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

Narayan, Gita Anjali; Hill, Kathryn; Wengler, Kenneth; He, Xiang; Wang, Junying; Yang, Jie; Parsey, Ramin V.; DeLorenzo, Christine

doi:10.1038/s41380-022-01730-4

Cited by 21 publications

(19 citation statements)

References 64 publications

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“…PET/MRI data from this cohort has been published in previous studies. 26,38,39 None have examined the relationship between PET and MRI measures examined in this work.…”

Section: Methodsmentioning

confidence: 99%

Investigating The Relationship Between Hippocampus:Dentate Gyrus Volume and Hypothalamus Metabolism in Participants with Major Depressive Disorder

Lin

Sunko²,

Wang³

et al. 2023

Preprint

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Reduced hippocampal volume occurs in major depressive disorder (MDD), theoretically due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume, and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET) / magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and treatment response.

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“…PET/MRI data from this cohort has been published in previous studies. 26,38,39 None have examined the relationship between PET and MRI measures examined in this work.…”

Section: Methodsmentioning

confidence: 99%

Investigating The Relationship Between Hippocampus:Dentate Gyrus Volume and Hypothalamus Metabolism in Participants with Major Depressive Disorder

Lin

Sunko²,

Wang³

et al. 2023

Preprint

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“…This study involved the analysis of simultaneously acquired PET/MRS neuroimaging data from a randomized, placebo-controlled, double-blind, single-site SSRI (Escitalopram) trial on 60 participants with MDD before initiating treatment. The study design and rationale for the data set have been previously described [ 6 , 10 ]. 43 regional measures of metabolic rate of glucose (MRGlu, mg/(min*100 mL)) from FDG-PET across multiple brain regions [ 6 ], and concentrations (mM) of Glx (Glu+Gln, a composite peak formed by Glu and Gln), GABA and the ratio of Glx to GABA (Glx/GABA)) in the ACC from MRS [ 10 ] were quantified as described in prior publications.…”

Section: Methodsmentioning

confidence: 99%

“…The study design and rationale for the data set have been previously described [ 6 , 10 ]. 43 regional measures of metabolic rate of glucose (MRGlu, mg/(min*100 mL)) from FDG-PET across multiple brain regions [ 6 ], and concentrations (mM) of Glx (Glu+Gln, a composite peak formed by Glu and Gln), GABA and the ratio of Glx to GABA (Glx/GABA)) in the ACC from MRS [ 10 ] were quantified as described in prior publications. After eight weeks of treatment, those with ≤ 7 on the 17-item Hamilton Depression Rating Scale were designated a priori as remitters (free of depression).…”

Section: Methodsmentioning

confidence: 99%

“…Glutamine (Gln) is the precursor to the excitatory neurotransmitter, glutamate (Glu) and inhibitory neurotransmitter, γ -aminobutyric acid (GABA), and all three are essential amino acids for brain metabolism [ 7 ]. Prior magnetic resonance spectroscopy (MRS) studies showed that higher pretreatment Glu in the anterior cingulate cortex (ACC) [ 8 ] can predict better response, but other MRS studies showed no predictive potential for antidepressant response using Glu [ 9 , 10 ], GABA [ 9 – 11 ], or Glx (Gln/Glu) [ 12 ], adding to the lack of consensus on biomarkers of MDD treatment. These prior inconsistent findings using single imaging modalities with fewer functional features and conventional statistical models have motivated the use of machine learning (ML) with multimodal neuroimaging (both PET and MRS measures) for better prediction accuracy [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Gradient boosting decision-tree-based algorithm with neuroimaging for personalized treatment in depression

Ali

Wengler

et al. 2022

Neuroscience Informatics

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“…All participants provided informed consent and were recruited as a community sample as described in Hill et al [52]. Data from this study (Advancing Personalized Antidepressant Treatment Using PET/MRI, Clin-icalTrials.gov, NCT02623205) has been previously published; however, none of the previous studies examined childhood trauma; they involved PET-only measures [52], or only magnetic resonance spectroscopy [53].…”

Section: Methods and Materials Participantsmentioning

confidence: 99%

Evaluation of brain structure and metabolism in currently depressed adults with a history of childhood trauma

et al. 2022

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Structural differences in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala were reported in adults who experienced childhood trauma; however, it is unknown whether metabolic differences accompany these structural differences. This multimodal imaging study examined structural and metabolic correlates of childhood trauma in adults with major depressive disorder (MDD). Participants with MDD completed the Childhood Trauma Questionnaire (CTQ, n = 83, n = 54 female (65.1%), age: 30.4 ± 14.1) and simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI). Structure (volume, n = 80, and cortical thickness, n = 81) was quantified from MRI using Freesurfer. Metabolism (metabolic rate of glucose uptake) was quantified from dynamic 18 F-fluorodeoxyglucose (FDG)-PET images ( n = 70) using Patlak graphical analysis. A linear mixed model was utilized to examine the association between structural/metabolic variables and continuous childhood trauma measures while controlling for confounding factors. Bonferroni correction was applied. Amygdala volumes were significantly inversely correlated with continuous CTQ scores. Specifically, volumes were lower by 7.44 mm 3 (95% confidence interval [CI]: –12.19, –2.68) per point increase in CTQ. No significant relationship was found between thickness/metabolism and CTQ score. While longitudinal studies are required to establish causation, this study provides insight into potential consequences of, and therefore potential therapeutic targets for, childhood trauma in the prevention of MDD. This work aims to reduce heterogeneity in MDD studies by quantifying neurobiological correlates of trauma within MDD. It further provides biological targets for future interventions aimed at preventing MDD following trauma. To our knowledge, this is the first simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) study to assess both structure and metabolism associated with childhood trauma in adults with MDD.

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

Cited by 21 publications

References 64 publications

Investigating The Relationship Between Hippocampus:Dentate Gyrus Volume and Hypothalamus Metabolism in Participants with Major Depressive Disorder

Investigating The Relationship Between Hippocampus:Dentate Gyrus Volume and Hypothalamus Metabolism in Participants with Major Depressive Disorder

Gradient boosting decision-tree-based algorithm with neuroimaging for personalized treatment in depression

Evaluation of brain structure and metabolism in currently depressed adults with a history of childhood trauma

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