Abstract
Seasonal affective disorder (SAD) is a type of unipolar depression characterized by depressive symptoms mainly during the cold season, which were often linked to alterations in the serotonergic system. It is assumed that other neurotransmitter systems, such as glutamate and GABA, are similarly affected. Hence, we investigated differences in glutamate and GABA between SAD patients and healthy control subjects using magnetic resonance spectroscopy imaging (MRSI). Fourteen SAD patients (11 female, 36 ± 11 years) and 14 sex- and age-matched healthy controls, were scanned once between October and February using multi-voxel 3D-GABA-edited MEGA-LASER MRSI at 3 T. Mean GABA+ and Glx (glutamate + glutamine) to total creatine (tCr) ratios were calculated in five brain regions. Mann–Whitney-U-Tests were performed for each region and neurotransmitter ratio independently as well as correlation analyses between neurotransmitter ratios and clinical scores, respectively. A significant reduction in GABA+/tCr ratios in the hippocampus (pcorr = 0.049) between SAD patients and healthy individuals was revealed. No significant changes in other brain regions or correlations with the investigated clinical scores were shown. Our findings of altered GABA concentrations in the hippocampus are in line with neurotransmitter alterations across other subtypes of depression, hinting towards common neurobiological mechanisms and highlights the interplay between environmental factors and neurotransmitter systems.
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Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.
References
Partonen, T. & Lonnqvist, J. Seasonal affective disorder. Lancet 352, 1369–1374. https://doi.org/10.1016/S0140-6736(98)01015-0 (1998).
Golden, R. N. et al. The efficacy of light therapy in the treatment of mood disorders: A review and meta-analysis of the evidence. Am. J Psychiatry 162, 656–662. https://doi.org/10.1176/appi.ajp.162.4.656 (2005).
Pjrek, E. et al. The efficacy of light therapy in the treatment of seasonal affective disorder: A meta-analysis of randomized controlled trials. Psychother. Psychosom. 89, 17–24. https://doi.org/10.1159/000502891 (2020).
Daut, R. A. & Fonken, L. K. Circadian regulation of depression: A role for serotonin. Front. Neuroendocrinol. 54, 100746. https://doi.org/10.1016/j.yfrne.2019.04.003 (2019).
Mc Mahon, B. et al. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder. Brain J. Neurol. 139, 1605–1614. https://doi.org/10.1093/brain/aww043 (2016).
Praschak-Rieder, N., Willeit, M., Wilson, A. A., Houle, S. & Meyer, J. H. Seasonal variation in human brain serotonin transporter binding. Arch. Gen. Psychiatry 65, 1072–1078. https://doi.org/10.1001/archpsyc.65.9.1072 (2008).
Spies, M. et al. Brain monoamine oxidase A in seasonal affective disorder and treatment with bright light therapy. Transl. Psychiatry 8, 198. https://doi.org/10.1038/s41398-018-0227-2 (2018).
Spindelegger, C. et al. Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain. World J. Biol. Psychiatry 13, 413–422. https://doi.org/10.3109/15622975.2011.630405 (2012).
Willeit, M. et al. Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 33, 1503–1513. https://doi.org/10.1038/sj.npp.1301560 (2008).
Li, T. et al. Effect of the pineal gland on 5-hydroxytryptamine and γ-aminobutyric acid secretion in the hippocampus of male rats during the summer and winter. J. Tradit. Chin. Med. Sci. 7, 283–290. https://doi.org/10.1016/j.jtcms.2020.07.004 (2020).
Godfrey, K. et al. The role of GABA, glutamate, and Glx levels in treatment of major depressive disorder: A systematic review and meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 141, 111455. https://doi.org/10.1016/j.pnpbp.2025.111455 (2025).
Schur, R. R. et al. Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies. Hum. Brain Mapp. 37, 3337–3352. https://doi.org/10.1002/hbm.23244 (2016).
Pehrson, A. L. & Sanchez, C. Altered gamma-aminobutyric acid neurotransmission in major depressive disorder: A critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des. Dev. Ther. 9, 603–624. https://doi.org/10.2147/DDDT.S62912 (2015).
Sanacora, G. et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch. Gen. Psychiatry 61, 705–713. https://doi.org/10.1001/archpsyc.61.7.705 (2004).
Sanacora, G., Treccani, G. & Popoli, M. Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62, 63–77. https://doi.org/10.1016/j.neuropharm.2011.07.036 (2012).
Spurny-Dworak, B. et al. The influence of season on glutamate and GABA levels in the healthy human brain investigated by magnetic resonance spectroscopy imaging. Hum. Brain Mapp. 44(6), 2654–2663. https://doi.org/10.1002/hbm.26236 (2023).
Rosenthal, N. E. Seasonal pattern assessment questionnaire. J. Affect. Disord. (1984).
Williams, B., Link, M., Rosenthal, N. & Terman, M. Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder Version, 2002 rev (New York State Psychiatric Institute, New York, 2002).
Bogner, W. et al. Real-time motion- and B0-correction for LASER-localized spiral-accelerated 3D-MRSI of the brain at 3T. Neuroimage 88, 22–31. https://doi.org/10.1016/j.neuroimage.2013.09.034 (2014).
Bogner, W. et al. 3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI. Neuroimage 103, 290–302. https://doi.org/10.1016/j.neuroimage.2014.09.032 (2014).
Andronesi, O. C. et al. Spectroscopic imaging with improved gradient modulated constant adiabaticity pulses on high-field clinical scanners. J. Magn. Reson. 203, 283–293. https://doi.org/10.1016/j.jmr.2010.01.010 (2010).
Bogner, W., Hangel, G., Esmaeili, M. & Andronesi, O. C. 1D-spectral editing and 2D multispectral in vivo(1)H-MRS and (1)H-MRSI - Methods and applications. Anal. Biochem. 529, 48–64. https://doi.org/10.1016/j.ab.2016.12.020 (2017).
Mullins, P. G. et al. Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage 86, 43–52. https://doi.org/10.1016/j.neuroimage.2012.12.004 (2014).
Hnilicova, P. et al. Spatial variability and reproducibility of GABA-edited MEGA-LASER 3D-MRSI in the brain at 3 T. NMR Biomed. 29, 1656–1665. https://doi.org/10.1002/nbm.3613 (2016).
Spurny, B. et al. Automated ROI-based labeling for multi-voxel magnetic resonance spectroscopy data using FreeSurfer. Front. Mol. Neurosci. 12, 28. https://doi.org/10.3389/fnmol.2019.00028 (2019).
Handschuh, P. A. et al. Summer and SERT: Effect of daily sunshine hours on SLC6A4 promoter methylation in seasonal affective disorder. World J. Biol. Psychiatry 26, 159–169. https://doi.org/10.1080/15622975.2025.2477463 (2025).
Duman, R. S., Sanacora, G. & Krystal, J. H. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron 102, 75–90. https://doi.org/10.1016/j.neuron.2019.03.013 (2019).
Abdallah, C. G. et al. Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder. Eur. Neuropsychopharmacol. 25, 1082–1090. https://doi.org/10.1016/j.euroneuro.2015.04.025 (2015).
Campbell, S. & Macqueen, G. The role of the hippocampus in the pathophysiology of major depression. J. Psychiatry Neurosci. 29, 417–426 (2004).
Del Arco, A. & Mora, F. Neurotransmitters and prefrontal cortex-limbic system interactions: implications for plasticity and psychiatric disorders. J. Neural Transm. (Vienna) 116, 941–952. https://doi.org/10.1007/s00702-009-0243-8 (2009).
Lemke, H. et al. The course of disease in major depressive disorder is associated with altered activity of the limbic system during negative emotion processing. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 7, 323–332. https://doi.org/10.1016/j.bpsc.2021.05.008 (2022).
Silberbauer, L. R. et al. Effect of ketamine on limbic GABA and glutamate: A human in vivo multivoxel magnetic resonance spectroscopy study. Front. Psych. 11, 549903. https://doi.org/10.3389/fpsyt.2020.549903 (2020).
Spurny, B. et al. Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm. Neuroimage https://doi.org/10.1016/j.neuroimage.2021.117913 (2021).
Spurny-Dworak, B. et al. Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort. Psychoneuroendocrinology 138, 105683. https://doi.org/10.1016/j.psyneuen.2022.105683 (2022).
Spurny, B. et al. Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm. Neuroimage 204, 116244. https://doi.org/10.1016/j.neuroimage.2019.116244 (2020).
Andersson, P., Li, X. & Persson, J. Hippocampal and prefrontal GABA and glutamate concentration contribute to component processes of working memory in aging. Cereb. Cortex https://doi.org/10.1093/cercor/bhaf105 (2025).
Jimenez-Balado, J. et al. Reduced hippocampal GABA+ Is associated with poorer episodic memory in healthy older women: A pilot study. Front. Behav. Neurosci. 15, 695416. https://doi.org/10.3389/fnbeh.2021.695416 (2021).
Tartt, A. N., Mariani, M. B., Hen, R., Mann, J. J. & Boldrini, M. Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications. Mol. Psychiatry 27, 2689–2699. https://doi.org/10.1038/s41380-022-01520-y (2022).
Gupta, A., Sharma, P. K., Garg, V. K., Singh, A. K. & Mondal, S. C. Role of serotonin in seasonal affective disorder. Eur. Rev. Med. Pharmacol. Sci. 17, 49–55 (2013).
Han, Q. et al. Molecular mechanisms of seasonal photoperiod effects of the pineal gland on the hippocampus in rats. J. Tradit. Chin. Med. Sci. 8, 135–144. https://doi.org/10.1016/j.jtcms.2021.05.002 (2021).
Cipriani, A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 391, 1357–1366. https://doi.org/10.1016/S0140-6736(17)32802-7 (2018).
Herrera-Guzman, I. et al. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res. 177, 323–329. https://doi.org/10.1016/j.psychres.2010.03.006 (2010).
Menegaz de Almeida, A. et al. Bright light therapy for nonseasonal depressive disorders: A systematic review and meta-analysis. JAMA Psychiat. 82, 38–46. https://doi.org/10.1001/jamapsychiatry.2024.2871 (2025).
Acknowledgements
We thank the graduated team members and the diploma students of the Neuroimaging Lab (NIL, headed by RL) as well as the clinical colleagues from the Department of Psychiatry and Psychotherapy for clinical and/or administrative support. We thank Kenan Al Barede for technical assistance, and David Gomola for administrative assistance.
Funding
This research was funded in whole, or in part by the Austrian Science Fund (FWF) [Grant-DOI https://doi.org/10.55776/KLI899-B, PI: D. Winkler; Grant-DOIs: https://doi.org/10.55776/PAT6608924, https://doi.org/10.55776/KLI1006, KLI 516 and KLI 504, PI: R. Lanzenberger and Grant-DOI https://doi.org/10.55776/KLI899-B10.55776/KLI827, PI: E. Winkler-Pjrek] and the Brain and Behavior Research Foundation (formerly NARSAD) [Young Investigator Grant 32307 to B. Spurny-Dworak and Grant 23741 to M. Spies]. G. Dörl is a recipient of a DOC Fellowship of the Austrian Academy of Sciences.
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BS was responsible for analysis, methodology, data curation and writing the original draft. GD, PS, MK and AI, MR and JD were responsible for data curation and investigation. PH, CS and MS were responsible for investigation and supervision. WB was responsible for methodology, validation and supervision. EW, DW and RL were responsible for conceptualization, project administration and funding acquisition. All authors participated in manuscript reviewing and editing.
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Spurny-Dworak, B., Dörl, G., Stöhrmann, P. et al. Neurotransmitter alterations in seasonal affective disorder. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37634-4
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DOI: https://doi.org/10.1038/s41598-026-37634-4
