Objective: The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy. Method: 276 patients with major depressive disorder (MDD) were treated with sertraline (150–200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy. Results: The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy. Conclusion: This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials.

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