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 Chakravarty; Gemma Modinos

doi:10.1038/s41386-024-01864-9

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 Chakravarty

Gemma Modinos

Department of Psychological Medicine
McGill Univ, McGill University, Montreal Childrens Hosp, Ctr Hlth, Dept Pediat
Institute of Cognitive Neuroscience
Department of Psychosis Studies
Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
1Department of Hepatology, Imperial College London, London, UK. 2Institute of Liver Studies at King's College School of Medicine at King's College Hospital, London, UK. 3Institute of Human Health and Performance, University College London, London, UK. 4Department of Asthma Allergy and Lung Biology, King's College London, London, UK. 5Division of Critical Care Medicine, University of Alberta, Edmonton, Canada.
Neuroimaging Department
Outreach and Support in South London (OASIS) Service
NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, Denmark Hill Campus, London, SE5 8EF, UK.
Department of Brain and Behavioural Sciences, University of Pavia
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Pavia, Italy.; University of Pavia, Pavia, Italy.
School of Social Work; University of Pittsburgh; Pittsburgh Pennsylvania

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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 language	English
Pages (from-to)	1448-1458
Number of pages	11
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume	49
Issue number	9
Early online date	24 Apr 2024
DOIs	https://doi.org/10.1038/s41386-024-01864-9
Publication status	Published - Aug 2024

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10.1038/s41386-024-01864-9Licence: CC BY

Cite this

Livingston, N. R., Kiemes, A., Devenyi, G. A., Knight, S., Lukow, P. B., Jelen, L. A., Reilly, T., Dima, A., Nettis, M. A., Casetta, C., Agyekum, T., Zelaya, F., Spencer, T., De Micheli, A., Fusar-Poli, P., Grace, A. A., Williams, S. C. R., McGuire, P., Egerton, A., ... Modinos, G. (2024). Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 49(9), 1448-1458. https://doi.org/10.1038/s41386-024-01864-9

@article{d6a432e62aed4c8d88a16b65a3c9e06f,

title = "Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis",

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.",

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

note = "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 \textbackslash{}u201CMNESYS, A multiscale integrated approach to the study of the nervous system in health and disease\textbackslash{}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: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = aug,

doi = "10.1038/s41386-024-01864-9",

language = "English",

volume = "49",

pages = "1448--1458",

journal = "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",

issn = "0893-133X",

publisher = "Springer Nature [academic journals on nature.com]",

number = "9",

}

Livingston, NR , Kiemes, A, Devenyi, GA, Knight, S , Lukow, PB , Jelen, LA, Reilly, T, Dima, A, Nettis, MA , Casetta, C, Agyekum, T, Zelaya, F , Spencer, T , De Micheli, A , Fusar-Poli, P, Grace, AA, Williams, SCR, McGuire, P, Egerton, A, Chakravarty, MM & Modinos, G 2024, 'Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis', Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 49, no. 9, pp. 1448-1458. https://doi.org/10.1038/s41386-024-01864-9

Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis. / Livingston, Nicholas R ; Kiemes, Amanda; Devenyi, Gabriel A et al.
In: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Vol. 49, No. 9, 08.2024, p. 1448-1458.

Research output: Contribution to journal › Article › peer-review

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 - https://www.scopus.com/pages/publications/85191318668

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 -

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

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