Biological psychiatry · 2025
TAAR1 Regulates Presynaptic Dopamine Function: Evidence From Preclinical Studies and a Phase 1b Trial in Patients With Schizophrenia.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Howes Oliver D, Vano Luke J, Petty Alice E, Rutigliano Grazia, Halff Els F, Veronese Mattia, Kaar Stephen J, Nordio Giovanna, Lopes Emanuel F, Cragg Stephanie J, Natesan Sridhar, Withers Dominic J, Rabiner Eugenii A, Wells Lisa, Dedic Nina, Milanovic Snezana, Koblan Kenneth, Hopkins Seth C, McCutcheon Robert A
Аннотация
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.
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.