Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia

Guo, Jia; Rothman, Douglas L.; Small, Scott

doi:10.1001/jamapsychiatry.2022.3849

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…Postmortem, preclinical, genetic, and clinical neuroimaging evidence suggests that hippocampal abnormalities are central to the pathophysiology of psychosis [ 7 – 9 ], thus representing a potential therapeutic target. Hippocampal dysfunction in psychosis is proposed to arise from a disruption in neural excitatory/inhibitory balance, likely driven by GABAergic inhibitory interneuron dysfunction [ 10 – 14 ], although glutamatergic receptor dysfunction is also implicated [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Baseline elevated hippocampal rCBF or rCBV was also found to predict higher positive and negative symptom severity [ 38 ], poor functioning [ 38 , 43 ], and transition to psychosis [ 38 , 39 , 44 ], and to normalize in those individuals who remit from the CHR-P state [ 40 ]. Within the hippocampus, hyperactivity is proposed to originate in the CA1 subfield and then extend to the subiculum and beyond [ 9 , 38 , 39 , 42 ]. Hence, hippocampal rCBF may be a marker for symptom severity and psychosis onset in CHR-P individuals, which preclinical evidence suggests may be prevented by pharmacological enhancement of hippocampal GABA levels [ 35 – 37 ].…”

Section: Introductionmentioning

confidence: 99%

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

Livingston,

Kiemes,

Devenyi

et al. 2024

Neuropsychopharmacol.

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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, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = −5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Livingston,

Kiemes,

Devenyi

et al. 2024

Neuropsychopharmacol.

View full text Add to dashboard Cite

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Categorical and Dimensional Approaches for Psychiatric Classification and Treatment Targeting: Considerations from Psychosis Biotypes

Clementz,

Assaf,

Sweeney

et al. 2024

Advances in Neurobiology

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Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk

Davies,

Bossong,

Martins

et al. 2023

Schizophrenia Bulletin Open

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Background Preclinical and human data suggest that psychosis onset involves hippocampal glutamatergic dysfunction, driving hyperactivity/hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at Clinical High Risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with perfusion remains unknown. Methods Using a double-blind, parallel-group design, 33 CHR patients were randomised to a single 600mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD) and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group x glutamate x cerebral perfusion (measured using Arterial Spin Labelling) interactions. Results Compared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (p=.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo and intermediate in CHR-CBD (p=.031). Moreover, there was a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate and perfusion in the putamen and insula (pFWE=.012), with a strong positive correlation in CHR-placebo vs a negative correlation in controls. Conclusions Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalised by a single dose of CBD. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and perfusion in the striatum and insula in CHR.

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Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia

Abstract: This article discusses why glutamate levels are abnormally elevated in the hippocampus of patients with schizophrenia and related disorders.

Cited by 3 publications

References 12 publications

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

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

Categorical and Dimensional Approaches for Psychiatric Classification and Treatment Targeting: Considerations from Psychosis Biotypes

Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk

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