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 GABAA/benzodiazepine receptor (GABAA/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 GABAA/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.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513

“…In vivo studies have reported a reduction in concentrations of GABA in cerebrospinal fluid concentrations in first-episode psychotic patients [7]. By contrast proton magnetic resonance spectroscopy (1H-MRS) have yielded discrepant findings, potentially due to the technical difficulties in accurately resolving GABA on MRS spectra and its complex relationship with synaptic GABA [8,9]. GABA acts on two different subtypes of receptors, GABA-A and GABA-B.…”

A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia

“…In the latter, consistent with our results, elevated immunoreactivity for GABRA2 has been observed in the DLPFC 38 . While this finding has been generally considered to be a post-synaptic homeostatic response to reduced presynaptic GABAergic synthesis and signalling 38 , in vivo brain imaging studies studies have not provided support for reduced GABA synthesis 39 . Indeed a recent in vivo study of antipsychotic naive patients showing increased GABA in patients challenges this view 40 , as do findings both of no reduction in the major GABA synthetic enzyme GAD67, and an increase in certain types of GABAergic pre-synaptic markers, in post-mortem prefrontal cortex of people with the disorder 41 .…”

Quantitative Rodent Brain Receptor Imaging

“…Clinical research is inevitably less standardized than the controlled environment of the preclinical field, leaving plenty of work for translational scientists. This is exemplified by a recent meta-analysis of human schizophrenia studies performed with [ 11 C]flumazenil, a tracer targeting GABA A receptors, which showed inconsistencies in reduced brain region uptake among the studies [247]. The authors remark that these results contrast with those of preclinical studies, which suggest that benzodiazepines can help prevent the neuroanatomical and neurophysiological dysfunctions related to schizophrenia [247].…”

“…This is exemplified by a recent meta-analysis of human schizophrenia studies performed with [ 11 C]flumazenil, a tracer targeting GABA A receptors, which showed inconsistencies in reduced brain region uptake among the studies [247]. The authors remark that these results contrast with those of preclinical studies, which suggest that benzodiazepines can help prevent the neuroanatomical and neurophysiological dysfunctions related to schizophrenia [247]. Of course, there are inherent differences between species, but the variance among human studies suggests inconsistency of experimental design in the clinic.…”