A double-blind study on ulotaront's impact on weight-related parameters in schizophrenia patients with metabolic syndrome and prediabetes: Part II.

AIMS: Antipsychotics increase metabolic syndrome (MetSyn) and diabetes risk. Preclinical and translational research data suggest that ulotaront, an investigational trace amine-associated receptor 1 (TAAR1) agonist, may have beneficial metabolic effects. This Phase 1b study collected pilot data on 4-week ulotaront exposure and weight-associated metabolic markers. MATERIALS AND METHODS: A double-blind, randomised, multiple-dose within subject trial compared ulotaront to continued prior antipsychotic (PA) on metabolic markers in schizophrenia patients at high diabetes risk (presence of MetSyn and prediabetes). Metabolic characteristics of patients at check-in were compared to a matched historical cohort without schizophrenia or antipsychotic exposure. RESULTS: When compared to PA, ulotaront treatment showed improvement trends for high glucose clamp, low glucose clamp, liver fat, liver fibro-inflammation, back muscle fat infiltration, pancreas fat and pancreas volume. Visceral adipose tissue and weight changes favoured ulotaront treatment (p < 0.001, p = 0.047). Liver fibro-inflammation distinguished antipsychotic-induced metabolic changes from the historical cohort (p = 0.002). CONCLUSIONS: Despite the sample size constraints due to early study termination, all key endpoint trends and statistically significant differences favoured ulotaront over previous antipsychotics, lending support that ulotaront may improve antipsychotic-induced weight-associated markers. Liver fibro-inflammation may serve as a potential marker for antipsychotic-induced MetSyn and prediabetes, and possible treatment target. Further research is needed to build on these findings.