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. 2015 Aug;25(8):1082-90.
doi: 10.1016/j.euroneuro.2015.04.025. Epub 2015 May 5.

Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder

Chadi G Abdallah  1 , Andrea Jackowski  2 , João R Sato  3 , Xiangling Mao  4 , Guoxin Kang  4 , Raminder Cheema  5 , Jeremy D Coplan  6 , Sanjay J Mathew  7 , Dikoma C Shungu  4
Affiliations

Prefrontal cortical GABA abnormalities are associated with reduced hippocampal volume in major depressive disorder

Chadi G Abdallah et al. Eur Neuropsychopharmacol. 2015 Aug.

Abstract

Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy ((1)H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes.

Keywords: Hippocampal volume; MRI; Magnetic resonance spectroscopy ((1)H MRS); Major depressive disorder (MDD); Treatment resistant depression; γ-Aminobutyric acid (GABA).

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Conflict of interest statement

Conflict of interest

CGA received research fund or consultation fee from Brain and Behavior Research Foundation (NARSAD), American Psychiatric Foundation, and Genentech. SJM received research funding or salary support over the last three years from the Banner Family Fund, Brain and Behavior Fund (NARSAD), The Brown Foundation, Inc., Bristol-Myers Squibb, Department of Veterans Affairs, Evotec, Johnson & Johnson, and the National Institute of Mental Health. He has received consulting fees or honoraria from Allergan, AstraZeneca, Cephalon, Corcept, Noven, Roche, and Takeda. He has received medication (Rilutek) from Sanofi-Aventis for a NIMH sponsored study. Dr. Mathew has been named as an inventor on a use-patent of ketamine for the treatment of depression. Dr. Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine were approved for this use. JDC received grant support from NIMH, NYSTEM, GlaxoSmithKline, Pfizer, and Alexza Pharmaceuticals. He is on the Pfizer advisory board and gives talks for BMS, AstraZeneca, GSK, and Pfizer. JDC received grant support from NIMH, NYSTEM, GlaxoSmithKline, Pfizer, and Alexza Pharmaceuticals. He is on the Pfizer advisory board and gives talks for BMS, AstraZeneca, GSK, and Pfizer. No biomedical financial interests or potential conflicts of interest are reported for AJ, JRS, XM, GK, RC, and DCS.

Figures

Figure 1
Figure 1
Anterior cingulate cortex (ACC) voxel size and location are shown on axial (A) and sagittal (B) images. Spectra acquired in 13 minutes for the ACC voxel, as well as their model fit and residual, are shown (C).
Figure 2
Figure 2. Hippocampal Volume in Major Depressive Disorder (MDD)
Comparison of hippocampal volumes across study groups showed no significant difference between MDD and HC (A). However, hippocampal volume reduction was observed in depressed subjects with (B) treatment resistance (TRD) or (C) low anterior cingulate GABA (MDD Low ACC GABA). No hippocampal volume differences were found between HC and non-TRD or HC and MDD High ACC GABA. Hippocampal Volume is the estimated marginal mean of right and left hippocampal volumes, controlling for intracranial volume and handedness. Error-bars represent the standard error of means. Effect sizes reported as η2partial.
Figure 3
Figure 3. Hippocampal Volume And Anterior Cingulate GABA
Anterior cingulate cortex (ACC) GABA positively correlated with standardized hippocampal volume (hippocampal (Hip)/intracranial volume (ICV) * 10000) in the MDD, but not in the HC group (rs = 0.27, p = 0.24).
Figure 4
Figure 4. Scatter Of The Anterior Cingulate GABA Among The Study Groups
Bars represent means and the standard error of means (SEM).
Figure 5
Figure 5. Scatter Of The Anterior Cingulate Glx Among The Study Groups
Bars represent means and the standard error of means (SEM).
See this image and copyright information in PMC

Comment in

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