OBJECTIVES: Inhibiting or inducing antipsychotic metabolism via the hepatic cytochrome P450 (CYP450) may have clinical and economic consequences. This study examined whether drug-drug interactions (DDIs) between oral antipsychotics and non-antipsychotic concomitant medications that are inhibitors or inducers of CYP450 isoenzymes are associated with increased health care utilization and costs in schizophrenics or schizoaffective-disorder patients. METHODS: Ohio State Medicaid data contributed patients (18≤age<65) who had schizophrenia or schizoaffective disorder and received an antipsychotic from 2000 to 2003 (N=31,716). Clinically significant DDI pairings (Facts & Comparisons 4.0) were examined, with concomitant exposure for an antipsychotic prescription overlapping with an interacting medication. Three adverse events (AEs) (extrapyramidal symptoms, increased seizure risk and QT-prolongation or arrhythmias) associated with DDIs were studied. Utilization and costs for inpatient and ambulatory care during a 90-day follow-up were examined. Regression analyses were used to adjust for confounding factors between patient groups.RESULTS: Most patients had non-DDI (26,546); 7060 had a DDI (no AE) and 110 experienced DDI+AE. Length of stay and emergency room visits (mean±SD) were highest for DDI+AE (25 days±17.8; 3.4±4.1) and lower for the DDI (11 days±9.9; 1.5±1.0) and non-DDI (3.6 days±15.6; 0.5±2.8) groups. Health care costs were higher with DDI+AE ($9699) or DDI ($2962) compared with non-DDI ($2201). Regression analysis indicated that patients with DDI+AE or DDI had significantly higher health care utilization and costs than patients without DDI (P<0.001). Stepwise regression showed that patients with a DDI or DDI+AE associated with olanzapine, risperidone and quetiapine had higher total costs than patients without a DDI.CONCLUSIONS: These data suggest that antipsychotic DDIs are related to higher healthcare utilization and costs. Efforts to avoid potential DDIs associated with some antipsychotics are critical for clinical practitioners to prevent costly clinical and economic consequences.