biostudies-literatureKiemes AWellcome Trust and the Royal SocietyNational Institute for Health Research (NIHR)National Institute for Health and Care ResearchWellcome TrustMaudsley Biomedical Research Centrepyaf078https://www.ebi.ac.uk/biostudies/studies/S-EPMC12874875biostudies-literatureUnknown29(2)<h4>Objective</h4>Preclinical evidence suggests that modulating neural excitation through administration of diazepam, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioral and neurobiological alterations relevant to psychosis in adulthood.<h4>Design and participants</h4>Here, we examine 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 and 9 male) aged 18-35 were scanned twice using proton magnetic resonance spectroscopy to measure anterior cingulate cortex Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg) and once after placebo.<h4>Results</h4>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).<h4>Conclusion</h4>These findings suggest that pharmacological modulation of GABAA receptors can alter Glx changes in and support a novel therapeutic mechanism of benefit for individuals at clinical high risk of psychosis.The international journal of neuropsychopharmacologyDiazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis.PMC12874875202397/Z/16/Z202397/Z/16/Z to G.M.McGuire PLivingston NRNettis MAStone JMModinos GGrace AACasetta CKnight SJelen LLythgoe DJDe Micheli AReilly TFusar-Poli PWilliams SCRLukow PBKiemes AEgerton ADima ASpencer TDavies CfalseDiazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis.<h4>Objective</h4>Preclinical evidence suggests that modulating neural excitation through administration of diazepam, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioral and neurobiological alterations relevant to psychosis in adulthood.<h4>Design and participants</h4>Here, we examine 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 and 9 male) aged 18-35 were scanned twice using proton magnetic resonance spectroscopy to measure anterior cingulate cortex Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg) and once after placebo.<h4>Results</h4>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).<h4>Conclusion</h4>These findings suggest that pharmacological modulation of GABAA receptors can alter Glx changes in and support a novel therapeutic mechanism of benefit for individuals at clinical high risk of psychosis.2026-01-01T00:00:00Z2026 Feb2026-06-30T03:28:18.002Z2026-06-30T03:21:56.676ZS-EPMC128748754138476410.1093/ijnp/pyaf078