γ-Aminobutyric Acid and Glutamate Dysregulation in the Dorsolateral Prefrontal Cortex of Adolescents with First-Episode Major Depressive Disorder and the Modulatory Effects of Repetitive Transcranial Magnetic Stimulation

Background Major depressive disorder (MDD) is associated with dysregulation of γ-aminobutyric acid (GABA) and glutamate (Glx) neurotransmission in the prefrontal cortex. Proton magnetic resonance spectroscopy (1H-MRS) can serve as a non-invasive method to quantify GABA and Glx levels in vivo. This study aimed to investigate the neurochemical transmitter characteristics of the left and right dorsolateral prefrontal cortex (DLPFC) in first episode adolescent major depressive disorder (FEA-MDD) and the impact of repetitive transcranial magnetic stimulation (rTMS) on these neurochemical changes. Methods 42 drug-naïve FEA-MDD underwent bilateral DLPFC MRS scans before and after rTMS, with 42 healthy controls (HCs) as baseline. All participants were right-handed. The Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) protocol was used to detect GABA and Glx levels. The detected signal included contributions from macromolecules and high carnosine, and was therefore referred to as GABA+. All data were processed using Gannet software. Results FEA-MDD exhibited significantly lower GABA+ and higher Glx levels in the left DLPFC than HCs;in the right DLPFC, no significant difference in GABA+ levels was observed, though Glx levels were elevated.After rTMS treatment, GABA+ levels in the left DLPFC increased significantly, whereas Glx levels showed a non-significant decreasing trend. Additionally, HCs had no hemispheric differences,while in FEA-MDD, the left DLPFC were observed to show lower GABA+ and Glx levels compared to the right. We also found that in the left DLPFC, baseline GABA+ levels were negatively correlated with Hamilton Depression Rating Scale (HAMD)scores; Glx levels showed positive correlations with scores on the Ruminative Response Scale (RRS), Self-Rating Depression Scale (SDS), and Self-Esteem Scale (SES). Conclusions FEA-MDD involves prefrontal GABA+/Glx dysregulation, and rTMS may aid in restoring neurotransmitter balance within the DLPFC. This study adds to the expanding body of evidence supporting the application of targeted neurochemical modulation in the treatment of FEA-MDD, while also providing insights into potential intervention mechanisms.