Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada.
Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada.
J Affect Disord. 2024 Oct 1;362:816-827. doi: 10.1016/j.jad.2024.07.030. Epub 2024 Jul 15.
Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD.
We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included.
Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns.
Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available.
Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms.
大约 30%的重性抑郁障碍（MDD）患者对常规抗抑郁药反应不足。κ阿片受体（KOR）拮抗剂aticaprant 和 navacaprant 正在开发中，作为 MDD 的治疗方法。在此，我们旨在全面评估 aticaprant 和 navacaprant 治疗 MDD 的安全性、疗效和药理学。
我们对 PubMed、OVID 和 Scopus 数据库中从成立到 2024 年 4 月的关于 aticaprant 和 navacaprant 的原始研究进行了系统评价。纳入报告 aticaprant 和 navacaprant 的药理学特征和/或安全性和疗效的研究。
navacaprant 单药治疗和 aticaprant 辅助治疗正在开发中，用于治疗 MDD。navacaprant 对 KOR 的选择性比μ阿片受体高 300 倍，而 aticaprant 的选择性高 30 倍。在临床相关剂量下，navacaprant 和 aticaprant 分别占据 KOR 的 87-95%和 73-94%。上述药物的临床试验（navacaprant 单药治疗和 actiprant 辅助治疗）报告了抑郁症状的显著改善，并且可能对快感缺失的临床指标有临床益处。两种药物均耐受良好，大多数不良事件轻微，无已知的安全性问题。
aticaprant 和 navacaprant 治疗 MDD 处于临床试验的早期阶段，目前还没有 3 期关键试验的结果。
κ阿片受体拮抗剂可能作为 MDD 的机制新颖的治疗方法，对常规抗抑郁药反应不足的患者有效。快感缺失是致残的，用常规抗抑郁药治疗效果不佳。未来的研究应在急性和维持期研究中，在 3 期研究中确定 KORAs 的疗效和安全性。
