Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis.

IF 5.5 2区医学 Q1 PSYCHIATRY

Psychological Medicine Pub Date : 2025-08-08 DOI:10.1017/S0033291725101268

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

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引用次数: 0

Abstract

Background: Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

Methods: In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

Results: In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, P_FWE = 0.002) and CA1-NAc (Z = 2.94, P_FWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, P_FWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, P_FWE = 0.002, diazepam Z = 3.33, P_FWE = 0.003; higher: placebo Z = 4.48, P_FWE < 0.001, diazepam Z = 4.22, P_FWE < 0.001).

Conclusions: This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

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安定调节精神病临床高危人群海马CA1功能连通性

背景：临床前证据表明，地西泮可增强海马γ-氨基丁酸（GABA）信号，并使与精神病相关的皮质-边缘-纹状体回路正常化。海马网络连接障碍，特别是来自CA1子区，在临床精神病高危人群（chrp）中很明显，代表了一个潜在的治疗目标。本研究旨在将这一临床前证据向前转化。方法：在这项随机、双盲、安慰剂对照的研究中，18名chrp患者接受了两次静息状态功能磁共振成像，一次服用5mg剂量的地西泮，一次服用安慰剂。将他们与20名未接受地西泮/安慰剂的健康对照组（HC）进行比较。计算海马CA1亚区与伏隔核（NAc）、杏仁核和腹内侧前额叶皮层（vmPFC）之间的功能连通性（FC）。混合效应模型研究了组（chrp - p安慰剂/地西泮vs HC）和条件（chrp - p地西泮vs安慰剂）对ca1 -区域FC的影响。结果：在安慰剂条件下，chrp患者的CA1-vmPFC （Z = 3.17, PFWE = 0.002）和CA1-NAc (Z = 2.94, PFWE = 0.005) FC明显低于HC。地西泮组与安慰剂组相比，CHR-P组CA1-vmPFC显著升高（Z = 4.13, PFWE = 0.008）， CA1-vmPFC和CA1-NAc FC均正常化至HC水平。相比之下，与HC相比，安慰剂组和地西泮组chrp患者的ca1 -杏仁核FC在对侧显著降低，在同侧显著升高(较低：安慰剂Z = 3.46, PFWE = 0.002，地西泮Z = 3.33, PFWE = 0.003；结论：本研究表明地西泮可以部分恢复CHR-P患者海马CA1连接障碍，提示调节gaba能功能可能对该临床组的治疗有用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychological Medicine 医学-精神病学

CiteScore

11.30

自引率

4.30%

发文量

711

审稿时长

3-6 weeks

期刊介绍： Now in its fifth decade of publication, Psychological Medicine is a leading international journal in the fields of psychiatry, related aspects of psychology and basic sciences. From 2014, there are 16 issues a year, each featuring original articles reporting key research being undertaken worldwide, together with shorter editorials by distinguished scholars and an important book review section. The journal''s success is clearly demonstrated by a consistently high impact factor.