Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment

Virtually no attention has been given to the relationship between antidepressant plasma drug concentrations and relapse-prevention during maintenance therapy. The purpose of this study was to investigate the relationship between steady-state plasma drug concentrations and outcome during relapse-prevention therapy with fluoxetine.

The patients studied had responded to acute fluoxetine treatment for major depression (defined by DSM-III-R). Patients who met criteria for remission after 10-12 weeks of open-label acute fluoxetine therapy (N=395 of 839 patients), were randomly assigned to one of four treatment arms (50 weeks of fluoxetine, 38 weeks of fluoxetine followed by 12 weeks of placebo, 14 weeks of fluoxetine followed by 36 weeks of placebo and 50 weeks of placebo). Plasma fluoxetine and norfluoxetine concentrations were measured (1) after 4 and 8 weeks of open-label treatment and (2) at the beginning and after 14 weeks of double-blind, relapse-prevention therapy.

Mean drug plasma levels were stable throughout the study. There was no significant difference in steady state plasma levels for the patients who relapsed compared to those who completed fluoxetine therapy without relapsing after 14, 38 or 50 weeks of fluoxetine relapse-prevention treatment. In addition, time-to-relapse was not related to steady-state drug plasma levels. Finally, after dividing patients into two groups based on their drug plasma levels, no significant differences were seen in the cumulative proportions of patients staying well during relapse-prevention therapy.

Plasma concentrations of fluoxetine and/or its metabolite norfluoxetine, are not correlated with relapse in patients treated with a fixed dose of 20 mg/day fluoxetine. Fluoxetine plasma levels cannot be used to guide relapse-prevention treatment.