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Trace Amine-Associated Receptor 1 as a Target for the Development of New Antipsychotics: Current Status of Research and Future Directions

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Abstract

Schizophrenia is a mental illness associated with an array of symptoms that often result in disability. The primary treatments for schizophrenia are termed antipsychotics. Although antipsychotics modulate a number of different receptor types and subtypes, all currently regulatory agency-approved antipsychotics share in common direct or functional antagonism at the dopamine type 2 receptor (D2R). The majority of people with schizophrenia do not achieve full resolution of their symptoms with antipsychotics, suggesting the need for alternative or complementary approaches. The primary focus of this review is to assess the evidence for the role of the trace amine-associated receptor 1 (TAAR-1) in schizophrenia and the role of TAAR-1 modulators as novel-mechanism antipsychotics. Topics include an overview of TAAR-1 physiology and pathophysiology in schizophrenia, interaction with other neurotransmitter systems, including the dopaminergic, glutamatergic and serotonergic system, and finally, a review of investigational TAAR-1 compounds that have reached Phase II clinical studies in schizophrenia: SEP-363856 (ulotaront) and RO6889450 (ralmitaront). Thus far, results are publicly available only for ulotaront in a relatively young (18–40 years) and acutely exacerbated cohort. These results showed positive effects for overall schizophrenia symptoms without significant tolerability concerns. An ongoing study of ralmitaront will assess specific efficacy in patients with persistent negative symptoms. If trials of TAAR-1 modulators, and other novel-mechanism targets for schizophrenia that are under active study, continue to show positive results, the definition of an antipsychotic may need to be expanded beyond the D2R target in the near future.

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  1. Department of Psychiatry, Columbia University, NYSPI, 1051 Riverside Drive, New York, NY, 10032, USA

    Joshua T. Kantrowitz

  2. New York State Psychiatric Institute, New York, NY, USA

    Joshua T. Kantrowitz

  3. Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Joshua T. Kantrowitz

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Dr. Kantrowitz reports having received consulting payments within the last 24 months from Alphasights, Charles River Associates, Medscape, Putnam, techspert.io, Third Bridge, MEDACorp, Parexel, GroupH, ECRI Institute, ExpertConnect, Parexel, Schlesinger Group, CelloHealth, Acsel Health, Antheum, Strafluence, Guidepoint, L.E.K., SmartAnalyst, and System Analytic. He has served on the MedinCell Psychiatry and the Karuna Mechanism of Action (MOA) Advisory Boards. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Alkermes, Cerevance, Corcept, Takeda, Taisho, Boehringer Ingelheim, NeuroRX, and Teva within the last 24 months. He owns a small number of shares of common stock from GSK.

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Dr. Kantrowitz was responsible for all aspects of the drafting and revision of the review, and agrees to be accountable for the work.

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Kantrowitz, J.T. Trace Amine-Associated Receptor 1 as a Target for the Development of New Antipsychotics: Current Status of Research and Future Directions. CNS Drugs 35, 1153–1161 (2021). https://doi.org/10.1007/s40263-021-00864-3

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