Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis.
Kiemes A., Livingston NR., Lukow PB., Knight S., Jelen L., Reilly T., Dima A., Nettis MA., Lythgoe DJ., Casetta C., Egerton A., Spencer T., De Micheli A., Fusar-Poli P., Grace AA., Williams SCR., McGuire P., Davies C., Stone JM., Modinos G.
OBJECTIVE: 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. DESIGN AND PARTICIPANTS: 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. 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 and support a novel therapeutic mechanism of benefit for individuals at clinical high risk of psychosis.