Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis

Background Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence. Methods In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC. Results In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, P FWE = 0.002) and CA1-NAc (Z = 2.94, P FWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, P FWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, P FWE = 0.002, diazepam Z = 3.33, P FWE = 0.003; higher: placebo Z = 4.48, P FWE < 0.001, diazepam Z = 4.22, P FWE < 0.001). Conclusions This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.