Glycyrrhizic acid as an adjunctive treatment for depression through anti-inflammation: A randomized placebo-controlled clinical trial

•GZA was effective in alleviating depressive symptoms as an adjunctive treatment.•TNF-α reduction partially mediated the association between GZA treatment and clinical improvement of depression.•High levels of serum CRP (> 3 mg/L) informed combined antidepressant therapy with anti-inflammatory agents like GZA. Recently, abundant evidence indicated proinflammatory cytokines might play a crucial role in pathophysiology and treatment of depression. According to our preclinical research, we propose glycyrrhizic acid (GZA) for an adjunctive treatment owing to its safety, economical and anti-inflammatory profile. Eligible participants were recruited and randomly allocated into independent treatment groups of SSRI+GZA (n = 30) and SSRI+PBO (placebo, n = 26). Depressive symptoms and specific serum biomarkers were detected during the 4-week treatment course. Afterward, the relationships between biomarkers and clinical effects were explored. Depressive symptoms relieved more in SSRI+GZA than SSRI+PBO, both at week 2 (P = 0.003) and week 4 (P = 0.016). Meanwhile, at week 4, both response rate (P = 0.035) and remission rate (P = 0.031) acutely became higher in SSRI+GZA compared with SSRI+PBO. Mediation analysis further demonstrated that TNF-α reduction mediated the association between GZA treatment and clinical improvement, the indirect effect lay between 0.124 and 3.514 (95% CI). The exploratory analysis also suggested that the symptomatic improvement existed in patients with high-inflammation (baseline CRP > 3 mg/L) rather than those with low-inflammation (baseline CRP ≤ 3 mg/L). The sample size in this study was not large enough and the follow-up duration was relatively short. This study offers a novel strategy for the diagnosis, categorization, individualization and prognosis regarding upgrading traditional antidepressant therapy, which is from biomarkers to diagnostic indicator and therapeutic target. Patients are necessary to be classified according to the inflammatory state, those with high levels of baseline inflammation should receive combined treatment with anti-inflammatory agents like GZA.