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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Early online date24 Apr 2024
DOIs
Publication statusE-pub ahead of print - 24 Apr 2024

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