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

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


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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Depressive Disorder, Major / metabolism*
  • Depressive Disorder, Major / pathology*
  • Female
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Organ Size
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • Proton Magnetic Resonance Spectroscopy
  • gamma-Aminobutyric Acid / metabolism*


  • gamma-Aminobutyric Acid