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

Abstract

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.

Figure 1: Two designs of randomized controlled trials used to investigate long-term antidepressant therapy.

Figure 2: Flow diagram for identification of classic placebo-controlled randomized controlled trials.

Figure 3: Pooled analysis of response to treatment (50% improvement in depression score relative to baseline) in 6 classic randomized controlled trials of selective serotonin reuptake inhibitors in patients with major depression. The vertical line represents no difference between compared treatments.

Figure 4: Pooled analysis of remission (score of 7 or below on the Hamilton rating scale for depression) in 4 classic randomized controlled trials of selective serotonin reuptake inhibitors in patients with major depression. The vertical line represents no difference between compared treatments.

Figure 5: Pooled analysis of overall acceptability (total dropouts) in 6 classic randomized controlled trials of selective serotonin reuptake inhibitors in patients with major depression. The vertical line represents no difference between compared treatments.