Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

Abstract

All antipsychotics currently used in clinic block D2 dopamine receptors. Trace amine-associated receptor 1 is emerging as a new therapeutic target for schizophrenia and several other neuropsychiatric disorders. SEP-363856 (International Nonproprietary Name: Ulotaront) is an investigational antipsychotic drug with a novel mechanism of action that does not involve antagonism of dopamine D2 receptors. Ulotaront is an agonist of trace amine-associated receptor 1 and serotonin 5-HT1A receptors, but can modulate dopamine neurotransmission indirectly. In 2019, the United States Food and Drug Administration granted Breakthrough Therapy Designation for ulotaront for the treatment of schizophrenia. Phase 2 clinical studies indicated that ulotaront can reduce both positive and negative symptoms of schizophrenia without causing the extrapyramidal or metabolic side effects that are inherent to most currently used antipsychotics. At present, it is in phase 3 clinical development for the treatment of schizophrenia and is expected to be introduced into clinical practice in 2023–2024. Clinical studies evaluating the potential efficacy of ulotaront in Parkinson’s disease psychosis, generalized anxiety disorder, and major depressive disorder have also been started. The aim of this scoping review is to summarize all currently available preclinical and clinical evidence on the utility of ulotaront in the treatment of schizophrenia. Here, we show the main characteristics and distinctive features of this drug. Perspectives and limitations on the potential use of ulotaront in the pharmacotherapy of several other neuropsychiatric disorders are also discussed.

Calneuron 1 reveals the pivotal roles in schizophrenia via perturbing human forebrain development and causing hallucination-like behavior in mice

“…Moreover, the frequencies of these unusual spontaneous startle behavior and headtwitch behavior significantly reduce in 3 hours after treatment with SEP-363856, an investigational antipsychotic drug (N=7, Figure 7q, r) 33 . In summary, these findings verified that Caln1 -/mice appear schizophrenia behaviors including the defects of spatial memory, cognition, social ability and pre-pulse inhibition, as well as unusual spontaneous startle behavior and head-twitch response similar to hallucination in human, which could be treated by antipsychotic drug SEP-363856 (Figure S11).…”

TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

“…The best known and most frequently studied of those, TAAR1, is already being actively investigated in the aspect of mental and neuropsychiatric disorders [ 75 ]. The ability of TAAR1 to regulate DA and 5-HT as well as glutamatergic neurotransmission formed the basis of this interest [ 55 ].…”

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

“…Trace amine-associated receptor 1 (TAAR1) is a member of the G-protein-coupled receptor (GPCR) TAAR family enriched in the central nervous system and periphery, which could couple to diverse G protein subtypes (G s , G q , and G i1 ) by recognizing a spectrum of different endogenous amine-containing hormones and metabolites (EAHs and EAMs) and has been confirmed to be associated with cognition, mood, antidepressant, and schizophrenia treatment. − SEP-363856 was identified as a TAAR1-G s pathway agonist with beneficial effects in MK-801-induced schizophrenia-like rodent models via high-throughput phenotypic behavioral screening . Notably, SEP-363856 did not cause the cognitive impairment and other serious side effects associated with current antipsychotics targeting the D2R or 5-HT2AR. ,− In 2019, SEP-363856 was granted a breakthrough therapy designation for the treatment of schizophrenia with significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score in clinical trials by the U.S. Food and Drug Administration (FDA). Unfortunately, the once-daily dose of SEP-363856 in acutely psychotic adults living with schizophrenia did not meet the primary end point in two therapeutic effect experiments of phase III.…”