Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis

Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABA _A receptors, can prevent the emergence of behavioural and neurobiological alterations relevant to psychosis in adulthood. Here, we examined this neurochemical mechanism in individuals at clinical high-risk for psychosis (CHRp) in a randomised, double-blind, placebo-controlled crossover study. Twenty-four individuals aged 18-35 were scanned twice using proton magnetic resonance spectroscopy ( ¹ H-MRS) to measure anterior cingulate cortex (ACC) Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg), and once after placebo. Mixed-effects model analyses revealed that diazepam reduced ACC Glx levels compared to placebo (t(20.8) = −2.14, p = 0.04). The effect of diazepam on Glx levels was greater in older CHRp individuals (t(12) = −4.36, p = 0.001). These findings suggest that pharmacological modulation of GABA _A receptors can alter glutamatergic changes in psychosis.