Højlund Mikkel, Correll Christoph U
Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Department of Psychiatry Aabenraa, Mental Health Services Region of Southern Denmark, Aabenraa, Denmark.
Expert Opin Investig Drugs. 2022 Dec;31(12):1279-1290. doi: 10.1080/13543784.2022.2158811. Epub 2022 Dec 22.
Current antipsychotics are postsynaptic dopamine-2(D) receptor blockers, which often, but not always, effectively improve acute psychotic symptoms and prevent relapse in schizophrenia and other severe mental disorders, but are associated with various side effects, including parkinsonism, akathisia, sedation/somnolence, and cardiometabolic alterations. Furthermore, the efficacy of current antipsychotics for negative and cognitive symptoms in schizophrenia is limited. Ulotaront is a novel trace-amine-associated receptor-1(TAAR1) agonist with serotonin-1A receptor agonist activity, and without postsynaptic D2-receptor antagonism. Phase 2 clinical data for ulotaront in patients with acutely exacerbated schizophrenia are promising regarding the potential improvement in positive, negative, and depressive symptoms.
An overview of the pharmacokinetic and pharmacodynamic properties of ulotaront is given. Summary of clinical efficacy and safety/tolerability from Phase 1/2-trials, and of ongoing Phase 3-trials, is also given.
Ulotaront is a promising agent for the treatment of schizophrenia with an apparent benign safety profile, which might provide a much-needed new and different treatment option for various domains of schizophrenia. Data from larger Phase 3-trials, including for relapse prevention, schizophrenia subdomains, and in adolescents, are awaited. If ongoing Phase 3-trials in adults are successful, further research on combination regimens with existing antipsychotics, and in treatment-resistant schizophrenia as well as in mood disorders would be desirable.
目前的抗精神病药物是突触后多巴胺-2（D）受体阻滞剂，它们通常（但并非总是）能有效改善急性精神病性症状，并预防精神分裂症和其他严重精神障碍的复发，但会伴有各种副作用，包括帕金森综合征、静坐不能、镇静/嗜睡以及心脏代谢改变。此外，目前的抗精神病药物对精神分裂症阴性和认知症状的疗效有限。乌洛托品是一种新型的与痕量胺相关受体-1（TAAR1）激动剂，具有5-羟色胺-1A受体激动剂活性，且无突触后D2受体拮抗作用。在急性加重的精神分裂症患者中，乌洛托品的2期临床数据显示，其在改善阳性、阴性和抑郁症状方面具有潜在前景。
本文概述了乌洛托品的药代动力学和药效学特性。还总结了1/2期试验以及正在进行的3期试验的临床疗效和安全性/耐受性。
乌洛托品是一种有前景的治疗精神分裂症的药物，其安全性明显良好，可能为精神分裂症的各个方面提供急需的全新治疗选择。我们期待来自更大规模3期试验的数据，包括预防复发、精神分裂症亚领域以及青少年患者的数据。如果正在进行的成人3期试验取得成功，那么进一步研究其与现有抗精神病药物的联合治疗方案，以及在难治性精神分裂症和情绪障碍中的应用将是很有必要的。
