Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials

Le, Gia Han; Gillissie, Emily S.; Rhee, Taeho Greg; Cao, Bing; Alnefeesi, Yazen; Guo, Ziji; Vincenzo, Joshua D. Di; Jawad, Muhammad Youshay; March, Andrew M; Ramachandra, Ranuk; Lui, Leanna M.W.; McIntyre, Roger S.

doi:10.1080/13543784.2023.2206559

Cited by 11 publications

(7 citation statements)

References 73 publications

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“…Nonetheless, the hTA1/5-HT1AR agonist ulotaront (SEP-363856) 13 has received FDA Breakthrough status. The compound showed promising results in recent Phase 2 trials for Parkinson’s disease psychosis 14 , as well as the treatment of schizophrenia 15 , supporting the notion that hTA1 may be a tractable therapeutic target 16 . While ulotaront has failed to meet primary endpoints in two recent Phase 3 trials for schizophrenia 17 , 18 , additional Phase 2/3 trials are scheduled to test its efficacy in the treatment of anxiety and depression 19 , 20 .…”

Section: Introductionmentioning

confidence: 78%

Molecular basis of human trace amine-associated receptor 1 activation

Zilberg,

Parpounas,

Warren

et al. 2024

Nat Commun

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The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1’s mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic orthologue, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologues, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.

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Section: Introductionmentioning

confidence: 78%

Molecular basis of human trace amine-associated receptor 1 activation

Zilberg,

Parpounas,

Warren

et al. 2024

Nat Commun

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“…We will also search in registries of preclinical animal studies (e.g., animalstudyregistry.org , preclinicaltrials.eu ) and clinical studies (e.g., clinicaltrials.gov and WHO-ICTRP ) and inspect the references lists of eligible studies and previous reviews 8 , 11 , 15 .…”

Section: Methods Of Living Systematic Reviewsmentioning

confidence: 99%

“…There are also several important unanswered questions, such as the precise mechanism of action (e.g., including the role of serotonin and the interplay between presynaptic and postsynaptic mechanisms), the effects of TAAR1 agonists on negative symptoms and cognitive impairment, and the evaluation of long-term efficacy and side-effects 11 . Therefore, we plan a living systematic review and meta-analysis, which goes beyond the scope of previous reviews that were primarily narrative, qualitative, static, or focused on a limited range of molecules (e.g., ulotaront) 8 , 11 , 15 . Such an analysis would provide a multifaceted synthesis of the available evidence, incorporating the latest studies in this rapidly evolving field.…”

Section: Introductionmentioning

confidence: 99%

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

Siafis,

McCutcheon,

Chiocchia

et al. 2023

Wellcome Open Res

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Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. Methods: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.

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“…Race, age, gender, drug formulation, or clinical status (healthy volunteer versus patient with schizophrenia) did not significantly impact the ulotaront pharmacokinetics. A recent systematic review [ 96 ] evaluated the available data on the safety, efficacy, and tolerability of ulotaront as a treatment for schizophrenia and suggested that it is a potentially effective antipsychotic agent with a good safety profile.…”

Section: New Agents For the Treatment Of Schizophreniamentioning

confidence: 99%

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

Tsapakis,

Diakaki,

Miliaras

et al. 2023

Brain Sciences

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Schizophrenia is a chronic neuropsychiatric syndrome that significantly impacts daily function and quality of life. All of the available guidelines suggest a combined treatment approach with pharmacologic agents and psychological interventions. However, one in three patients is a non-responder, the effect on negative and cognitive symptoms is limited, and many drug-related adverse effects complicate clinical management. As a result, discovering novel drugs for schizophrenia presents a significant challenge for psychopharmacology. This selective review of the literature aims to outline the current knowledge on the aetiopathogenesis of schizophrenia and to present the recently approved and newly discovered pharmacological substances in treating schizophrenia. We discuss ten novel drugs, three of which have been approved by the FDA (Olanzapine/Samidorphan, Lumateperone, and Pimavanserin). The rest are under clinical trial investigation (Brilaroxazine, Xanomeline/Trospium, Emraclidine, Ulotaront, Sodium Benzoate, Luvadaxistat, and Iclepertin). However, additional basic and clinical research is required not only to improve our understanding of the neurobiology and the potential novel targets in the treatment of schizophrenia, but also to establish more effective therapeutical interventions for the syndrome, including the attenuation of negative and cognitive symptoms and avoiding dopamine blockade-related adverse effects.

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Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials

Cited by 11 publications

References 73 publications

Molecular basis of human trace amine-associated receptor 1 activation

Molecular basis of human trace amine-associated receptor 1 activation

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

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