Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia

Eur Arch Psychiatry Clin Neurosci. 2023 Oct;273(7):1543-1556. doi: 10.1007/s00406-023-01580-3. Epub 2023 May 10.


Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist in Phase 3 clinical development for the treatment of schizophrenia. Ulotaront was discovered through a unique, target-agnostic approach optimized to identify drug candidates lacking D2 and 5-HT2A receptor antagonism, while demonstrating an antipsychotic-like phenotypic profile in vivo. The mechanism of action (MOA) of ulotaront is thought to be mediated by agonism at TAAR1 and serotonin 5-HT1A receptors. Ulotaront has completed two Phase 2 trials (4-week acute study and 26-week open-label extension) which led to Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of schizophrenia. In the double-blind, placebo-controlled, acute study, ulotaront was associated with significant (p < 0.001) improvement in Positive and Negative Syndrome Scale (PANSS) total score (effect size [ES]: 0.45), with improvements vs. placebo also observed across secondary endpoints. Post-hoc analyses of the acute trial revealed additional evidence to support the effect of ulotaront on negative symptoms. In the 4-week study, ulotaront was well-tolerated, with an incidence of adverse events (AEs) numerically lower compared to placebo (45.8% vs. 50.4%; with a number needed to harm [NNH] for individual ulotaront AEs all > 40). The open-label extension demonstrated further improvement across schizophrenia symptoms and confirmed the tolerability of ulotaront, with a 6-month completion rate of 67%. Based on current data, ulotaront shows potential to be a first-in-class TAAR1 agonist for the treatment of schizophrenia with a safety and efficacy profile distinct from current antipsychotics.

Keywords: Schizophrenia; Serotonin 5-HT1A; Trace amine-associated receptor 1.

Publication types

  • Review

MeSH terms

  • Antipsychotic Agents* / adverse effects
  • Humans
  • Randomized Controlled Trials as Topic
  • Schizophrenia* / diagnosis
  • Treatment Outcome
  • United States


  • Trace amine-associated receptor 1
  • SEP-363856
  • Antipsychotic Agents