TAAR1 Regulates Presynaptic Dopamine Function: Evidence From Preclinical Studies and a Phase 1b Trial in Patients With Schizophrenia

Background Schizophrenia remains a leading cause of disability globally. Elevated striatal dopamine (DA) synthesis capacity is a hallmark of its pathophysiology, but it is unknown whether this can be reduced and whether such reductions lead to symptom improvement. TAAR1 may regulate dopaminergic function, and ulotaront (SEP-363856), a TAAR1 agonist, offers a potential novel treatment strategy. Methods We conducted combined translational preclinical and clinical tests of mechanism studies. Preclinical work involved TAAR1 knockout (KO) and wild-type (WT) mice ( N = 27), as well as ex vivo striatal brain slices. In a phase 1 open-label trial, 22 patients with symptomatic schizophrenia (mean age = 32.5 years; 72.7% male) received 14 days of adjunctive ulotaront treatment. DA synthesis capacity (Ki) was measured using [18F]-DOPA positron emission tomography in animals and humans. DA release in brain slices was assessed using fast-scan cyclic voltammetry. Results TAAR1-KO mice showed significantly higher striatal Ki than WT controls ( p < .05). Ulotaront reduced evoked DA release in brain slices after single ( p < .0005) and repeated ( p < .005) stimulation. In patients, ulotaront significantly reduced striatal Ki ( p < .01), particularly in the putamen. Reductions in Ki correlated with improvements in positive symptoms ( r = 0.5, p < .05) but not with changes in negative or total symptoms. The most common adverse events were somnolence and dizziness. Conclusions TAAR1 regulates DA synthesis and release. Adjunctive ulotaront reduces presynaptic DA function and psychotic symptoms in schizophrenia. These findings support TAAR1 as a promising target for treating antipsychotic nonresponsive schizophrenia and other dopaminergic disorders.