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

鉴定N-乙酰半胱氨酸在青少年和青壮年非自杀性自我伤害中的生物学特征 非自杀性自我伤害(NSSI)是一种故意破坏自己组织而没有自杀意图的行为，是青少年和年轻人的常见问题，并与包括未来自杀企图在内的严重后果有关。对这种习惯性的、自我毁灭的行为模式的治疗是极其有限的。确定新的、基于生物信息的治疗青年NSSI的方法可以改善一生中的健康结果。N-乙酰半胱氨酸(NAC)是一种天然产品，广泛用作非处方膳食补充剂。它还可以作为口服和静脉(IV)处方药使用，并有望成为治疗青年NSSI的一种新疗法。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岁的女性青少年NSSI频率降低(p=0.02)。为了准备一项最终的NAC临床试验，关键的初步步骤是澄清NAC的生物学特征，或其临床效果潜在机制的测量，这将为优化疗效试验的生物知情设计提供基础。这项建议将研究NAC行为效应的可能生物学特征：(1)增加大脑中主要抗氧化剂谷胱甘肽(GSH)；和/或(2)调节谷氨酸(Glu)-半胱氨酸逆向转运体，有效地减少过度的Glu传递。这两种机制都可以减轻患有NSSI的青少年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生物学特征的确认具有挑战性，因为其复杂的药代动力学(PK)，存在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，但生物利用度较低(5-10%)。测试NAC精神健康指征的研究通常没有将临床测试与PK或生物特征测试配对。为了解决知识空白和促进NAC作为青少年NSSI治疗方法的发展，我们提出了一个R61/R33项目，以调查NAC在NSSI年轻女性中的生物学特征(GSH和/或Glu的变化)。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名患有NSSI的女性青少年和16-24岁的年轻成年人随机分为4周，分别服用口服NAC(每天3600 mg或5400 mg)或安慰剂。进入R33的GO/NOGO标准将是：如果发生以下任何一种情况：(A)血中谷胱甘肽氧化还原比率增加50%；(B)脑内≥浓度增加5%；(C)脑内谷氨酸浓度下降5%。R33的剂量和剂量将根据R61中观察到的生物学变化和耐受性来选择。R33阶段将寻求在一项为期8周的试验中复制生物学特征发现，使用新样本中的慢性剂量，并检查生物特征、NAC PK和临床反应之间的关系。

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.