TAAR1 agonist ulotaront delays gastric emptying of solids in patients with schizophrenia and concurrent metabolic syndrome with prediabetes

Abstract Background 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. Methods 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 99m 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 1/2 ) and percentage gastric retention at 1, 2 and 4 h. Results Thirty‐one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T 1/2 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. Conclusion 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.