Trajectory of efficacy and safety across ulotaront dose levels in schizophrenia: A systematic review and dose-response meta-analysis

Background 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. Methods 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). Results 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]). Conclusion 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.