Non-invasive neurostimulation for enhancing peripheral brain-derived neurotrophic factor levels in major depressive disorder: A meta-analysis of randomized controlled trials.

BACKGROUND: Brain-derived neurotrophic factor (BDNF), a critical modulator of neuroplasticity, has been strongly implicated in the pathophysiology of major depressive disorder (MDD). Non-invasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), shows therapeutic promise for MDD. However, their impact on peripheral BDNF levels remains inconclusive. OBJECTIVE: This meta-analysis aimed to quantify the effects of NIBS on peripheral BDNF levels in MDD patients and to evaluate BDNF as a potential biomarker of treatment response. METHODS: Following PRISMA guidelines, randomized controlled trials (RCTs) comparing NIBS with sham stimulation in MDD were identified through a systematic search of five databases. Sixteen RCTs (n = 1271) were included. Random-effects models were used to estimate pooled standardized mean differences (SMDs) for peripheral BDNF levels and depressive symptom severity. Subgroup and moderator analyses examined the effects of BDNF elevation, stimulation modality, and treatment duration. RESULTS: NIBS significantly increased peripheral BDNF levels (SMD = 1.05, 95% CI: 0.57 to 1.52, p < 0.001) and reduced depressive symptoms (SMD = -0.90, 95% CI: -1.13 to -0.67, p < 0.001). Moderator analyses demonstrated that BDNF elevation was associated with greater antidepressant effects. Subgroup analyses revealed that rTMS significantly increased BDNF levels, whereas tDCS did not. Extended rTMS protocols (≥4 weeks) were associated with greater BDNF increases than shorter durations. CONCLUSION: NIBS is associated with increased peripheral BDNF levels and improved depressive symptoms in MDD patients, suggesting the potential utility of BDNF as a biomarker for neuromodulation efficacy. PROSPERO REGISTRATION: CRD42025630845.