TY - JOUR
T1 - Trace amine-associated receptor 1 (TAAR1) agonism for psychosis
T2 - a living systematic review and meta-analysis of human and non-human data
AU - Siafis, Spyridon
AU - Chiocchia, Virginia
AU - Macleod, Malcolm R
AU - Austin, Charlotte
AU - Homiar, Ava
AU - Tinsdeall, Francesca
AU - Friedrich, Claire
AU - Ramage, Fiona J
AU - Kennett, Jaycee
AU - Nomura, Nobuyuki
AU - Maksym, Olena
AU - Rutigliano, Grazia
AU - Vano, Luke J
AU - McCutcheon, Robert A
AU - Gilbert, David
AU - Ostinelli, Edoardo G
AU - Stansfield, Claire
AU - Dehdarirad, Hossein
AU - Juma, Damian Omari
AU - Wright, Simonne
AU - Simple, Ouma
AU - Elugbadebo, Olufisayo
AU - Tonia, Thomy
AU - Mantas, Ioannis
AU - Howes, Oliver D
AU - Furukawa, Toshi A
AU - Milligan, Lea
AU - Moreno, Carmen
AU - Elliott, Julian H
AU - Hastings, Janna
AU - Thomas, James
AU - Michie, Susan
AU - Sena, Emily S
AU - Seedat, Soraya
AU - Egger, Matthias
AU - Potts, Jennifer
AU - Cipriani, Andrea
AU - Salanti, Georgia
AU - Leucht, Stefan
N1 - Copyright: © 2024 Siafis S et al.
PY - 2024/7/19
Y1 - 2024/7/19
N2 - 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
2 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
2 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.
AB - 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
2 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
2 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.
U2 - 10.12688/wellcomeopenres.21302.1
DO - 10.12688/wellcomeopenres.21302.1
M3 - Article
C2 - 39036710
SN - 2398-502X
VL - 9
SP - 182
JO - Wellcome Open Research
JF - Wellcome Open Research
ER -