrist, who was blinded to the results of the genotyping. RESULTS: We found that extrapyramidal syndrome or tardive dyskinesia (EPS/TD) was significantly more frequent among PM patients than among the matched IM and EM control subjects. This finding was further supported by the significantly higher prevalence of noncompliance among the same PM patients. Importantly, this association was not due to differences in the use of CYP2D6-dependent or EPS/TD-causing medication across the 3 matched patient groups. CONCLUSIONS: This leads us to conclude that genetically encoded differences in the rate of drug metabolism through CYP2D6 can predict antipsychotic side effects and prompts the question of whether genotyping early in the course of illness to facilitate adjustment of pharmacotherapy will improve treatment outcomes and reduce side effects.