No trials assessing the efficacy of selective serotonin reuptake inhibitor therapy over a period of more than 1 year met our eligibility criteria. Only 6 trials met our eligibility criteria; these studies, which had a moderate risk of bias, had randomly assigned a total of 1299 participants with depression to receive placebo or selective serotonin reuptake inhibitor and had followed both groups for 6–8 months. The mean dropout rate after 6–8 months was 48% (range 27%–87%), which exceeds the 15% maximum previously recommended for studies lasting longer than 3 months.31
High dropout rates tend to reduce the level of confidence in the internal validity of trial results, as well as their applicability to general clinical practice. The only classic randomized clinical trial extending past 8 months that we identified was excluded from our review (see Appendix 3, at www.cmaj.ca/cgi/content/full/178/10/1293/DC2
). That study involved children and adolescents with depression, and participants with a response to medication or placebo were followed for 12 months. However, with an overall completion rate of only 16%, the trial was difficult to evaluate.
We observed statistically significant improvements in response to treatment but not in remission or acceptability (which might have been due to lack of power) after 6–8 months of selective serotonin reuptake inhibitor therapy. The effects appeared greater in patients without comorbidities. However, given the limited reporting of participants' course of illness, we were unable to determine whether particular subgroups, such as those with highly recurrent depression, benefited more than those with single episodes. Furthermore, we found few data about the long-term effects of selective serotonin reuptake inhibitors on a range of important clinical outcomes, such as time off work, the need for cointerventions and self-harm, relative to those of placebo.
The study populations had been recruited from a range of settings, including psychiatric clinics, general medical hospitals and private community clinics. Groups with a higher prevalence of severe or recurrent depression may benefit most from antidepressants, and the distribution of more severe depressive illness may differ across these settings.32–34
One of the strengths of our systematic review is that it focused on classic long-term randomized controlled trials of selective serotonin reuptake inhibitors for the treatment of depression. Previous reviews included and were dominated by studies with discontinuation designs, which are difficult to interpret and which may overestimate the benefits of treatments.
Our study has several limitations. Because of resource constraints, we included only studies published in English, but this restriction is unlikely to have biased our results.35,36
We did not detect any evidence of publication bias.
The main limitations of our review reflect the weaknesses of the included studies. The studies were at moderate risk of bias and failed to report key methodologic issues. No study reported data beyond 12 months. The most commonly reported outcome was “response to treatment” rather than “full remission.” Response was defined in terms of a 50% improvement in depression scores relative to baseline, whereas “full remission” was defined by pre-established cut-points on depression scores. Full remission from depression correlates with better longer-term functional recovery, lower risk of relapse and higher levels of patient satisfaction than partial response without remission.37
Another limitation is that 4 of the 6 included trials reported outcomes in terms of the “last observation carried forward,” a method that may underestimate true treatment effects in short-term trials but overestimate active interventions in long-term trials.38
Five of the 6 studies were commercially sponsored. This might have led to an exaggeration of treatment effects, since industry-sponsored trials have been shown to be 4 times as likely as independent studies to demonstrate positive effects of the sponsor's drug.39–41
Similar to concerns with shorter-term trials of selective serotonin reuptake inhibitors, the study participants in the included trials may not be representative of those seen in everyday practice.42
For example, 5 of the 6 trials excluded patients with substance abuse, a common comorbidity, and all trials excluded patients with suicidal ideation, one of the diagnostic criteria for major depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders
, 4th edition.