Trace Amine-Associated Receptors (TAARs) as Emerging Targets in Neuropsychiatric Disorders

Abstract

Trace amines (TAs) are endogenous biogenic amines present at low concentrations in the brain and were historically considered byproducts of monoamine metabolism. The discovery of trace amine-associated receptors (TAARs), a family of G protein-coupled receptors, has redefined their physiological and pharmacological relevance. TAAR1 regulates dopaminergic, serotonergic, and glutamatergic signaling and is increasingly implicated in neuropsychiatric disorders. Preclinical studies show that TAAR1 agonists normalize dopaminergic function and improve cognitive deficits in schizophrenia models. Early clinical evidence suggests potential antipsychotic efficacy with a favorable extrapyramidal and metabolic safety profile. However, the failure of subsequent phase III trials to meet their primary efficacy endpoints highlights the need to identify responsive patient subgroups, optimize trial design, and clarify the clinical settings in which TAAR1 agonism may provide the greatest therapeutic benefit. In depression, TAAR1 activation produces antidepressant-like effects in preclinical models, whereas findings in anxiety are variable and context-dependent. TAAR1 may also modulate reward-driven feeding and metabolic parameters. Mechanistically, TAAR1 agonists differ in their effects on dopamine transporter function and monoaminergic neuron activity, indicating that their pharmacological effects are compound-specific rather than class-wide. These properties distinguish TAAR1-targeting compounds from classical D2 receptor antagonists and may underlie their clinical profile. Further translational studies are required to confirm their efficacy across symptom domains and establish long-term clinical benefit.