Hsu Yu-Chia, Hung Tzu-Yen, Chen Yang-Chieh Brian, Hung Kuo-Chuan, Liang Chih-Sung, Tseng Ping-Tao, Tu Yu-Kang, Correll Christoph U, Hsu Chih-Wei, Solmi Marco
Department of Medical Education, National Cheng Kung University Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Int J Neuropsychopharmacol. 2025 Sep 1;28(9). doi: 10.1093/ijnp/pyaf059.
Ulotaront is an experimental antipsychotic for schizophrenia, but its optimal dose is unclear. This study aimed to evaluate dose-response relationships for efficacy and safety in people with schizophrenia.
A systematic review of four databases (until January 22, 2025; INPLASY202510091) identified randomized clinical trials assessing ulotaront. Outcomes included efficacy, measured by changes in the Positive and Negative Syndrome Scale (PANSS) total score (primary outcome), positive and negative subdomains, and the Clinical Global Impression Scale-Severity, and safety, assessed by all-cause dropout (co-primary outcome, dropout due to adverse event, serious, non-serious, and specific adverse events). We employed one-stage dose-response meta-analysis (random-effects model) calculating standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs).
Analysis of three randomized clinical trials (n = 1144) indicated that the 100 mg dose of ulotaront provided the greatest improvement in PANSS total score (standardized mean difference = -0.23 [95% CI: -0.43, -0.02]), PANSS positive symptom score (-0.30 [-0.70, 0.10]), and PANSS negative symptom score (-0.28 [-0.48, -0.08]). However, Clinical Global Impression Scale-Severity scores did not exhibit a clear dose-response relationship. Regarding safety, all-cause dropout (RR at 100 mg = 1.10 [95% CI: 0.57, 2.12]), adverse event-related dropout, serious, non-serious, and most specific adverse events showed no significant dose-response relationship. The risk of anxiety-related adverse events was significantly higher than placebo at 50 and 75 mg doses (RR at 75 mg = 2.06 [95% CI: 1.11, 3.80]).
Ulotaront 100 mg appears greatest efficacy with favorable safety for acute schizophrenia. However, effect sizes were small, and higher ulotaront doses should be tested. Significance Statement Ulotaront is a new medication being tested for treating schizophrenia. Unlike most existing antipsychotic drugs that block dopamine receptors in the brain, ulotaront works through a different mechanism by activating trace amine-associated receptor 1 and serotonin 1A receptors. These novel targets may help reduce both hallucinations and negative symptoms like social withdrawal and lack of motivation, with fewer side effects. In this study, we analyzed data from several clinical trials to understand how different doses of ulotaront affect patients. We found that higher doses-especially around 100 mg-can improve schizophrenia symptoms without increasing safety concerns. These findings are important because they suggest that ulotaront may offer a new and safer treatment option for people with schizophrenia, and they help guide doctors toward the most effective dose.
乌洛托品是一种用于治疗精神分裂症的实验性抗精神病药物，但其最佳剂量尚不清楚。本研究旨在评估精神分裂症患者中疗效和安全性的剂量反应关系。
对四个数据库进行系统综述（截至2025年1月22日；INPLASY202510091），确定评估乌洛托品的随机临床试验。结局包括疗效，通过阳性和阴性症状量表（PANSS）总分变化（主要结局）、阳性和阴性子域以及临床总体印象量表-严重程度来衡量，以及安全性，通过全因脱落（共同主要结局，因不良事件、严重、非严重和特定不良事件导致的脱落）进行评估。我们采用单阶段剂量反应荟萃分析（随机效应模型）计算标准化均数差（SMD）和风险比（RR）以及95%置信区间（CI）。
对三项随机临床试验（n = 1144）的分析表明，100 mg剂量的乌洛托品在PANSS总分（标准化均数差 = -0.23 [95% CI：-0.43，-0.02]）、PANSS阳性症状评分（-0.30 [-0.70，0.10]）和PANSS阴性症状评分（-0.28 [-0.48，-0.08]）方面提供了最大程度的改善。然而，临床总体印象量表-严重程度评分未呈现明确的剂量反应关系。关于安全性，全因脱落（100 mg时的RR = 1.10 [95% CI：0.57，2.12]）、不良事件相关脱落、严重、非严重和大多数特定不良事件均未显示出显著的剂量反应关系。在50和75 mg剂量下，与焦虑相关的不良事件风险显著高于安慰剂（75 mg时的RR = 2.06 [95% CI：1.11，3.80]）。
100 mg的乌洛托品对急性精神分裂症似乎疗效最佳且安全性良好。然而，效应量较小，应测试更高剂量的乌洛托品。意义声明乌洛托品是一种正在测试用于治疗精神分裂症的新药。与大多数现有的阻断大脑中多巴胺受体的抗精神病药物不同，乌洛托品通过激活痕量胺相关受体1和5-羟色胺1A受体以不同的机制发挥作用。这些新靶点可能有助于减少幻觉以及诸如社交退缩和缺乏动力等阴性症状，且副作用较少。在本研究中，我们分析了多项临床试验的数据以了解不同剂量的乌洛托品如何影响患者。我们发现更高剂量——尤其是约100 mg——可改善精神分裂症症状而不增加安全担忧。这些发现很重要，因为它们表明乌洛托品可能为精神分裂症患者提供一种新的更安全的治疗选择，并且有助于指导医生选择最有效的剂量。
