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 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. Trace amine-associated receptor 1 (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 test of mechanism studies. Preclinical work involved TAAR1 knockout (KO) and wild-type mice (n = 27), as well as ex vivo striatal brain slices. In a phase I open-label trial, 22 patients with symptomatic schizophrenia (mean age=32.5 years; 72.7% male) received 14 days of adjunctive ulotaront treatment. Dopamine synthesis capacity (K i ) was measured using [18F]-DOPA PET in animals and humans. Dopamine release in brain slices was assessed using fast-scan cyclic voltammetry. Results TAAR1-KO mice showed significantly higher striatal K i than wild-type controls (p < 0.05). Ulotaront reduced evoked dopamine release in brain slices after single (p < 0.0005) and repeated (p < 0.005) stimulation. In patients, ulotaront significantly reduced striatal K i (p < 0.01), particularly in the putamen. Reductions in K i correlated with improvements in positive symptoms (r = 0.5, p < 0.05), but not with changes in negative or total symptoms. The most common adverse events were somnolence and dizziness. Conclusions TAAR1 regulates dopamine synthesis and release. Adjunctive ulotaront reduces presynaptic dopamine function and psychotic symptoms in schizophrenia. These findings support TAAR1 as a promising target for treating antipsychotic non-responsive schizophrenia and other dopaminergic disorders.