Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies

Abstract

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337-3352, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: 1H-MRS; ASD; GABA; MDD; meta-analysis; psychopathology.

Figure 1

Forest plots of brain GABA levels in major depressive disorder, schizophrenia, and autism spectrum disorder. Diamond shaped orange symbols represent (from top to bottom) current MDD, remitted MDD, frontal regions in schizophrenia and non‐frontal regions in schizophrenia. Size of the blue squares is proportionate to the sample size used. OCC, occipital cortex; ACC, anterior cingulate cortex; dm/daPFC, dorsomedial dorsal anterolateral prefrontal (region partly overlaps with vmPFC in the same study); (vm/m)PFC, (Ventromedial/Medial) prefrontal cortex; MDD(‐R), major depressive disorder (remitted). FL, frontal lobe; dlPFC, dorsolateral prefrontal cortex; CSO, centrum semiovale; POC, parieto‐occipital cortex; Temp, temporal lobe; PMC, primary motor cortex. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Forest plot showing brain GABA levels in bipolar disorder, panic disorder, PTSD, and ADHD. Size of the blue squares is proportionate to the sample size used. (v)mPFC, (ventro)medial prefrontal cortex; OCC, occipital cortex; ACC, anterior cingulate cortex; POC, parieto‐occipital cortex; dm/daPFC, dorsomedial/dorsal anterolateral prefrontal cortex (region partly overlaps with vmPFC in the same study); dlPFC, dorsolateral prefrontal cortex; Temp, temporal cortex; PMC, primary motor cortex. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Schematic overview of SMDs in GABA per region of interest for MDD, schizophrenia and ASD (minimum of two studies per region). Frontal, temporal, parietal, occipital, and basal ganglia are color coded and the brain is shown from a lateral and medial perspective. Dark blue: SMD close to 0, light blue: SMD close to −1.5, gray: not reported. Red outline: significant difference between patients and controls (P < 0.05). The following SMDs were found in this meta‐analysis and used in this figure: MDD: occipital −0.597 (P = 0.043), frontal −0.445 (P = 0.149); schizophrenia: occipital −0.343 (P = 0.232), frontal −0.197 (P = 0.313), basal ganglia −0.483 (P = 0.259); ASD: frontal −0.831 (P = 0.001), temporal −1.252 (P = 0.001). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]