¹University of Pisa, Department of Pathology, Pisa, Italy

Background: Current antipsychotic treatments primarily rely on dopamine D2 receptor antagonism and show limited efficacy for negative and cognitive symptoms, as well as in treatment-resistant schizophrenia. Trace amine-associated receptor 1 (TAAR1) agonists represent a promising non-dopaminergic approach with a distinct mechanism of action.

Aims & Objectives: To investigate the pharmacological and translational potential of TAAR1 agonists using preclinical models, and to evaluate their relevance for domains poorly addressed by current antipsychotics.

Method: Preclinical models integrating behavioural, neurochemical, and pharmacological approaches to assess TAAR1 agonists. These models were used to examine modulation of dopaminergic, serotonergic, and glutamatergic systems, with particular focus on dopamine synthesis and monoaminergic regulation.

Results: TAAR1 activation modulated dopamine synthesis and broader monoaminergic signalling, producing effects across behavioural paradigms relevant to psychosis, including domains related to negative and cognitive symptoms. These findings are consistent with emerging clinical data on TAAR1 agonists such as ulotaront, although Phase 3 results remain mixed.

Discussion & Conclusions: TAAR1 agonists provide a mechanistically distinct alternative to D2 antagonists, with potential advantages in tolerability and metabolic profile. Preclinical models support their relevance for symptom domains inadequately targeted by current therapies. Further clinical investigation is warranted to clarify their therapeutic role and broader applicability, including in bipolar spectrum disorders.