Efficacy of Pharmacological Interventions in Milder Depression: A Systematic Review and Meta-Analysis

Mild depression lacks a consistent definition across diagnostic criteria and rating scales, posing challenges to standardizing treatment strategies. International guidelines predominantly recommend psychotherapy as the first-line treatment for mild depression, while the use of antidepressants remains contentious. Supplements such as omega-3 fatty acids, St. John's Wort, and magnesium have garnered attention as alternative therapeutic options for depression. This systematic review aims to assess the efficacy of pharmacological interventions, including supplements, in the treatment of mild depression.

Comprehensive searches were performed in PubMed and Embase through November 2024 to identify randomized controlled trials (RCTs) investigating pharmacotherapy or supplements for mild depression diagnosed using standardized criteria. Eligible studies underwent screening and risk of bias assessment utilizing the ROB2 tool. Data on remission rates, symptom improvement, dropout rates, and adverse events were extracted, with meta-analyses conducted where applicable.

Eight RCTs comprising 1049 participants met inclusion criteria. Among the agents studied, St. John's Wort was analyzed in two trials, both comparing it to fluoxetine. A meta-analysis found no significant difference in response rates between the two treatments (risk ratio [RR] = 0.96, 95% CI: 0.78-1.18) or dropout rates (RR = 1.08, 95% CI: 0.62-1.88). For other agents, single studies evaluated their effects. Eicosapentaenoic acid and Rhodiola rosea demonstrated significant improvements in depressive symptoms compared to placebo. In non-blinded trials, magnesium chloride showed efficacy in alleviating depressive symptoms. Other interventions, such as lavender, lemon balm, and transcranial electroacupuncture stimulation, were as effective as antidepressants. Conversely, S-adenosylmethionine did not produce significant improvements relative to placebo.

This review demonstrates that certain supplements, such as eicosapentaenoic acids and Rhodiola rosea, are therapeutic options for mild depression. However, no RCTs compared antidepressants directly to placebo for mild depression. The paucity of high-quality RCTs exclusively targeting mild depression limits definitive conclusions, warranting further rigorous research.