Levetiracetamin in First Episode Psychosis

海马CA 1区灌注增加是早期精神病的临床生物标志物， 预测海马体积的损失。越来越多的证据表明，CA 1高灌注反映了过度的 海马能传递，驱动精神病，并可能产生兴奋毒性海马损伤， 与不良结果相关。抗精神病药物降低海马活性，但可能使海马 通过增加多巴胺释放的氧化应激损伤。我们最近证明了海马体积 在抗精神病药物治疗的前8周内，年平均损失率为6.5%。左乙拉西坦， 抗惊厥药，通过靶向 突触囊泡蛋白（SVP 2A）。左乙拉西坦在动物和人类模型中具有神经保护作用。 海马过度活跃我们假设左乙拉西坦可以防止海马体积的损失 并通过减少过量的谷氨酸和多巴胺来改善早期精神病的临床结果 传输方法：我们将通过测量以下因素的影响来确定靶点参与和剂量选择： 左乙拉西坦185 mg和500 mg对海马灌注的影响：一项安慰剂对照试验，24种药物- 首次精神病发作的天真个体。然后，我们将研究最佳左乙拉西坦剂量添加到 在84名首次发作的药物初治患者中进行的12周安慰剂对照试验中的抗精神病药 精神病我们将研究左乙拉西坦是否可以防止海马体积的损失，并改善临床症状。 症状和认知，并将探讨潜在的介质和调节剂的影响。意义： 纠正海马神经传递的基本失调，我们相信左乙拉西坦将 改善首次发作精神病的初始治疗反应，并从根本上改变疾病的进程。

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.