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. 2025 Apr 8:16:1584673.
doi: 10.3389/fpsyt.2025.1584673. eCollection 2025.

Impact of repetitive transcranial magnetic stimulation on clinical and cognitive outcomes, and brain-derived neurotrophic factor levels in treatment-resistant depression

Enrico Ginelli  1 , Lucia Sanna  1 , Pasquale Paribello  1   2 , Ulker Isayeva  1   2 , Giorgio Corona  3 , Clement C Zai  4   5 , Daniela Manca  1 , Maria Novella Iaselli  1 , Roberto Collu  6 , Federica Pinna  1   2 , Maria Scherma  6   7 , Mirko Manchia  1   2   8 , Paola Fadda  6   7 , Bernardo Carpiniello  1   2
Affiliations

Impact of repetitive transcranial magnetic stimulation on clinical and cognitive outcomes, and brain-derived neurotrophic factor levels in treatment-resistant depression

Enrico Ginelli et al. Front Psychiatry. .

Abstract

Introduction: Treatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder (MDD), for whom effective treatment options are limited. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy in alleviating depressive symptoms in TRD. However, it remains unclear if these improvements are driven or mediated by changes in cognitive function or biological markers, such as brain-derived neurotrophic factor (BDNF).

Methods: This study examines the effects of rTMS on depressive symptoms, cognition, and BDNF levels, as well as the potential moderating role of lifetime suicidal attempts (LSA) on cognition and the predictive value of baseline BDNF for clinical outcomes. Twenty-five TRD patients were included, with 13 in the rTMS treatment group (receiving 20 sessions of rTMS over four weeks) and 12 as control group. Depression severity, cognitive function (Mini-Mental State Examination, Verbal Fluency, Digit Span), and serum BDNF levels were measured pre- and post-treatment. Mixed-effects linear regression models assessed clinical and biological associations.

Results: rTMS significantly reduced HAM-D (p < 0.001) and CGI (p < 0.001) scores compared to controls. Cognitive performance improved significantly in MMSE (p = 0.049) and Digit Span (p = 0.04), with no significant changes in BDNF levels (p = 0.39). LSA did not moderate cognitive outcomes, and baseline BDNF did not predict clinical improvement (p = 0.68).

Discussion: rTMS reduced depressive symptoms in TRD patients, with modest cognitive benefits. Baseline BDNF did not predict outcomes, though the lack of significant change suggests complex neuroplastic responses. Future studies should include larger samples and refined biomarker assessments.

Keywords: BDNF; depression; neuroplasticity; rTMS; suicidality; treatment-resistance.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Change in HAM-D scale score during open label trial with rTMS between baseline and endpoint.
Figure 2
Figure 2
Change in CGI scale score during open label trial with rTMS between baseline and endpoint.
See this image and copyright information in PMC

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