Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis

Abstract

Context: Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment.

Objective: To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression.

Data sources: Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews.

Study selection: Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities.

Data extraction: Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer.

Data synthesis: Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n=5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo.

Conclusions: Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks.

Figure 1

Flow diagram of the trial. RCT indicates randomized controlled trial.

Figure 2

Differences in depression symptom rating scale scores across time between groups treated with selective serotonin reuptake inhibitors and placebo. A, Best-fit model (logarithmically increasing treatment response) for the difference in standardized effect size between groups (placebo: n=2254 and selective serotonin reuptake inhibitor: n=3618) Dotted lines represent 95% confidence intervals. B, Weighted mean difference in scores using the Hamilton Depression Rating Scale (left) (n=1893-3433) and the Montgomery-Asberg Depression Rating Scale (right) (n=133-3159). Error bars represent 95% confidence intervals.

Figure 3

Absolute difference in rate (A) and relative risk (B) of response between groups treated with selective serotonin reuptake inhibitors and placebo across time: 50% reduction in Hamilton Depression Rating Scale (HDRS) score (n=688-1428) (left); Clinical Global Impression moderately or much improved (n=166-203) (center); and HDRS score less than 7 or less than 8 (n=684) (right). Error bars represent 95% confidence intervals.