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

Kiemes, A.; Livingston, N. R.; Lukow, P. B.; Knight, S.; Jelen, L. A.; Reilly, T. J.; Dima, A.; Nettis, M. A.; Lythgoe, D. J.; Casetta, C.; Egerton, A.; Spencer, T.; De Micheli, A.; Fusar-Poli, P.; Grace, A. A.; Williams, S. C. R.; McGuire, P.; Davies, C.; Stone, J.; Modinos, G.

2024-12-30 psychiatry and clinical psychology
10.1101/2024.12.28.24319730 medRxiv
Show abstract

Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABAA 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 (1H-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 GABAA receptors can alter glutamatergic changes in psychosis.

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