Efficacy and tolerability of antidepressants for sub-threshold depression and for mild major depressive disorder

Background: It is commonly assumed that robust evidence exists for the lack of efficacy of antidepressants at the milder end of the depression severity spectrum. In light of specific limitations of existing reviews, we assess if antidepressants are efficacious and tolerable for sub-threshold or mild major depressive disorder (MDD).

Method: Systematic review and meta-analysis of randomised controlled trials of adults with sub-threshold depression or mild MDD (initial baseline symptom severity of HRSD≤20) comparing an antidepressant with placebo or treatment as usual (TAU) however defined. A pre-specified protocol was published (Prospero reference: CRD42013004505).

Results: 8 trials were included: 5 trials (453 participants) of sub-threshold depression and 3 trials (502 participants) of mild MDD. Trials of sub-threshold depression exhibited low risk of bias whereas those of mild MDD exhibited high risk. Two trials of sub-threshold depression were pooled (n=102) to assess efficacy and favoured antidepressants over placebo statistically but the difference was small and unlikely to be clinically meaningful: mean difference -1.39 (-2.41, -0.36). Due to heterogeneity, no trials of mild MDD could be pooled for efficacy. There was no difference between antidepressant treatment and placebo for drop out due to adverse events. The maximum proportion in those receiving antidepressants dropping out due to adverse events was 17%, with indication of a dose effect.

Limitations: Not all data from identified trials could be included in the meta-analyses due to a lack of availability of relevant data.

Conclusion: There is insufficient evidence to support or contest the efficacy of antidepressant medication for sub-threshold depression or mild MDD. More trials, with adequate follow up, are required to address this question.