Background: Primary care patients and clinicians may prefer alternative options to second-generation antidepressants for major depressive disorder (MDD).
Purpose: To compare the benefits and harms of nonpharmacologic treatments with second-generation antidepressants as first-step interventions for acute MDD, and to compare second-step treatment strategies for patients who did not achieve remission after an initial attempt with antidepressants.
Data sources: English-language studies from several electronic databases from 1 January 1990 to 8 August 2022, trial registries, gray literature databases, and reference lists to identify unpublished research.
Study selection: 2 investigators independently selected randomized trials of at least 6 weeks' duration.
Data extraction: Reviewers abstracted data about study design and conduct, participants, interventions, and outcomes. They dually rated the risk of bias of studies and the certainty of evidence for outcomes of interest.
Data synthesis: 65 randomized trials met the inclusion criteria; eligible data from nonrandomized studies were not found. Meta-analyses and network meta-analyses indicated similar benefits of most nonpharmacologic treatments and antidepressants as first-step treatments. Antidepressants had higher risks for discontinuation because of adverse events than most other treatments. For second-step therapies, different switching and augmentation strategies provided similar symptomatic relief. The certainty of evidence for most comparisons is low; findings should be interpreted cautiously.
Limitations: Many studies had methodological limitations or dosing inequalities; publication bias might have affected some comparisons. In some cases, conclusions could not be drawn because of insufficient evidence.
Conclusion: Although benefits seem to be similar among first- and second-step MDD treatments, the certainty of evidence is low for most comparisons. Clinicians and patients should focus on options with the most reliable evidence and take adverse event profiles and patient preferences into consideration.
Primary funding source: American College of Physicians. (PROSPERO: CRD42020204703).