Livingston Nicholas R, Kiemes Amanda, O'Daly Owen, Knight Samuel R, Lukow Paulina B, Jelen Luke A, Reilly Thomas J, Dima Aikaterini, Nettis Maria A, Casetta Cecilia, Devenyi Gabriel A, Spencer Thomas, De Micheli Andrea, Fusar-Poli Paolo, Grace Anthony A, Williams Steve C R, McGuire Philip, Chakravarty M Mallar, Egerton Alice, Modinos Gemma
Department of Psychological Medicine, https://ror.org/0220mzb33Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Psychol Med. 2025 Aug 8;55:e230. doi: 10.1017/S0033291725101268.
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.
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.
In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC ( = 3.17, = 0.002) and CA1-NAc ( = 2.94, = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased ( = 4.13, = 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 = 3.46, = 0.002, diazepam = 3.33, = 0.003; higher: placebo = 4.48, < 0.001, diazepam = 4.22, < 0.001).
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.
临床前证据表明，地西泮可增强海马体γ-氨基丁酸（GABA）信号传导，并使与精神病相关的皮质-边缘-纹状体回路正常化。海马体网络连接异常，特别是来自CA1亚区的连接异常，在临床高危精神病患者（CHR-P）中很明显，这是一个潜在的治疗靶点。本研究旨在将这一临床前证据进行前瞻性转化。
在这项随机、双盲、安慰剂对照研究中，18名CHR-P个体接受了两次静息态功能磁共振成像，一次是在服用5毫克地西泮后，一次是在服用安慰剂后。将他们与20名未接受地西泮/安慰剂的健康对照者（HC）进行比较。计算海马体CA1亚区与伏隔核（NAc）、杏仁核和腹内侧前额叶皮质（vmPFC）之间的功能连接（FC）。混合效应模型研究了组（CHR-P安慰剂/地西泮与HC）和条件（CHR-P地西泮与安慰剂）对CA1到区域FC的影响。
在安慰剂条件下，与HC相比，CHR-P个体的CA1-vmPFC（t = 3.17，p = 0.002）和CA1-NAc（t = 2.94，p = 0.005）FC显著降低。在服用地西泮的条件下，与安慰剂相比，CHR-P个体的CA1-vmPFC FC显著增加（t = 4.13，p = 0.008），并且CA1-vmPFC和CA1-NAc FC均恢复到HC水平。相比之下，与HC相比，在安慰剂和地西泮条件下，CHR-P个体的对侧CA1-杏仁核FC显著降低，同侧则显著升高（降低：安慰剂t = 3.46，p = 0.002，地西泮t = 3.33，p = 0.003；升高：安慰剂t = 4.48，p < 0.001，地西泮t = 4.22，p < 0.001）。
本研究表明，地西泮可以部分恢复CHR-P个体中海马体CA1的连接异常，这表明调节GABA能功能可能对治疗该临床群体有用。
