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Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial

Abstract

Previous proton magnetic resonance spectroscopy (1H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS17) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS17, regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI, ClinicalTrials.gov, NCT02623205.

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Fig. 1: A sample 1H-MRS spectra (top) showing Glx and GABA (including macromolecules) peaks, acquired from the anterior cingulate cortex (ACC), with voxel size and location shown in the bottom panel in sagittal (left), coronal (middle), and axial (right) views.
Fig. 2: Concentrations (mM) of GABA (left) and Glx (right) as a function of depression (HDRS17) in the ACC.
Fig. 3: Percent change in HDRS17 as a function of % change in Glx (top) and GABA (bottom), n = 60 (placebo: n = 30, escitalopram: n = 30).
Fig. 4: Percent difference in HDRS17 as a function of % change in Glx/GABA, with outlier (top, n = 60; placebo n = 30, escitalopram n = 30) and without outlier (bottom, n = 59; placebo n = 29, escitalopram n = 30).

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Acknowledgements

We would like to thank the Biostatistical Consulting Core at the Stony Brook University Renaissance School of Medicine, and the clinical team who coordinated participant screening and symptom scale rating: Greg Perlman, Juhayer Alam, Kate Bartolotta, Dr. Yashar Yousefzadeh-Fard, Michala Godstrey, Qurat-ul-ain Gulamhussein, Nichole Hoehn, Dan Holzmacher, Dr. Sridhar Kadiyala, Colleen Oliva, Nehal Vadhan, Jennifer Rubinstein, Dr. Laura Kunkel, and Dr. Lucian Manu. This study (ID # 570152) was approved by the IRB (3/20/2015–12/21/2021).

Funding

This study is funded by NIMH (National Institute of Mental Health) R01MH104512, Brain & Behavior Research Foundation, The Dana Foundation, and NYS Faculty Development Grant.

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CD and RVP designed the study and completed data collection. KW, XH, JW, and JY analyzed the data. GAN, KRH, and CD interpreted data and drafted the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to G. Anjali Narayan.

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GAN has no financial disclosures or conflicts of interest to declare. KRH has no financial disclosures or conflicts of interest to declare. XH has no financial disclosures or conflicts of interest to declare. KW has no financial disclosures or conflicts of interest to declare. JY has no financial disclosures or conflicts of interest to declare. JW has no financial disclosures or conflicts of interest to declare. RVP has no financial disclosures or conflicts of interest to declare. CD has no financial disclosures or conflicts of interest to declare.

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Narayan, G.A., Hill, K.R., Wengler, K. et al. Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01730-4

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