¹Medical University of Vienna, Austria, Psychiatry and Psychotherapy, Vienna, Austria, ²Medical University of Vienna, Austria, Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Vienna, Austria, ³Medical University of Vienna, Austria, Department of Biomedical Imaging and Image-guided Therapy, High Field MR Center, Vienna, Austria, ⁴Medical University of Vienna, Austria, Christian Doppler Laboratory for MR Imaging Biomarkers (BIOMAK), Vienna, Austria

Background: Neurotransmitter alterations in the main inhibitory and excitatory systems, GABA and glutamate, have frequently been reported in major depressive disorder (MDD) (Kalueff and Nutt, 2007; Godfrey, 2025). Disruptions in the inhibitory/excitatory (I/E) balance may be linked pathophysiological mechanisms across different subtypes of depression (Ge, 2025). Thus, investigation of I/E balance in distinct subtypes potentially contributes to the development of precision medicine approaches. Seasonal affective disorder (SAD) is primarily treated with bright light therapy (Golden, 2005). Although SAD follows seasonal patterns in symptom severity and allows different treatment regimes, underlying neurobiological changes are thought to be in line with other subtypes of depression. On the other hand, treatment resistant depression (TRD), defined as persistence of symptoms after two pharmacological treatment trials in adequate length and dosage, represents the most severe form of MDD. While both subtypes show similar serotonergic alterations (Spindelegger, 2012; Kajumba, 2024), common mechanisms and differences in the main neurotransmitter systems are of high interest. Hence, we aimed to investigate region-specific variations in I/E ratios of patients suffering from SAD and TRD.

Aims & Objectives: In the course of this work, we aimed to investigate potential differences in I/E balance across subcortical brain regions between SAD and TRD patients. Common mechanisms across subtypes of depression allow the opportunity to link shared symptoms to underlying neuropathological mechanisms and to develop specific treatment regimes.

Method: Neurotransmitter ratios were assessed in fourteen patients suffering from SAD (11 female, mean age±SD= 36±11 years) and 18 patients suffering from treatment resistant depression (9 female, 37±11 years), using a multi-voxel 3D GABA-edited MEGA-LASER MRSI sequence (Bogner, 2014) on a 3 Tesla MR Scanner (MAGNETOM Prisma, Siemens Medical, Erlangen, Germany), with a TE of 68 ms, volume of interest (VOI) = 80 (l-r) x 90 (a-p) x 80 (s-i) mm³ and field of view (FOV) = 160 x 160 x 160 mm³. All spectra within the VOI were processed using MATLAB, MINC and LCModel software. For region of interest (ROI)-based analysis, structural T1-weighted MPRAGE images, acquired prior to each MRSI scan, were segmented using FreeSurfer. Maps of GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) were interpolated to the resolution of structural images, overlaid with masks and mean GABA+/Glx ratios calculated for each ROI: hippocampus, putamen, pallidum and thalamus bilaterally. Mann-Whitney-U Tests were calculated for each ROI. Bonferroni correction was applied for multiple comparison.

Results: Mann-Whitney-U Tests revealed significant differences in the hippocampal GABA+/Glx ratios between SAD and TRD patients (p_corr.= 0.04). No differences were detected in other regions.

Discussion & Conclusions: Here we report subtype-specific differences in hippocampal I/E ratios. The hippocampus represents one of the epicenters in neurotransmitter alterations and treatment effects on GABA and glutamate in MDD (Silberbauer, 2020; Spurny, 2021). While common patterns in serotonergic dysfunction were shown, region-specific changes in I/E balance seem to differentiate those subtypes. However, differences in the hippocampal I/E balance across subtypes emphasize the complexity and heterogeneity within MDD.