OBJECTIVE: In obsessive-compulsive disorder, the relationship between blood levels of serotonin reuptake inhibitors and clinical outcome is unclear. In a multicenter trial, the authors examined the relationship between steady state plasma levels of fluoxetine and norfluoxetine (determined after 7 weeks of treatment), and their sum, and clinical outcome. METHOD: Ratings of symptom severity of obsessive-compulsive disorder (Yale-Brown Obsessive Compulsive Scale scores) were obtained at baseline and after 13 weeks for 200 adult outpatients with moderately severe obsessive-compulsive disorder treated with fluoxetine doses of 20 mg/day (N = 68), 40 mg/day (N = 64), and 60 mg/day (N = 68). RESULTS: Mean plasma levels of fluoxetine and norfluoxetine were statistically significantly higher with higher dose. Statistical analyses revealed no significant relationship for plasma level of either molecule or their sum in predicting endpoint percent change in obsessive-compulsive scores. Plasma levels of patients with a marked response (decrease of 50% or more in obsessive-compulsive score) did not differ significantly from those of nonresponders (less than a 25% decrease in obsessive-compulsive score). No hint was seen of a therapeutic window or of a relationship limited to one gender or within the lowest dose group (20 mg/day). However, since S-norfluoxetine is a much more potent serotonin reuptake inhibitor than R-norfluoxetine, the absence of chiral (stereospecific) assays in this study limits the results. CONCLUSIONS: Steady state plasma levels of fluoxetine and norfluoxetine are not related to clinical outcome in patients with obsessive-compulsive disorder. Individual patients can be told only that the optimum dose of fluoxetine for them will be the dose that produces the largest therapeutic effect with the smallest side effect burden. Future studies should examine the predictive utility of measures of serotonergic neuronal function and, if plasma levels of norfluoxetine are examined, the use of chiral assays.Abstract Teaser