Trace Amine-associated Receptor 1 (TAAR1) Agonism for Psychosis: a Living Systematic Review and Meta-analysis of Human and Non-human Data

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies.

Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses.

Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling.

Conclusions: TAAR1 agonists may be less efficacious than dopamine D receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted.

Registration: PROSPERO-ID: CRD42023451628.

Citing Articles

Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: protocol for a systematic review and meta-analysis.

Siafis S, Nomura N, Schneider-Thoma J, Bighelli I, Bannach-Brown A, Ramage F F1000Res. 2025; 13:1017.

PMID: 39844929 PMC: 11751611. DOI: 10.12688/f1000research.155356.2.

References

Revel F, Meyer C, Bradaia A, Jeanneau K, Calcagno E, Andre C . Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine. Neuropsychopharmacology. 2012; 37(12):2580-92. PMC: 3473323. DOI: 10.1038/npp.2012.109. View

Saarinen M, Mantas I, Flais I, Agren R, Sahlholm K, Millan M . TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT receptor agonist SEP-383856. Neuropsychopharmacology. 2022; 47(13):2319-2329. PMC: 9630386. DOI: 10.1038/s41386-022-01421-2. View

Balduzzi S, Rucker G, Schwarzer G . How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 2019; 22(4):153-160. PMC: 10231495. DOI: 10.1136/ebmental-2019-300117. View

Revel F, Moreau J, Gainetdinov R, Ferragud A, Velazquez-Sanchez C, Sotnikova T . Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry. 2012; 72(11):934-42. DOI: 10.1016/j.biopsych.2012.05.014. View

Krasavin M, Peshkov A, Lukin A, Komarova K, Vinogradova L, Smirnova D . Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)--(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders. Int J Mol Sci. 2022; 23(19). PMC: 9569940. DOI: 10.3390/ijms231911579. View

Isaacson S, Goldstein M, Pahwa R, Singer C, Klos K, Pucci M . Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. Neurol Clin Pract. 2023; 13(4):e200175. PMC: 10238151. DOI: 10.1212/CPJ.0000000000200175. View

Kay S, Fiszbein A, Opler L . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2):261-76. DOI: 10.1093/schbul/13.2.261. View

Girgis R, Zoghbi A, Javitt D, Lieberman J . The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review. J Psychiatr Res. 2018; 108:57-83. DOI: 10.1016/j.jpsychires.2018.07.006. View

Howes O, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A . The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012; 69(8):776-86. PMC: 3730746. DOI: 10.1001/archgenpsychiatry.2012.169. View

10.

Howes O, Shatalina E . Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022; 92(6):501-513. DOI: 10.1016/j.biopsych.2022.06.017. View

11.

Wang Y, Liu Z, Lu J, Wang W, Wang L, Yang Y . Biological evaluation and studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment. Front Pharmacol. 2023; 14:1161964. PMC: 10160475. DOI: 10.3389/fphar.2023.1161964. View

12.

Leo D, Sukhanov I, Zoratto F, Illiano P, Caffino L, Sanna F . Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats. J Neurosci. 2018; 38(8):1959-1972. PMC: 5824739. DOI: 10.1523/JNEUROSCI.1931-17.2018. View

13.

Kokkinou M, Irvine E, Bonsall D, Natesan S, Wells L, Smith M . Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2020; 26(6):2562-2576. PMC: 8440182. DOI: 10.1038/s41380-020-0740-6. View

14.

Tsukada H, Milanovic S, Darpo B, Xue H, Xiong K, Tripp E . A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia. Clin Transl Sci. 2023; 16(6):1063-1074. PMC: 10264939. DOI: 10.1111/cts.13512. View

15.

Koblan K, Kent J, Hopkins S, Krystal J, Cheng H, Goldman R . A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia. N Engl J Med. 2020; 382(16):1497-1506. DOI: 10.1056/NEJMoa1911772. View

16.

Correll C, Koblan K, Hopkins S, Li Y, Dworak H, Goldman R . Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ Schizophr. 2021; 7(1):63. PMC: 8660889. DOI: 10.1038/s41537-021-00190-z. View

17.

Shang P, Rong N, Jiang J, Cheng J, Zhang M, Kang D . Structural and signaling mechanisms of TAAR1 enabled preferential agonist design. Cell. 2023; 186(24):5347-5362.e24. DOI: 10.1016/j.cell.2023.10.014. View

18.

Xu Z, Guo L, Yu J, Shen S, Wu C, Zhang W . Ligand recognition and G-protein coupling of trace amine receptor TAAR1. Nature. 2023; 624(7992):672-681. DOI: 10.1038/s41586-023-06804-z. View

19.

Hair K, Wilson E, Wong C, Tsang A, Macleod M, Bannach-Brown A . Systematic online living evidence summaries: emerging tools to accelerate evidence synthesis. Clin Sci (Lond). 2023; 137(10):773-784. PMC: 10220429. DOI: 10.1042/CS20220494. View

20.

Pratt J, Winchester C, Dawson N, Morris B . Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. Nat Rev Drug Discov. 2012; 11(7):560-79. DOI: 10.1038/nrd3649. View