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.