Efficacy in long-term treatment of depression

Available evidence suggests that antidepressants need to be continued on a long-term basis after the acute response. Premature discontinuation soon after symptomatic response is associated with the return of depression (relapse) in many patients. One efficacy measure of an antidepressant required by many regulatory authorities prior to approval of the agent is the ability of the antidepressant to continue the acute response compared with a placebo control. The reference tricyclic antidepressants (TCAs) amitriptyline and imipramine both have been shown to be effective in this continuation phase, but there is surprisingly little evidence on the efficacy of the other TCAs. The serotonin selective reuptake inhibitors paroxetine, fluoxetine, sertraline, and citalopram, as well as nefazodone, a new antidepressant with a dual mechanism of action that is classified as a serotonin receptor modulator, are effective compared with placebo. Placebo appears to be a good comparator in assessing the long-term efficacy of antidepressants. For example, in an assessment of the long-term efficacy of citalopram, patients who responded while taking placebo and were continued on placebo treatment were compared with patients who responded to drug and were transferred to placebo. The relapse rates in both cases were similar, validating placebo as a useful control. Most studies of long-term efficacy use the discontinuation design in which patients are treated with an active drug until response is obtained and then are either continued on the active drug or switched to placebo in a random and blinded manner. Alternatively, studies with nefazodone have used the double-blind continuation design, which may be preferred because it avoids any confounding effects of the discontinuation of drug in a drug-responsive patient. For example, in acute studies, responders to treatment with nefazodone, imipramine, or placebo were continued on the same treatment under double-blind conditions for 1 year; both antidepressants were effective compared with placebo. This study design may be useful in providing an estimate of long-term efficacy that can be obtained relatively early in a drug development program. The length of treatment in the continuation phase of therapy is also of interest. The separation of drug and placebo efficacy is sharpest in the first 4 months, which is consistent with the recommendation that all treatment for depression should continue for a minimum of 4 to 6 months to prevent relapse after symptomatic response of the acute episode. After the continuation phase (relapse prevention), evolving evidence strongly indicates that antidepressant treatment should be continued in patients at risk for recurrence. Depending on the number of recurrences, lifelong prophylactic therapy may be warranted.