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

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 (¹H-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 ¹H-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.

Fig. 1

CONSORT Diagram.

Fig. 2. Sample 1H-MRS Location.

¹H-MRS voxel size and location in the medial frontal cortex, encompassing part of the dorsal anterior cingulate cortex and parts of the frontal pole, shown in the sagittal (left), coronal (middle), and axial (right) views.

Fig. 3. Pretreatment Metabolites Concentrations in Remitters and Non-remitters Group.

Pretreatment GABA (A), Glx (a combination of glutamate and glutamine) (B) or Glx/GABA (C) in remitters and non-remitters. Error Bars are the 95% confidence interval. The bottom and the top of the box mark the 25 and 75th percentiles, and the line inside the box indicates the 50th percentile.

Fig. 4. Correlation of Pretreatment Metabolites Concentrations and Percent Difference in Hamilton Depression Rating Scale.

Percent difference in Hamilton Depression Rating Scale with treatment versus pretreatment GABA (A), Glx (a combination of glutamate and glutamine) (B) or Glx/GABA (C). Treatment type is indicated by color. Positive y-values indicate a reduction in symptoms. (R: correlation coefficient; p: p-value). SSRI selective serotonin reuptake inhibitor (escitalopram).

Fig. 5. Correlation of Pretreatment Metabolites Concentrations and Days to Response.

Days to response (in responders only) versus pretreatment GABA (A), Glx (a combination of glutamate and glutamine) (B) or Glx/GABA (C). Treatment type is indicated by color. (R: correlation coefficient; p: p-value). SSRI selective serotonin reuptake inhibitor (escitalopram).