Identifying Biological Signatures of N-acetylcysteine for Non-Suicidal Self-Injury in Adolescents

识别青少年和年轻人非自杀性自伤的N-乙酰半胱氨酸生物学特征 非自杀性自伤（NSSI）是一种没有自杀意图的故意损害自身组织的行为，是青少年和年轻人的常见问题，并与严重后果有关，包括未来的自杀企图。对这种习惯性的自我毁灭行为模式的治疗非常有限。确定新的、生物学上知情的青年NSSI治疗方法可以改善整个生命周期的健康结果。N-乙酰半胱氨酸（NAC）是一种天然产物，广泛用作非处方膳食补充剂。它也可作为口服和静脉注射（IV）处方产品，并可能有希望作为一种新的治疗NSSI的青年。在第一项此类研究中，我们的开放标签研究显示，口服NAC 8周后，13-21岁女性青少年的NSSI频率降低（p=0.02）。在准备确定的NAC临床试验时，关键的初步步骤是澄清NAC的生物学特征，或其临床效应的机制的措施，这将为优化疗效试验的生物学设计提供基础。该提案将研究NAC行为效应的可能生物学特征：（1）增加谷胱甘肽（GSH），大脑中的主要抗氧化剂;和/或（2）调节谷氨酸（Glu）-半胱氨酸反向转运蛋白，有效减少过量Glu传输。这两种机制都可以减轻青少年NSSI的应激诱导的神经毒性，但这两种机制都没有在NSSI中进行评估。NAC生物特征的确认具有挑战性，因为其复杂的药代动力学（PK），造成与最佳剂量相关的不确定性。口服NAC主要用于精神病学研究，因为它易于使用，但生物利用度低（5-10%）。测试NAC心理健康适应症的研究通常不会将临床测试与PK或生物特征测试配对。为了解决知识差距和推进NAC作为青少年NSSI治疗的发展，我们提出了一个R61/R33项目，以调查NAC的生物特征（GSH和/或Glu的变化）与NSSI的年轻女性。R61将专注于确定在短期NAC治疗期间实现GSH和Glu有意义变化的最佳剂量。我们将36名年龄在16-24岁之间的女性青少年和年轻成年人随机分配至4周的口服NAC（每天3600 mg或5400 mg）或安慰剂治疗组。进入R33的Go/NoGo标准为：如果发生以下任一情况，则为“Go”：（a）血液GSH氧化还原比增加≥ 50%;（B）脑GSH浓度增加5%;（c）脑Glu浓度降低5%。将根据R61中观察到的生物学变化和耐受性选择R33的剂量。R33阶段将试图在一项为期8周的试验中使用新样本的长期给药复制生物特征结果，并检查生物特征、NAC PK和临床应答之间的关系。

Identifying Biological Signatures of N-Acetylcysteine for Non-Suicidal Self-Injury in Adolescents and Young Adults Non-suicidal self-injury (NSSI), the deliberate act of damaging one’s own tissues without suicidal intent, is a common problem in adolescents and young adults, and is associated with severe consequences including future suicide attempts. Treatments for this habitual, self-destructive behavior pattern are sorely limited. Identification of novel, biologically-informed treatments for NSSI in youth could improve health outcomes over the lifespan. N-acetylcysteine (NAC) is a natural product that is widely-available as an over-the-counter dietary supplement. It is also available as oral and intravenous (IV) prescription products, and may have promise as a novel treatment for NSSI in youth. In the first study of its kind, our open-label study showed reduced NSSI frequency (p=0.02) in female adolescents aged 13-21 after 8 weeks of oral NAC. In preparation for a definitive clinical NAC trial, a critical preliminary step is to clarify NAC’s biological signatures, or measures of the mechanisms underlying its clinical effects, which would provide the basis for biologically-informed design of optimized efficacy trials. This proposal will investigate possible biological signatures for NAC’s behavioral effects: (1) increased glutathione (GSH), the primary antioxidant in the brain; and/or (2) modulation of the glutamate (Glu)-cysteine antiporter, effectively decreasing excessive Glu transmission. Both of these mechanisms could alleviate stress-induced neurotoxicities in adolescents with NSSI, but neither mechanism has been evaluated in NSSI. Confirmation of NAC biological signatures is challenging due its complex pharmacokinetics (PK), posing uncertainty related to optimal dose. Oral NAC is primarily used in psychiatric studies because of its ease of use, but has low bioavailability (5-10%). Studies testing NAC for mental health indications have generally not paired clinical testing with PK or biological signature testing. To address knowledge gaps and advance development of NAC as a treatment for adolescent NSSI, we propose an R61/R33 project to investigate NAC’s biological signatures (changes in GSH and/or Glu) in young women with NSSI. The R61 will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term NAC treatment. We will randomize 36 female adolescents and young adults aged 16-24 years with NSSI to 4 weeks of treatment with either oral NAC (3600mg or 5400mg per day) or to placebo. Go/NoGo criteria for advancing to R33 will be: “Go” if any one of the following occurs: (a) ≥ 50% increase in blood GSH redox ratio; (b) 5% increase in brain GSH concentrations; (c) 5% decrease in brain Glu concentrations. Dose and for the R33 will be selected based on the biological changes and the tolerability observed in the R61. The R33 phase will seek to replicate the biological signature findings in an 8-week trial using chronic dosing in a new sample, and examine the relationships among biological signatures, NAC PK, and clinical response.