Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials

Background

Selective serotonin reuptake inhibitors are increasingly used in the long-term treatment of depression. Much of the supporting evidence about the effects of these drugs comes from discontinuation trials, a variant of randomized controlled trials whose design is problematic to interpret. We conducted a systematic review to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of unipolar depression.

Methods

We identified placebo-controlled randomized trials with a treatment duration of at least 6 months by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to update a recently published systematic review. Efficacy was defined in terms of response to treatment (50% improvement in depression score relative to baseline) and remission (score of 7 or below on the Hamilton rating scale for depression). Key secondary outcomes included quality of life, return to work, need for additional treatment and self-harm. Overall acceptability was defined in terms of dropouts for any reason over a course of treatment.

Results

Of the 2693 records identified initially, we included 6 randomized controlled trials that met our eligibility criteria. These studies had a moderate risk of bias, had assigned a total of 1299 participants with depression to either treatment or placebo and had followed both groups for 6–8 months. We observed statistically significant improvements in response to treatment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.12–2.48), but not in remission (OR 1.46, 95% CI 0.92–2.32) or acceptability (OR 0.87, 95% CI 0.67–1.14). The effects appeared greater among patients without comorbidities.

Interpretation

There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6–8 months of antidepressant treatment following initial recovery but provide no guidance for longer treatment.Over the past decade, the use of selective serotonin reuptake inhibitors for the management of depression has increased dramatically, and preliminary evidence suggests that long-term use, for more than 1 or 2 years, accounts for much of this rise.^1–3 Clinical practice guidelines generally recommend a 6- to 9-month course following initial recovery after a first episode of depression and longer, sometimes indefinite, therapy after subsequent episodes, to prevent relapse.^4–10Long-term randomized controlled trials of antidepressants have typically used 1 of 2 possible designs, each answering different questions (Figure 1).¹¹ The most widely used design is called the “discontinuation trial,” a 2-phase study in which all participants are initially treated with an open (unblinded) course of drug therapy. Participants attaining a certain response during the open-treatment phase enter the second phase, during which they are randomly assigned to continue active drug treatment or to receive placebo.^12–14 Discontinuation trials are believed to minimize the number of participants with depression who must be exposed to placebo. This advantage comes at a cost, since the results apply only to patients with a response to the medication, not to those who experience spontaneous recovery; furthermore, withdrawal symptoms may lead to an overestimate of the true effect of the medication. When this design is used to test long-term therapy with selective serotonin reuptake inhibitors for the treatment of depression, the results are difficult to interpret with confidence because rates of spontaneous recovery in depression are potentially high and because withdrawal effects can mimic depression.^13–15Open in a separate windowFigure 1: Two designs of randomized controlled trials used to investigate long-term antidepressant therapy.The second type of randomized trial used to test long-term therapy with selective serotonin reuptake inhibitors is a 2-arm parallel randomized controlled trial, hereafter referred to as a classic randomized controlled trial (Figure 1).¹⁶ In this type of trial, participants with acute depression are assigned to receive either placebo or active drug, and all those achieving a certain response, either to the drug or to the placebo, are followed. The advantage of classic randomized controlled trials is that data from all participants contribute to our understanding of the drug''s real-world effectiveness. Their main drawback is that a greater number of acutely ill people may have to receive placebo than in a discontinuation trial.¹³ Most classic trials of antidepressants are short-term studies. Fergusson and colleagues,¹⁷ in a systematic review examining selective serotonin reuptake inhibitors and suicide, identified 702 classic trials involving a total of 18 413 participants, the majority of which (93%) lasted less than 6 months.A recent systematic review based mainly on studies with discontinuation designs showed that, in a subgroup of patients who experienced recovery while taking medications, long-term therapy with selective serotonin reuptake inhibitors reduced the chances of relapse by up to 70% for up to 36 months, relative to patients whose therapy was discontinued earlier.⁶ However, there has been no systematic review of classic randomized trials of long-term therapy with this drug class to determine the potential benefits in all patients with depression, including those with spontaneous recovery.We sought to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of moderate to severe depression, including subgroups of patients with major chronic health conditions. We also examined a number of key indicators of the quality of evidence and its clinical importance.