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Lack of association between pretreatment glutamate/GABA and major depressive disorder treatment response

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Dai, Feiyang, Wengler, Kenneth, He, Xiang, Wang, Junying, Yang, Jie, Parsey, Ramin V., DeLorenzo, Christine·2025·Translational Psychiatry
DOI 10.1038/s41398-025-03292-9PMC PMC11873289
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Abstract

Studies have shown gamma-amino-butyric acid (GABA) and Glx (a combination of glutamate and glutamine) to be altered in major depressive disorder (MDD). Using proton Magnetic Resonance Spectroscopy (1 H-MRS), this study aimed to determine whether lower pretreatment GABA and Glx levels in the medial frontal cortex, a region implicated in MDD pathophysiology, are associated with better antidepressant treatment response. Participants with MDD (N = 74) were antidepressant naïve or medication-free for at least three weeks before imaging. Two MEGA-PRESS 1 H-MRS acquisitions were collected, interleaved with a water unsuppressed reference scan. GABA and Glx concentrations were quantified from an average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Following imaging, participants were randomized to escitalopram or placebo for 8 weeks in a double-blind design. Multivariable logistic regression models were applied with treatment type and age as covariates. Bayes Factor hypothesis testing was used to interpret the strength of the evidence. No significant association was found between pretreatment Glx, GABA, or Glx/GABA and depression remission status or the continuous outcome, percent change in symptom severity. In an exploratory analysis, no significant correlation was found between pretreatment Glx, GABA or Glx/GABA and days to response. Bayes factor analysis showed strong evidence towards the null hypotheses in all cases. To date, there are no replicated biomarkers in psychiatry. To address this, well-powered, placebo-controlled trials need to be undertaken and reported. The present analysis suggests pretreatment GABA, Glx, or their ratio cannot predict antidepressant treatment response. Future direction including examining glutamate and glutamine separately or examining biological subtypes of MDD separately. Trial Name: Advancing Personalized Antidepressant Treatment Using PET/MRI. Registration Number: NCT02623205 URL: https://clinicaltrials.gov/ct2/show/NCT02623205

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Cited by

Sorted by citations

Authors
Dai, F., Wengler, K., He, X., Wang, J., Yang, J., Parsey, R. V., & DeLorenzo, C.
Affiliations
  • University of California, Berkeley (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Northwell Health (US)
  • Stony Brook University (US)
Corresponding author
Dai, Feiyang
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2025-03-02
Volume
15
Issue
1
Pages
71-71
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-025-03292-9
PMC
PMC11873289
OpenAlex
W4408083818
Cited by
12
References
8
Citations by year
2026: 7 · 2025: 5
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH104512)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
major depressive disorder, glutamate, GABA, glutamine, antidepressant response, medial frontal cortex, 1H NMR, escitalopram, biomarkers, depression remission
MeSH terms
Escitalopram, Adult, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Female, gamma-Aminobutyric Acid, Glutamine, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Treatment Outcome, Glutamic Acid, Young Adult, Proton Magnetic Resonance Spectroscopy

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