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

ABSTRACT

Introduction

Schizophrenia is a mental illness that can disrupt emotions, perceptions, and cognition and reduce quality of life. The classical approach to treat schizophrenia is to use typical and atypical antipsychotics; however, limitations include low efficacy in mitigating negative symptoms and cognitive dysfunctions and a range of adverse effects. Evidence has accumulated on trace amine-associated receptor 1 (TAAR1) as a novel therapeutic target for treating schizophrenia. This systematic review investigates the available evidence on a TAAR1 agonist, ulotaront, as a treatment for schizophrenia.

Methods

A systematic search was conducted on PubMed/MEDLINE and Ovid databases for English-published articles from inception to 18 December 2022. The literature focusing on the association between ulotaront and schizophrenia was evaluated based on an inclusion/exclusion criterion. Selected studies were assessed for the risk of bias, using the Cochrane Collaboration tool, and summarized in a table to generate discussion topics.

Results

Three clinical, two comparative, and five preclinical studies examining ulotaront’s pharmacology, tolerability and safety, and/or efficacy were identified. Results indicate that ulotaront has a differing adverse effect profile from other antipsychotics, may mitigate metabolic-related adverse effects commonly associated with antipsychotics, and may be effective for treating positive and negative symptoms.

Conclusions

Findings from the available literature present ulotaront as a potential and promising alternative treatment method for schizophrenia. Despite this, our results were limited due to the lack of clinical trials on ulotaront’s long-term efficacy and mechanisms of action. Future research should focus on these limitations to elucidate ulotaront’s efficacy and safety for the treatment of schizophrenia and other mental disorders with similar pathophysiology.

KEYWORDS:

• Ulotaront
• SEP-363856
• TAAR1
• schizophrenia
• antipsychotics
• cognition
• depression
• anhedonia

Declaration of interest

T. Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. T. Rhee has also been funded by the NIA (#R21AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. T. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. T. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. T. Rhee is currently a co-editor-in-chief of Mental Health Science and has received honorarium payments from the publisher, John Wiley & Sons, Inc. R. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. R. McIntyre is a CEO of Braxia Scientific Corp. L. Lui has received personal fees from Braxia Scientific Corp. and honoraria from Medscape. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

One peer reviewer has received manuscript or speaker’s fee from Astellas, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Sumitomo Pharma, Takeda Pharmaceutical, Tsumura, Viatris, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma, Shionogi, and Sumitomo Pharma. One peer reviewer declares publication of a recent review on the clinical development of ulotaront; honoraria for speaking/consultancy from the Lundbeck Foundation, H. Lundbeck, and Otsuka. Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

G. Le conceptualized the Article. G. Le and E. Gillissie reviewed the articles. G. Le and A. March collected the data. G. Le wrote the first draft of the article and made revisions based on feedback from coauthors. All authors reviewed and approved the final article to be published.

Supplementary Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2023.2206559

Additional information

Funding

This paper was not funded.