Journal Article

Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis

Lukow, Paulina B., Livingston, Nicholas R., Kiemes, Amanda, Casetta, Cecilia, Zelaya, Fernando, Fusar-Poli, Paolo, Williams, Steve C. R., Nettis, Maria Antonietta, Reilly, Thomas, Spencer, Thomas, De Micheli, Andrea, Dima, Aikaterini, Agyekum, Tyler, Grace, Anthony A., Jelen, Luke A., McGuire, Philip, Knight, Samuel, Chakravarty, M. Mallar, Modinos, Gemma, Devenyi, Gabriel A., Egerton, Alice

2024

Overview

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus ( F (1,41) = 24.7, p FDR  < 0.001) and across its subfields (all p FDR  < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all p FDR  < 0.001) was significantly reduced ( t (69) = −5.1, p FDR  < 0.001) and normalized to HC levels ( F (1,41) = 0.4, p FDR  = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

• Publisher: Nature Publishing Group,Springer International Publishing
• Subject: Adolescent / Adult / Blood flow / Cerebral blood flow / Cerebrovascular Circulation - drug effects / Cerebrovascular Circulation - physiology / Clinical trials / Cross-Over Studies / Dentate gyrus / Diazepam / Diazepam - pharmacology / Double-Blind Method / Female / Hippocampus / Hippocampus - blood supply / Hippocampus - diagnostic imaging / Hippocampus - drug effects / Humans / Hyperactivity / Magnetic Resonance Imaging / Male / Perfusion / Phenotypes / Placebos / Psychosis / Psychotic Disorders - diagnostic imaging / Psychotic Disorders - drug therapy / Psychotic Disorders - physiopathology / Spin labeling / Subiculum / Young Adult / γ-Aminobutyric acid