Levetiracetamin in First Episode Psychosis

海马区CA1区灌注量增加是早期精神病的临床生物标志物 预示着海马体体积的减少。越来越多的证据表明，CA1过度灌注反映了过度 谷氨酸能传递导致精神病，并可能产生兴奋性毒性海马区损伤，即 与糟糕的结果相关。抗精神病药物降低了海马区的活动，但可能会恶化海马区 由于多巴胺释放增加而造成的氧化应激损伤。我们最近展示了海马体的体积 在抗精神病药物治疗的前8周，年平均丢失率为6.5%。左乙拉西坦，一种 抗惊厥药，通过靶向谷氨酸和多巴胺能神经传递来正常化过度的谷氨酸和多巴胺能神经传递 突触囊泡蛋白(SVP2A)。左乙拉西坦在动物和人类模型中具有神经保护作用 海马区过度活跃。我们假设左乙拉西坦可以保护海马区的体积减少。 并通过减少过量的谷氨酸和多巴胺改善早期精神病的临床结果 变速箱。方法：我们将通过测量以下因素的影响来确定靶点接触和剂量选择 左乙拉西坦185 mg和500 mg对24种药物的安慰剂对照试验中对海马区血流的影响 患有首发精神病的天真的人。然后我们将研究左乙拉西坦的最佳剂量 84例首发用药幼稚患者的12周安慰剂对照试验中的抗精神病药物 精神错乱。我们将研究左乙拉西坦是否能防止海马体体积减少并改善临床。 症状和认知，并将探索潜在的中介和调节效应。重要意义：由 纠正海马神经传递的根本失调，我们相信左乙拉西坦将 改善首发精神病患者的初始治疗反应，从根本上改变病程。

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.