The trace amine-associated receptor 1 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 (Ki) 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 Ki 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 Ki (p < 0.01), particularly in the putamen. Reductions in Ki 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.