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

Journal: Wellcome open research

Volume: 9

Issue: 

Year of Publication: 

Affiliated Institutions:  Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK. Department of Psychiatry, University of Oxford, Oxford, England, UK. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England, UK. GALENOS Global Experiential Advisory Board, InHealth Associates, London, UK. EPPI Centre, Social Research Institute, University College London, London, England, UK. My Mind Our Humanity, Young Leaders for Global Mental Health, Mombasa, Kenya. Stellenbosch University/South African Medical Research Council Genomics of Brain Disorders Extramural Research Unit, Department of Psychiatry, Stellenbosch University, Stellenbosch, Western Cape, South Africa. Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan. MQ Mental Health Research, London, UK. Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, ISCIII, School of Medicine, Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain. Cochrane Australia, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia. Institute for Implementation Science in Health Care, University of Zurich, Zurich, Switzerland. Centre for Behaviour Change, University College London, London, England, UK.

Abstract summary 

Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies.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.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.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.PROSPERO-ID: CRD42023451628.

Authors & Co-authors:  Siafis Spyridon S Chiocchia Virginia V Macleod Malcolm R MR Austin Charlotte C Homiar Ava A Tinsdeall Francesca F Friedrich Claire C Ramage Fiona J FJ Kennett Jaycee J Nomura Nobuyuki N Maksym Olena O Rutigliano Grazia G Vano Luke J LJ McCutcheon Robert A RA Gilbert David D Ostinelli Edoardo G EG Stansfield Claire C Dehdarirad Hossein H Juma Damian Omari DO Wright Simonne S Simple Ouma O Elugbadebo Olufisayo O Tonia Thomy T Mantas Ioannis I Howes Oliver D OD Furukawa Toshi A TA Milligan Lea L Moreno Carmen C Elliott Julian H JH Hastings Janna J Thomas James J Michie Susan S Sena Emily S ES Seedat Soraya S Egger Matthias M Potts Jennifer J Cipriani Andrea A Salanti Georgia G Leucht Stefan S

Study Outcome 

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Citations :  Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. : Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–51. 10.1016/S0140-6736(19)31135-3
Authors :  39
Identifiers
Doi : 182
SSN : 2398-502X
Study Population
Male,Female
Mesh Terms
Other Terms
Antipsychotics;TAAR1;clinical trials;living evidence;meta-analysis;preclinical studies;schizophrenia;systematic review
Study Design
Study Approach
Systemic Review
Country of Study
Publication Country
England