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. 2024 Apr 11:9:182.
doi: 10.12688/wellcomeopenres.21302.1. eCollection 2024.

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

Spyridon Siafis  1   2 , Virginia Chiocchia  3 , Malcolm R Macleod  4 , Charlotte Austin  5   6 , Ava Homiar  5   6 , Francesca Tinsdeall  4 , Claire Friedrich  5   6 , Fiona J Ramage  4 , Jaycee Kennett  5   6 , Nobuyuki Nomura  1   2 , Olena Maksym  4 , Grazia Rutigliano  7 , Luke J Vano  7 , Robert A McCutcheon  5   6   7   8 , David Gilbert  9 , Edoardo G Ostinelli  5   6   8 , Claire Stansfield  10 , Hossein Dehdarirad  10 , Damian Omari Juma  11 , Simonne Wright  12 , Ouma Simple  12 , Olufisayo Elugbadebo  13 , Thomy Tonia  3 , Ioannis Mantas  14 , Oliver D Howes  7   15 , Toshi A Furukawa  16   17 , Lea Milligan  18 , Carmen Moreno  19 , Julian H Elliott  20   21 , Janna Hastings  22   23 , James Thomas  10 , Susan Michie  24 , Emily S Sena  4 , Soraya Seedat  12 , Matthias Egger  3 , Jennifer Potts  5   6 , Andrea Cipriani #  5   6   8 , Georgia Salanti #  3 , Stefan Leucht #  1   2
Affiliations

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

Spyridon Siafis et al. Wellcome Open Res. .

Abstract

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.

Keywords: Antipsychotics; TAAR1; clinical trials; living evidence; meta-analysis; preclinical studies; schizophrenia; systematic review.

Plain language summary

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a “living” systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.

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Conflict of interest statement

Competing interests: Andrea Cipriani received research, educational and consultancy fees from the Italian Network for Paediatric Trials, CARIPLO Foundation, Lundbeck, and Angelini Pharma. Toshi A. Furukawa reports personal fees from Boehringer-Ingelheim, Daiichi Sankyo, DT Axis, Kyoto University Original, Shionogi, and SONY, and a grant from Shionogi outside the submitted work; in addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. Oliver D. Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. In the last three years Stefan Leucht has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva. Robert A. McCutcheon has received speaker/consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and is a director of a company that hosts psychotropic prescribing decision tools. Carmen Moreno received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Compass, Esteve, Exeltis Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion outside the submitted work. Nobuyuki Nomura has received speaker fees from Eisai, Meiji Seika Pharma, Otsuka, and Sumitomo Pharma; and manuscript fees from Sumitomo Pharma. Edoardo G. Ostinelli has received research and consultancy fees from Angelini Pharma. No other competing interests were disclosed.

Figures

Figure 1.
Figure 1.. PRISMA flow diagram for study selection of human studies.
**One single-arm neuroimaging study (NCT04038957) had originally been listed here as excluded, but its findings were post-hoc considered to provide mechanistic insights of the effects of TAAR1 agonists.
Figure 2.
Figure 2.. TAAR1 agonists versus placebo on overall symptoms in acute schizophrenia.
A. Forest plot of TAAR1 agonists versus placebo on overall symptoms in acute schizophrenia. There were available data for ulotaront and ralmitaront. The findings of random- and fixed-effects meta-analyses are presented. The overall risk of bias according to RoB2 is also presented, with all studies having an overall low risk of bias. B. Effect sizes for each dose level of ulotaront and ralmitaront compared to placebo on overall symptoms in acute schizophrenia. The findings of each study are presented separately, and the effect sizes were corrected for using the same control in each study by subdividing accordingly the sample size. The study of Koblan et al. 2020 was a flexible dosing study, which used of ulotaront between 50 to 75mg/d and its effect size is placed in the middle of the range. SMD: Standardised mean difference, 95%CI: 95% confidence interval.
Figure 3.
Figure 3.. TAAR1 agonists versus placebo on dropouts and adverse events in human studies.
Summary forest plot of TAAR1 agonists versus placebo on dropouts and adverse events. The pooled estimates from meta-analyses or effect sizes from single studies are presented for each of the outcomes relevant to dropouts and adverse events, separately for two timepoints with usable data. To ease the interpretation, adverse events were grouped in categories. There were usable data for treatment of ulotaront and ralmitaront for 4 to 6 weeks in acute schizophrenia or Parkinson’s disease psychosis, and after a single dose of ulotaront in participants with schizophrenia, healthy volunteers and narcolepsy-cataplexy. *This time point referred to events experienced after a single dose of ulotaront, except for additional and limited data for any and serious adverse events from the study by Szabo et al. 2023 examining treatment of 2 weeks with ulotaront. A logarithmic x-axis was used. N: number of studies; n: number of participants; OR: Odds ratio; 95%CI: 95% confidence interval.
Figure 4.
Figure 4.. PRISMA flow diagram for study selection of non-human studies.
Figure 5.
Figure 5.. TAAR1 agonists versus control condition for locomotor activity in animal models of psychosis.
A. Subgroup analysis of TAAR1 agonists versus control condition (e.g., vehicle) for locomotor activity in animal models of psychosis by the specific compound administered. The forest plot presents the overall estimate and the pooled estimates for each of the 10 different TAAR1 agonists by combining data from experimental comparisons. SEP-363856 refers to ulotaront. B. Meta-regression analysis of standardized dose of TAAR1 agonists versus control on locomotor activity in animal models of psychosis. A standardised dose was calculated by taking into consideration the drug potency to TAAR1 receptor, with a standardised dose of 0 reflecting 50% and of 1 around 80% of the maximum effect, respectively (see extended data). The dashed lines represent the 95% confidence intervals, and the dotted lines the 95% prediction intervals. The beta for the slope is also presented indicating the change in the magnitude of the effect size per unit change in standardised dose. SMD: Standardized mean difference; 95%CI: 95% confidence intervals.
Figure 6.
Figure 6.. TAAR1 agonists versus already licensed antipsychotics for locomotor activity in animal models of psychosis.
Forest plot of TAAR1 agonists versus antipsychotic drugs already licensed for schizophrenia on locomotor activity in animal models of psychosis. The effect sizes for each experimental comparison and the pooled estimate from the multilevel meta-analysis are presented. The dotted lines around the pooled estimate represent the 95% prediction intervals. The reporting completeness according to the modified ARRIVE checklist is also presented. SEP-363856 refers to ulotaront. SMD: Standardised mean difference, 95%CI: 95% confidence interval.
See this image and copyright information in PMC

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