Increased Rostral Medial Frontal GABA in Early Psychosis is Obscured by Levels of Negative Affect

Background Evidence suggests dysfunction of GABAergic interneurons in psychosis, and prior research has linked GABAergic function with a tendency toward negative affective states. Magnetic resonance spectroscopy (MRS) studies measuring GABA have yielded inconsistent findings. We investigate GABA concentrations in young adults with attenuated psychosis syndrome (APS) and first episode psychosis (FEP), as well as testing the hypothesis that negative affect is a clinical phenotype that is associated with reduced GABA. Materials MRS data were obtained from 14 patients with FEP, 7 patients with APS and 15 healthy controls (HC), using a MEGA-PRESS sequence on a 3T Philips Ingenia scanner. Voxels were placed in rostral MFC and midline-occipital cortex. Gannet 3.1 was used to determine GABA+ and Glx (glutamate and glutamine combined) concentrations. Results We found a trend towards increased rostral MFC GABA+ concentrations in FEP, but no group differences in occipital GABA+ concentrations. When covarying for scores on the Psychological Stress Index, rostral MFC GABA+ levels in FEP were significantly greater than APS and HC. Planned comparisons revealed a trend towards increased rostral MFC GABA+ in APS relative to HC. No group differences in Glx or occipital GABA+ were found. Conclusion These results, considered alongside previously published findings, suggest multiple factors influencing GABA+ in psychosis. We conclude a process exists which drives up GABA+ in early psychosis, alongside a separate process in which reduced GABA+ is associated with increased negative affect. These multiple processes have resulted in contradictory findings, and their untangling is critical to understanding of GABA+ in psychosis. ### Competing Interest Statement Stephan F. Taylor has received contracted research support from Boehringer-Ingelheim, and he receives consulting fees for membership on scientific advisory boards for NIH- and privately funded projects. Molly Simmonite, Beier Yao and Robert C. Welsh have no financial disclosures or conflicts of interest. ### Funding Statement This research is funded by NIH grants R21MH101676 and R01MH118634 awarded to Stephan F. Taylor. The funders had no role in study design; collection, analysis and interpretation of data; the writing of the report; or in the decision to submit the article for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Michigan Medical School gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors