Sumitomo Pharma America, Inc., Marlborough, Massachusetts, USA.
Mayo Clinic, Rochester, Minnesota, USA.
Diabetes Obes Metab. 2024 Jun;26(6):2466-2475. doi: 10.1111/dom.15569. Epub 2024 Mar 27.
Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes.
Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a Tc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T) and percentage gastric retention at 1, 2 and 4 h.
Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal.
Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.
代谢综合征（MetS）可由当前的抗精神病药物诱发或加重，在精神分裂症患者中极为普遍，对患者终生疾病管理提出了重大挑战。受初步临床结果的支持，痕量胺相关受体 1（TAAR1）激动剂已成为治疗精神分裂症的潜在新疗法。值得注意的是，非临床研究还表明 TAAR1 激动剂具有降低体重和调节血糖的作用，包括研究药物 ulotaront。然而，这些发现对人类的转化作用尚未得到充分评估。鉴于胃排空延迟（GE）被确定为 TAAR1 激动剂在啮齿动物中发挥代谢益处的潜在机制，本研究旨在评估 ulotaront 对伴有前驱糖尿病的代谢综合征的精神分裂症患者的 GE 的影响。
精神分裂症患者以开放标签、交叉、两序列设计（NCT05402111）随机接受单口服剂量的 ulotaront（150mg）和先前的抗精神病药物（PA）。符合条件的参与者至少符合五个代谢综合征标准中的三个标准，且糖化血红蛋白（5.7-6.4%）和/或空腹稳态模型评估的胰岛素抵抗升高（即≥2.22）定义为前驱糖尿病。禁食过夜和给药后 4 小时后，参与者摄入 Tc-硫胶体放射性标记的鸡蛋餐（320 卡路里，30%脂肪）。通过闪烁扫描术在 4 小时内测量 GE。终点包括固体半时 GE（T）和 1、2 和 4 小时时的胃潴留百分比。
31 名成年人被随机分配，27 名完成了研究。与参与者的 PA 相比，ulotaront 显著延迟了固体 GE [ulotaront 固体 GE T 的中位数为 139 分钟（119，182），而 124 分钟（109，132），p=0.006]。与 PA 组相比，ulotaront 组在 1 小时（80%对 75%，p=0.015）、2 小时（61%对 50%，p=0.023）和 4 小时（17%对 7%，p=0.002）时胃潴留显著增加。
ulotaront 延迟了伴有前驱糖尿病的精神分裂症患者的固体 GE。需要进一步研究以评估 TAAR1 激动剂治疗是否与体重减轻和血糖调节改善相关。
