Baseline glutamate-glutamine complex levels modulate antidepressant response to rTMS in major depressive disorder: Insights from magnetic resonance spectroscopy.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but its neurometabolic effects remain unknown. This study examined whether rTMS outcomes depend on baseline medial prefrontal cortex (mPFC) glutamate-glutamine complex (Glx) levels and aimed to identify clinically translatable imaging biomarkers.

Methods: Seventy-six MDD patients and 44 healthy controls (HC) were enrolled. 39 patients underwent 20-session rTMS treatments and were divided into high Glx (hGlx, N = 20) and low Glx (lGlx, N = 19) subgroups based on the median baseline Glx levels of all patients in the MDD group (N = 76). Metabolite concentrations (GABA, Glx, Glx/GABA) changes within the mPFC were quantified via magnetic resonance spectroscopy. Baseline subgroup differences and their associations with treatment outcomes investigated. Diffusion MRI metrics were extracted from the corpus callosum (CC) for correlation analysis, including fractional anisotropy, radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD).

Results: After rTMS treatment, both Glx subgroups regained significant Glx-GABA coupling, mirroring the HC pattern. In the hGlx subgroup, baseline mPFC Glx, GABA, and Glx/GABA predicted improvements in Montgomery-Åsberg Depression Rating Scale and Hamilton Depression Rating Scale factor scores. Notably, hGlx patients exhibited higher CC RD and MD values, with mPFC Glx levels correlating specifically with the splenium of CC MD and AD.

Conclusion: Subgroup analyses demonstrated baseline mPFC excitatory neurotransmission modulates rTMS efficacy. Higher Glx concentrations may synergize with adjacent white matter integrity to restore excitatory-inhibitory balance, supporting higher mPFC Glx as a predictive biomarker for rTMS outcomes.