TY - JOUR
T1 - Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis
AU - Livingston, Nicholas R
AU - Kiemes, Amanda
AU - Devenyi, Gabriel A
AU - Knight, Samuel
AU - Lukow, Paulina B
AU - Jelen, Luke A
AU - Reilly, Thomas
AU - Dima, Aikaterini
AU - Nettis, Maria Antonietta
AU - Casetta, Cecilia
AU - Agyekum, Tyler
AU - Zelaya, Fernando
AU - Spencer, Thomas
AU - De Micheli, Andrea
AU - Fusar-Poli, Paolo
AU - Grace, Anthony A
AU - Williams, Steve C R
AU - McGuire, Philip
AU - Egerton, Alice
AU - Chakravarty, M Mallar
AU - Modinos, Gemma
N1 - Funding Information:
This independent research was funded by the Wellcome Trust & The Royal Society (grant number 202397/Z/16/Z to GM), and was partly funded and carried out at the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the Wellcome Trust & The Royal Society, the NIHR, or the Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Accepted Author Manuscript version arising from this submission. NRL is supported by an MRC DTP PhD studentship. LAJ is supported by an MRC Clinical Research Training Fellowship (MR/T028084/1). PFP is supported by the European Union funding within the MUR PNRR Extended Partnership initiative on Neuroscience and Neuropharmacology (Project no. PE00000006 CUP H93C22000660006 \u201CMNESYS, A multiscale integrated approach to the study of the nervous system in health and disease\u201D). TJR Is supported by an MRC Clinical Research Training Fellowship (MR/W015943/1). AAG is supported by the National Institute of Mental Health (USPHS MH57440).
Funding Information:
GM has received consulting fees from Boehringer Ingelheim. AE has received consulting fees from Leal Therapeutics. AAG has received funds from Lundbeck, Pfizer, Lilly, Roche, Janssen, Alkermes, Newron, Takeda and Merck. SCRW has recently received research funding from Boehringer Ingelheim and GE Healthcare to perform investigator-led research. All other authors have nothing to disclose.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85191318668&partnerID=8YFLogxK
U2 - 10.1038/s41386-024-01864-9
DO - 10.1038/s41386-024-01864-9
M3 - Article
C2 - 38658738
SN - 0893-133X
VL - 49
SP - 1448
EP - 1458
JO - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
IS - 9
ER -