Effects of magnesium supplementation on serum brain-derived neurotrophic factor levels and cognitive function in patients undergoing fluoxetine therapy for depression

OBJECTIVES: To evaluate the effects of magnesium supplementation as an adjunct to fluoxetine on serum brain-derived neurotrophic factor (BDNF) levels and cognitive function in patients with depression. METHODS: Outpatients aged 18 to 50 years diagnosed with depression who were receiving fluoxetine treatment at various hospitals in Makassar, Indonesia, between July and August 2025 were invited to participate. Participants were randomly allocated to either the control group, which received fluoxetine therapy alone for 6 weeks, or the treatment group, which received fluoxetine therapy plus 350 mg of oral magnesium supplementation once daily for 6 weeks. Patients were assessed at baseline and 6 weeks. BDNF levels were measured using peripheral venous blood samples. Serum BDNF concentrations (in pg/mL) were quantified using an enzyme-linked immunosorbent assay kit. Cognitive function was assessed using the validated Indonesian version of the Montreal Cognitive Assessment (MoCA-Ina). RESULTS: In total, 40 participants were randomly allocated to either the control group (n = 20) or the treatment group (n = 20). Both groups had significant improvements in MoCA-Ina scores from baseline to week 6 (both p < 0.001), but the improvement was greater in the treatment group (4.8 vs 1.35, p < 0.001), particularly in the domains of attention (from 2.90 to 4.05, p < 0.001) and memory (from 2.25 to 3.85, p < 0.001). At week 6, scores were significantly higher in the treatment group in the domains of attention (4.05 vs 3.10, p = 0.002), memory (3.85 vs 2.70, p < 0.001), and orientation (5.75 vs 5.05, p < 0.001). Although improvement in MoCA-Ina scores was greater in the treatment group, change in serum BDNF levels between groups was not significant (60.59 vs -29.01 pg/mL, p = 0.584). Changes in serum BDNF levels were more strongly correlated with changes in MoCA-Ina scores in the treatment group (ρ = 0.667, p = 0.001) than in the control group (ρ = 0.483, p = 0.031). CONCLUSION: Magnesium supplementation as an adjunct to fluoxetine was associated with greater improvement in cognitive function than fluoxetine alone in patients with depression. Changes in serum BDNF levels were positively associated with cognitive improvement, particularly in the treatment group. These findings suggest a role for magnesium in enhancing cognitive recovery, possibly through modulation of neuroplasticity-related pathways.