Poor response to fluoxetine: Underlying depression, serotonergic overstimulation, or a 'therapeutic window'?

Background: Symptoms of serotonergic overstimulation may resemble depressive symptoms. Postulating that overmedication with fluoxetine can appear as response failure (as norfluoxetine accumulates), systematic trials of lower doses were conducted in patients who failed to respond despite apparent initial improvements. Method: Of 23 consecutive outpatients treated with fluoxetine 20 mg/day for DSM-III-R major depression, 4 failed to sustain initial improvements during 4-8 weeks of treatment (in the absence of apparent side effects). In these 4 patients, fluoxetine was withdrawn for 2 weeks, then reinstituted at 20 mg q.o.d. All patients were followed up weekly to monthly (for up to 17 months) and administered the 17-item Hamilton Rating Scale for Depression. Results: Four of 4 patients improved during washout and went on to respond to the lower dose. All 4 cases are presented. On review of the literature, fluoxetine fixed-dose studies reveal increased adverse effects with no increase in efficacy at dosages above 5 mg/day and decreased efficacy at dosages above 40 mg/day. Special issues inherent in the study and use of an antidepressant with a 1- to 3-week active half-life are discussed. Conclusion: Even in the apparent absence of side effects, nonresponse to fluoxetine may be due to overmedication in some patients. Standard doses of fluoxetine may be higher than 'optimum.' The apparent difficulty distinguishing fluoxetine's adverse effects/toxicity (or a 'therapeutic window' effect) from underlying depressive symptoms, taken in conjunction with the 3-9 weeks required to approach steady state, may suggest the option of lowering the dose in some cases of nonresponse or 'relapse.'