Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis

Abstract

Data from animal models and from postmortem studies suggest that schizophrenia is associated with brain GABAergic dysfunction. The extent to which this is reflected in data from in vivo studies of GABA function in schizophrenia is unclear. The Medline database was searched to identify articles published until 21 October 2016. The search terms included GABA, proton magnetic resonance spectroscopy (¹H-MRS), positron emission tomography (PET), single photon emission computed tomography (SPECT), schizophrenia and psychosis. Sixteen GABA ¹H-MRS studies (538 controls, 526 patients) and seven PET/SPECT studies of GABA_A/benzodiazepine receptor (GABA_A/BZR) availability (118 controls, 113 patients) were identified. Meta-analyses of ¹H-MRS GABA in the medial prefrontal cortex (mPFC), parietal/occipital cortex (POC) and striatum did not show significant group differences (mFC: g=-0.3, 409 patients, 495 controls, 95% confidence interval (CI): -0.6 to 0.1; POC: g=-0.3, 139 patients, 111 controls, 95% CI: -0.9 to 0.3; striatum: g=-0.004, 123 patients, 95 controls, 95% CI: -0.7 to 0.7). Heterogeneity across studies was high (I²>50%), and this was not explained by subsequent moderator or meta-regression analyses. There were insufficient PET/SPECT receptor availability studies for meta-analyses, but a systematic review did not suggest replicable group differences in regional GABA_A/BZR availability. The current literature does not reveal consistent alterations in in vivo GABA neuroimaging measures in schizophrenia, as might be hypothesized from animal models and postmortem data. The analysis highlights the need for further GABA neuroimaging studies with improved methodology and addressing potential sources of heterogeneity.

Figure 1

Voxel locations in medial frontal cortex GABA ¹H-MRS studies. Numbers provide effect sizes (Hedge’s g) for the difference in ¹H-MRS GABA level between patients and control participants for each study. Negative effect sizes indicate lower GABA in patients; positive effect sizes indicate lower GABA in controls. Subgroup membership was defined by voxel locations primarily in the Brodmann Areas (BA) BA4 and BA24 (posterior medial frontal cortex), BA24 and BA32 (medial prefrontal cortex) or BA24 and BA11 (ventromedial prefrontal cortex). ¹H-MRS, proton magnetic resonance spectroscopy.

Figure 2

(a–d) Forest plots showing effect sizes (Hedge’s g) for ¹H-MRS GABA studies in schizophrenia versus control. Error bars represent 95% confidence intervals. Black squares indicate data from clinical patient samples (FEP or SCZ) while white squares indicate data from CHR or sibling samples. CHR, clinical high risk; FEP, first episode psychosis; ¹H-MRS, proton magnetic resonance spectroscopy; SCZ, schizophrenia or schizoaffective disorder; sibling, unaffected siblings of patients with schizophrenia; med, currently receiving antipsychotic medication; unmed, currently unmedicated with antipsychotics.

Figure 3

Illustration of effect sizes (Hedge’s g) for PET/SPECT studies of regional GABA_A/BDZ receptor availability in schizophrenia versus control. Error bars represent 95% confidence intervals. ACC, anterior cingulate cortex; Cing. Ctx, cingulate cortex; dlPFC, dorsolateral prefrontal cortex; EC, entorhinal cortex; FC, frontal cortex; Hip, hippocampus; ¹H-MRS, proton magnetic resonance spectroscopy; mFC, medial frontal cortex; mTC, medial temporal cortex; NAc, nucleus accumbens; OFC, orbitofrontal cortex; ParaHip, parahippocampus; PFC, prefrontal cortex; TC, temporal cortex. Studies reporting only voxel-wise analyses^, are excluded from the figure.