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Levetiracetamin in First Episode Psychosis

左乙拉西他明在首发精神病中的应用

基本信息

批准号：
9298321
负责人：
DONALD C. GOFF
金额：
$ 51.27万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-24 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298321
关键词：
Adverse effects Animal Model Animals Anticonvulsants Antiepileptic Agents Antipsychotic Agents Biological Markers Blood Blood flow Brain Brain imaging Clinical Clinical Research Cognition Dopamine Dose Early Intervention Early treatment Generations Glutamates Hippocampus (Brain)Hour Human Hyperactive behavior Impaired cognition Individual Injury Intervention Left Levetiracetam Link Magnetic Resonance Imaging Measures Mediator of activation protein Modeling Neurodegenerative Disorders Onset of illness Outcome Oxidative Stress Patients Perfusion Pharmaceutical Preparations Pharmacology Physiologic pulse Placebo Control Placebos Prevention strategy Proteins Psychotic Disorders Sampling Schizophrenia Serum Site Spin Labels Symptoms Synaptic Vesicles TXN gene Testing Ventral Tegmental Area base clinical biomarkers clinically significant cognitive function dopaminergic neuron double-blind placebo controlled trial excitotoxicity first episode psychosis high risk improved mild cognitive impairment neurotoxic neurotoxicity neurotransmission open label placebo controlled study prevent primary outcome response symptomatic improvement transmission process treatment response

项目摘要

Increased perfusion of the hippocampal CA1 subfield is a clinical biomarker for early psychosis that also predicts hippocampal volume loss. Converging evidence suggests that CA1 hyperperfusion reflects excessive glutamatergic transmission which drives psychosis and may produce excitotoxic hippocampal injury that is associated with poor outcomes. Antipsychotics reduce hippocampal activity but may worsen hippocampal injury via oxidative stress from increased dopamine release. We recently demonstrated hippocampal volume loss at an annualized mean rate of 6.5% during the first 8 weeks of antipsychotic treatment. Levetiracetam, an anticonvulsant, normalizes excessive glutamatergic and dopaminergic neurotransmission by targeting the synaptic vesicle protein (SVP2A). Levetiracetam is neuroprotective in animal and human models of hippocampal hyperactivity. We hypothesize that levetiracetam will protect against hippocampal volume loss and improve clinical outcomes in early psychosis by reducing excessive glutamate and dopamine transmission. Approach: We will establish target engagement and dose selection by measuring the effects of levetiracetam 185 mg and 500 mg on hippocampal perfusion in a placebo-controlled trial in 24 medication- naïve individuals with first episode psychosis. We will then study the optimal levetiracetam dose added to antipsychotic in a 12-week placebo-controlled trial in 84 medication naïve individuals with first episode psychosis. We will examine whether levetiracetam prevents hippocampal volume loss and improves clinical symptoms and cognition and will explore potential mediators and modulators of effect. Significance: By correcting a fundamental dysregulation of hippocampal neurotransmission, we believe levetiracetam will improve initial treatment response in first episode psychosis and fundamentally change the course of illness.

海马CA1亚区灌注增加是早期精神病的临床生物标志物