Functional connectivity (FC) is consistently altered in patients with schizophrenia. The brain’s primary inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and its relationship to FC in psychosis spectrum disorders are under-investigated. The anterior cingulate cortex (ACC) has been implicated in many cognitive functions impaired in psychosis. We hypothesize that the relationships between ACC GABA and FC in key brain networks will be altered in first-episode psychosis (FEP) patients as compared to healthy controls (HC).

We used magnetic resonance spectroscopy (MRS) with a MEGA-PRESS sequence to quantify ACC GABA levels in 67 antipsychotic medication-naïve FEP patients and 110 HC. Resting state functional magnetic resonance imaging (fMRI) was used to assess positive and negative FC within the default mode (DMN), salience (SN), dorsal attention (DAN), and executive control (ECN) networks. We used linear regressions to test GABA–FC relationships in each network between groups.

FEP patients had significantly lower GABA levels compared to HC. We also found several clusters in the ECN, DAN, and DMN where FC differed between groups. Ultimately, we found significant GABA–FC group interactions in two ECN clusters and one SN cluster, where GABA and FC were positively correlated in HC but negatively correlated in FEP.

Our data add to the growing literature supporting GABA’s significant role in psychosis spectrum disorders, especially as it relates to FC in key brain networks. Our findings call for further investigation of the mechanisms underlying altered neurometabolic activity and connectivity in psychosis spectrum disorders.