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

Background Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioral and neurobiological alterations relevant to psychosis in adulthood. Methods Here, we examined this neurochemical mechanism in individuals at clinical high-risk for psychosis in a randomized, double-blind, placebo-controlled crossover study. Twenty-four individuals (15 female, 9 male) aged 18-35 were scanned twice using proton magnetic resonance spectroscopy (1H-MRS) to measure anterior cingulate cortex Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg), and once after placebo. Results Mixed-effects model analyses revealed that diazepam reduced anterior cingulate cortex Glx levels compared to placebo (t(20.8) = -2.14, p=.04). The effect of diazepam on Glx levels was greater in older individuals at clinical high-risk for psychosis (t(12) = -4.36, p=.001). Conclusion These findings suggest that pharmacological modulation of GABAA receptors can alter Glx changes in clinical high-risk for psychosis and support a novel therapeutic mechanism of benefit for individuals at clinical high-risk of psychosis. Significance Statement Psychotic disorders, such as schizophrenia, are often preceded by subtle changes in brain chemistry. In this study, we explored whether diazepam, a medication commonly used to treat anxiety, could influence brain chemistry in individuals at high risk for developing psychosis. Our findings revealed that a single dose of diazepam reduced levels of Glx (glutamate and glutamine) — key metabolites in excitatory neurotransmission — in a region of the brain involved in psychosis. These results suggest that diazepam may alter differences in brain chemistry linked to the development of psychosis, offering potential insights for early intervention strategies.