N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Åsberg Depression Rating Scale (MADRS) and were dichotomised into “responders” (MADRS at week 16 < 50% of MADRS at baseline) and “non-responders” (MADRS at week 16 > 50% at baseline). Untargeted gas chromatography–mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R² = 0.853; adjusted R² = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.

N-乙酰半胱氨酸 (NAC) 作用于谷氨酸能和氧化还原系统，这两个系统与双相情感障碍 (BD) 的病理生理学有关。这导致了 NAC 作为治疗 BD 的潜在候选药物的研究。本研究的目的是调查代谢组学标志物，以确定一组 BD 参与者中 NAC 反应的预测因子。这项研究是对 16 周、多地点、随机、双盲、平行组、安慰剂对照试验的二次分析，该试验在患有当前急性抑郁发作的 BD 参与者中进行。这项研究包括接受 NAC 2000 毫克/天或安慰剂的试验参与者。参与者（NAC：n  = 31，安慰剂：n = 29) 在基线和第 16 周使用蒙哥马利 Åsberg 抑郁评定量表 (MADRS) 进行评估，并分为“响应者”（第 16 周的 MADRS < 基线时 MADRS 的 50%）和“无响应者”（第 1 周的 MADRS） 16 > 50% 在基线）。进行非靶向气相色谱-质谱分析以分析 68 种血清代谢物的基线水平。在区分安慰剂组和 NAC 组的 9 种代谢物中，与 NAC 无反应者相比，NAC 反应者组中有 5 种是水平较低的氨基酸。进一步分析生成了 MADRS 改善的预测模型，包括甘氨酸、正亮氨酸、苏氨酸、脯氨酸、苯丙氨酸、酪氨酸、谷氨酸、赖氨酸和亮氨酸（R ²  = 0.853；调整后的 R ² = 0.733）。该预测模型预测了 NAC 辅助治疗后 MADRS 结果中 85% 的差异。基线时血清游离氨基酸水平较低的 BD 参与者可能更有可能对 NAC 的辅助治疗做出反应。