Trace amine-associated receptor 1 (TAAR1) agonists for psychosis - Results from the human studies

1. Description of the methodological approach

1. We searched for all controlled and uncontrolled studies examining TAAR1 agonists. In this first iteration of the review, we analyzed usable data from all randomized controlled studies comparing any TAAR1 agonist to placebo or current antipsychotics in people with psychosis, other mental health conditions, or healthy volunteers.

2. We examined efficacy outcomes, including overall symptoms of psychosis (primary outcome) and symptom domains, dropouts due to any reason, and adverse events. Safety outcomes included death, serious adverse events, and specific adverse events. We also sought mechanistic outcomes, specifically neurobiological measures of dopaminergic, glutamatergic, and serotonergic signalling. We examined these outcomes at three time points: immediately after a single dose up to 2 weeks of treatment, 3-13 weeks of treatment (preferably at 6 weeks), and longer-term outcomes.

3. In terms of efficacy outcomes, we pooled the data for each specific subgroup, considering that differences can be expected among different diagnoses (e.g., schizophrenia and Parkinson’s disease psychosis) and patient subgroups (e.g., patients with an acute episode of schizophrenia or with predominant negative symptoms). In terms of other outcomes, we combined data from all subgroups but also presented data separately for each subgroup.

4. Summary of data extraction: For continuous outcomes, we preferred change over endpoint scores and data from appropriate models or imputations considering missing outcome data. For dichotomous outcomes, we again preferred data from all participants, but in case of participants with missing outcome data, we assumed that they did not experience the event; an assumption usually used in meta-analysis in schizophrenia (e.g., Huhn et al. (2019)). In terms of crossover studies, we preferred data from appropriate models considering period or carry-over effects. If not available, we assumed a correlation (i.e., 0.2 for adverse events) to correct the variance of the estimates according to Elbourne et al. (2002) . If an outcome was measured multiple times after a single dose of the drug, we calculated the area under the curve according to the linear trapezoid rule (Chiou 1978) and divided by the time of assessment to remove the time component.

5. Risk of bias was assessed using the RoB2 tool (Sterne et al. 2019) for parallel and crossover studies. When only one domain had some concerns, we assigned an overall low risk of bias. Otherwise, we used the worst judgment across domains.

6. The effect sizes were as follows: 1) standardized mean differences (SMD) for efficacy outcomes, given that various scales have been used in the literature to allow comparability of the findings with other studies of antipsychotic drugs; 2) mean differences (MD) for laboratory measures, i.e., weight (kg), QTc interval (msec), and prolactin levels (ng/ml); 3) odds ratios (OR) for dichotomous outcomes, which were also converted to absolute risks using a control event rate (S. Leucht et al. 2022). 95% confidence intervals (95% CI) are presented, but 95% prediction intervals are not presented due to the small number of studies. Other effect sizes were not used in the first iteration of the review, e.g., those used in meta-analysis of variance due to the paucity of data.

7. Meta-analysis was conducted primarily using a random-effects model with inverse variance and REML estimator of tau-squared. Due to the small number of studies (<5) in all analyses, we corrected the confidence intervals using the Hartung-Knapp method (IntHout, Ioannidis, and Borm 2014), and we also presented the findings from fixed-effects models using the Mantel-Haenszel method throughout. Meta-analysis of proportions was conducted to pool the control groups to estimate the control event rate using logit transformation of the proportions and inverse variance method (Schwarzer et al. 2019). Moreover, continuity corrections of 0.5 were applied in case of 0 events in one of the groups.

8. Sensitivity analysis of the primary outcome included using fixed-effect methods (post-hoc due to the small number of studies), restricting the analysis to studies with an overall low risk of bias, and excluding studies with imputed values.

9. Subgroup analyses and meta-regressions were not conducted due to the paucity of data. However, we explored potential dose-effects for the primary outcome by plotting the effect sizes for different fixed doses of TAAR1 agonists compared to placebo (while correcting for the use of common comparators (Higgins et al. 2019)).

10. Summary of evidence tables were constructed for all outcomes, including a summary of the association, within-study biases, across-study biases, biases due to indirectness, and other biases. We used the RoB2 tool (Sterne et al. 2019) to assess within-study biases, as mentioned above. We used the ROB-ME approach (Matthew J. Page et al. 2023) for evaluating biases in missing evidence and across-study biases. Indirectness was considered especially relevant for non-efficacy outcomes, where we pooled data across diagnoses and subgroups, and considered the percentage of studies and participants with schizophrenia, the main group for which this evidence would be applicable.

11. Finally, as there were no usable data from controlled experimental studies on the effects of TAAR1 agonists on neurobiological measures relevant to dopaminergic, serotonergic, or glutamatergic signalling, we could not analyze them as secondary outcomes in the current review. Nevertheless, to provide mechanistic insights, we narratively described the findings of any available mechanistic data from controlled and uncontrolled studies, irrespective of their inclusion in this review, given that we had comprehensively searched for them (Siafis et al. 2023). We also presented the findings of these studies narratively in summary of evidence tables and discussed potential issues of risk of bias, reporting bias, indirectness, and other biases, but without formally using risk of bias tools.

Please see the manuscript, extended data (https://osf.io/tdmau/) and the protocol (Siafis et al. 2023) for more details.

A list of abbreviations can be find towards the end of the document.

2. Results

We present below the results, including the PRISMA flow diagram (Matthew J. Page et al. 2021) , table of included studies, risk of bias assessment, and forest plots, to facilitate a better understanding of the summary of evidence tables and the manuscript. Please refer to the detailed description of the findings in the latter part of the manuscript for more information.

2.1 Flow of study selection

Figure 1 PRISMA 2020 flow diagram. *It should be noted that due to the limited data on mechanistic insights, we also presented narratively the findings from one of the excluded uncontrolled studies, since this was the only molecular neuroimaging study Sumitomo Pharma America (2023a); this study is listed along with the 26 excluded studies due to wrong study design in the PRISMA flow diagram.

2.2 Table of included studies

Name	Title	ID	Sponsor	Design	Population	Intervention	Sample size	Objectives	Start date	Completion date	Completion year	Status	Available data
*NCT04038957	A Clinical Study to Investigate the Effect of an Investigational Drug as an Added Medication to an Antipsychotic, in Adults With Schizophrenia, as Measured Positron Emission Tomography (PET) Imaging	SEP361-118, NCT04038957, 2019-000568-65	Sunovion/Sumitomo	Open single-arm study; 2 weeks (phase 1)	Men/women 18-65 year with schizophrenia (stable, DSM-5)	Ulotaront 50-75mg/d (add-on to current antipsychotic treatment)	22	F-DOPA PET	August 7, 2019	June 6, 2023	2023	completed	F-DOPA (narratively)
DA801002 (in Galluppi 2021)	Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia	DA801002	Sunovion/Sumitomo	SB-RCT single ascending dose (phase I)	Men >18 years	Ulotaront (25mg to 50mg); Placebo	16	Pharmacokinetics	NA	NA	2021	completed	None
Fowler (2015)	A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure	NA	Hoffmann-La Roche	DB-RCT; single ascending dose (phase I)	Men 18-45 years	RO5263397 (1mg to 125mg); Placebo	49	Tolerability, pharmacokinetics	NA	NA	2015	completed	None
Hopkins (2021)	Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans	SEP361-103	Sunovion/Sumitomo	DB-RCT two-period crossover; single dose (phase I)	Men 18-35 years	Cohort 1: Ulotaront 10mg; Placebo; Cohort 2: Ulotaront 50mg; Placebo	24	Sleep parameters, pharmacokinetics	NA	NA	2021	completed	Dropouts, side-effects
Isaacson (2023)	Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study.	SEP361-203, NCT02969369	Sunovion/Sumitomo	DB-RCT; 6 weeks (with open label extension) (phase 2)	Men/women ≥55 years with Parkinson’s disease psychosis (acute)	Ulotaront 20-75mg/d; Placebo	39	Efficacy (acute), safety	November 21 2016	July 5 203	2023	completed	Efficacy, dropouts, side-effects
JapicCTI-194581 (2019)	A Phase I Single-Ascending Dose and Multiple-Ascending Dose Study of RO6889450 in Healthy Japanese Male	JapicCTI-194581	Hoffmann-La Roche	DB-RCT; single and multiple ascending dose (phase I)	Men 20-45 years	Ralmitaront; Placebo	64	Tolerability, pharmacokinetics	January 27 2019	October 2023 2019	2019	completed	None
Koblan (2016)	A phase 1 open label safety and tolerability study of SEP-363856, a novel NON-D2 mechanism of action molecule, in patients with schizophrenia	SEP361-106, NCT01994473	Sunovion/Sumitomo	SB-RCT; multiple ascending dose for 1 week (including open label extension) (phase 1)	Men/women 18-55 years with schizophrenia (stable, DSM-IV-TR)	Ulotaront (10mg/d to 100mg/d); Placebo	48	Tolerability, pharmacokinetics	October 1 2013	December 1 2014	2014	completed	None
Koblan (2020)	A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia	SEP361-201, NCT02969382, EUCTR2016-001555-41	Sunovion/Sumitomo	DB-RCT; 4 weeks (with open label extension) (phase 2)	Men/women 18-40 years with schizophrenia (acute, DSM-5)	Ulotaront (50-75mg/d); Placebo	245	Efficacy (acute), tolerability	December 5 2016	July 21 2018	2018	completed	Efficacy, dropouts, side-effects
NCT01940159 (2013)	A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia	SEP361-105, NCT01940159	Sunovion/Sumitomo	SB-RCT; single ascending dose (phase 1)	Men/women 18-50 years with schizophrenia (stable, DSM-IV-TR)	Ulotaront (50mg to 150mg); Placebo	48	Tolerability, pharmacokinetics	August 1 2013	March 1 2014	2014	completed	None
NCT02699372 (2016)	The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers	BP30134, NCT02699372	Hoffmann-La Roche	DB-RCT; single and multiple ascending dose up to 2 weeks (phase I)	Men/women 18-45 years	Ralmitaront (5 mg to 450mg); Placebo	164	Tolerability, pharmacokinetics	March 21 2016	April 17 2014	2017	completed	None
NCT03669640 (2018)	A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms	BP40283, NCT03669640, EUCTR2020-004752-16, JPRN-jRCT2031200287	Hoffmann-La Roche	DB-RCT; 12 weeks (phase II)	Men/women 18-55 years with schizophrenia or schizoaffective (predominant negative symptoms, DSM-5)	Part A: Ralmitaront; placebo (monotherapy); Part B: Ralmitaront low or high dose; placebo (add-on to current antipsychotics)	128	Efficacy (negative symptoms), tolerability	December 4 2018	May 8 2023	2023	completed	None
NCT04072354 (2019)	A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia	SEP361-301, NCT04072354, EUCTR2019-000470-36	Sunovion/Sumitomo	DB-RCT; 6 weeks (phase 3)	Men/women 13-17 and 18-65 years with schizophrenia (acute, DSM-5)	Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo	463	Efficacy (acute), tolerability	September 11 2019	June 8 2023	2023	completed	Efficacy, dropouts
NCT04092686 (2019)	A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia	SEP361-302, NCT04092686, EUCTR2019-000697-37	Sunovion/Sumitomo	DB-RCT; 6 weeks (phase 3)	Men/women 18-65 years with schizophrenia (acute, DSM-5)	Ulotaront 75mg/d; Ulotaront 100mg/d; Placebo	462	Efficacy (acute), tolerability	September 30 2019	September 08 2023	2023	completed	Efficacy, dropouts
NCT04115319 (2019)	A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia.	SEP361-304, NCT04115319 , EUCTR2019-002259-40	Sunovion/Sumitomo	DB-RCT; 52 weeks (phase 3)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Ulotaront 50-100mg/d; Quetiapine XR 400-800mg/d	475	Efficacy (maintenance), tolerability	November 15 2019	December 30 2022	2022	completed	None
NCT04325737 (2020)	Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Japanese Male and Female Subjects With Schizophrenia	DA801102, NCT04325737, jRCT2080225100	Sunovion/Sumitomo	DB-RCT; 2 weeks (phase 1)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Cohort 1: Ulotaront (50mg/d to 100mg/d); Placebo; Cohort 2: Ulotaront (25mg/d to 100mg/d); Placebo	13	Tolerability, pharmacokinetics	March 31 2020	August 7 2020	2020	completed	None
NCT04512066 (2020)	A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder	BP41743, NCT04512066, JPRN-jRCT2031200288	Hoffmann-La Roche	DB-RCT; 4 weeks (up to 48 weeks extension) (phase II)	Men/women 18-45 years with schizophrenia or schizoaffective disorder (acute, DSM-5)	Ralmitaront 45mg/d; Ralmitaront 150mg/d; Risperidone 4mg/d; Placebo	287	Efficacy (acute), tolerability	September 8 2020	June 21 2022	2022	completed	Efficacy, dropouts, side-effects
NCT04825860 (2021)	A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase	DA801201, NCT04825860, jRCT2071210003	Sunovion/Sumitomo	DB-RCT; 6 weeks (and open label extension) (phase 2/3)	Men/women 18-65 years with schizophrenia (acute, DSM-5)	Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo	480	Efficacy (acute), tolerability	March 29 2021	June 30 2025	NA	ongoing	None
NCT05402111 (2022)	A Clinical Study That Will Assess How Food Moves Through the Stomach and Effects Blood Glucose Levels in Subjects With Schizophrenia Taking SEP-363856 or and Prior Antipsychotic (PA) Standard	SEP361-124, NCT05402111 (2022)	Sunovion/Sumitomo	Open RCT two-period crossover; single dose (phase 1)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Ulotaront (25mg to 50mg); Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole)	36	Pharmacokinetics, metabolic parameters	June 13 2022	July 13 2023	NA	completed	None
NCT05542264 (2022)	A Clinical Study That Will Assess the Effect of SEP-363856 or Prior Antipsychotic (PA) Standard of Care on Body-weight Associated Parameters in Subjects With Schizophrenia	SEP361-122, NCT05542264	Sunovion/Sumitomo	DB-RCT; 2 weeks (phase 1)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Ulotaront; Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole)	60	Metabolic parameters	November 15 2022	March 29 2024	NA	ongoing	None
NCT05593029 (2022)	A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder	382-201-00001, NCT05593029	Sunovion/Sumitomo	DB-RCT; 14 weeks (phase 2/3)	Men/women 18-65 years with MDD (acute, DSM-5)	Ulotaront; Placebo (add-on to antidepressants)	900	Efficacy (MDD), tolerability	November 9 2022	May 1 2025	NA	ongoing	None
NCT05729373 (2023)	A Clinical Study That Will Meaure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anixety Disorder	SEP361-226, NCT05729373, EUCTR2022-502077-42-00	Sunovion/Sumitomo	DB-RCT; 8 weeks (phase 2/3)	Men/women 18-65 years with GAD (acute, DSM-5)	Ulotaront (50-75mg/d); Placebo	464	Efficacy (GAD), tolerability	March 8 2023	February 8 2025	NA	ongoing	None
NCT05848700 (2023)	A Clinical Study to Learn if SEP-363856 Has Physical Dependence in Adults With Schizophrenia	SEP361-121, NCT05848700	Sunovion/Sumitomo	DB-RCT; 10 weeks (phase 1)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Ulotaront continuation; Ulotaront discontinuation (switch to placebo)	60	Physical dependence, pharmacokinetics	June 21 2023	February 23 2024	NA	ongoing	None
Perini (2023)	Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy	SEP361-104, NCT01972711	Sunovion/Sumitomo	DB-RCT; single dose (phase 1)	Men/women 18-45 years (high or low levels of schizotypy)	Ulotaront 50mg; Amisulpride 400mg; Placebo	105	fMRI	March 1 2014	July 1 2015	2015	completed	Dropouts, side-effects, fMRI (narratively)
SEP361-101 (in Galluppi 2021 and Chen 2022)	A sensitive LC-MS/MS method for simultaneous quantification of ulotaront and its N-desmethyl metabolite in human plasma and application to a clinical study	SEP361-101	Sunovion/Sumitomo	SB-RCT; single ascending dose (phase I)	Men >18 years	Ulotaront (5mg to 125mg); Placebo	52	Pharmacokinetics	NA	NA	2021	completed	None
Szabo (2023)	A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy.	SEP361-108 , NCT05015673	Sunovion/Sumitomo	DB-RCT three-period crossover; 2 weeks (phase 1)	Men/women 18-55 years with narcolepsy/cataplexy	Ulotaront 25mg; Ulotaront 50mg; Placebo	18	Sleep parameters, pharmacokinetics, tolerability	June 5 2014	May 26 2015	2015	completed	Dropouts, side-effects
Tsukada (2023)	A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia.	SEP361-114, NCT04369391	Sunovion/Sumitomo	DB-RCT three-period crossover; single dose (phase 1)	Men/women 18-65 years with schizophrenia (stable, DSM-5)	Ulotaront 150mg; Placebo; Moxifloxacin 400mg (ineligible for the review)	68	QTc interval, tolerability, pharmacokinetics	June 18 2020	November 10 2020	2020	completed	Dropouts, side-effects

Table 1 Table of included studies. *It should be noted that due to the limited data on mechanistic insights, we also presented narratively the findings from one of the excluded uncontrolled studies, since this was the only molecular neuroimaging study (Sumitomo Pharma America 2023a), which characteristics are also presented here as an exception along with the included RCTs. SB: Single-Blind, DB: Double-Blind, DSM: Diagnostic and Statistical Manual for Mental Disorders, RCT: Randomized controlled trial, MDD: Major Depressive Disorder, GAD: Generalzied Anxiety Disorder, fMRI: functional neuroimaging, PET: Positron emission tomography.

2.3 Description of included studies

There were 25 eligible studies, which characteristics can be found in Table 1, with 20 studies (2147 participants) being completed and 5 studies being still ongoing (according to the status reported in clinicaltrials.gov up to 20.01.2024). There were usable data for this analysis from 9 studies (1683 participants) (Hopkins, Dedic, and Koblan 2021; Isaacson et al. 2023; Koblan et al. 2020; Sumitomo Pharma America 2023b, 2023c; Roche 2022; Perini et al. 2023; Szabo et al. 2023; Tsukada et al. 2023), which enrolled adult populations across multiple countries and were funded by the industry manufacturing the TAAR1 agonists.

The usable studies compared single or multiple doses of two TAAR1 agonists (i.e., ulotaront or ralmitaront) with placebo or current antipsychotics (i.e., risperidone or amisulpride) in people with schizophrenia, Parkinson’s disease psychosis, other mental health conditions (narcolepsy/cateplexy as sleep disorder) and healthy volunteers.

Five studies used a parallel design to examine the efficacy and safety of multiple doses of TAAR1 agonists in psychosis within 3-13 weeks: Four studies examining daily doses of TAAR1 agonists in adults with an acute episode of schizophrenia spectrum conditions for 4-6 weeks, 3 examined ulotaront (Koblan et al. 2020; Sumitomo Pharma America 2023b, 2023c) and 1 examined ralmitaront (Roche 2022). These studies used placebo as a control group, and the 1 study on ralmitaront also used the antipsychotic risperidone as an active comparator. One study comparing daily doses of ulotaront in Parkinson’s disease psychosis to placebo for 4 weeks (Isaacson et al. 2023).

Four studies examined the pharmacokinetics, safety and/or neuroimaging of single doses of TAAR1 agonists or multiple doses for up to 2 weeks: One study examining the effects of a single dose of 150mg ulotaront in clinically stable adults with schizophrenia on QTc interval within a day (Tsukada et al. 2023). The study utilized a three-period crossover period comparing ulotaront with placebo and moxifloxacin (an antibiotic used as active comparator, not relevant for our analysis). Two studies examined the effects of single doses of ulotaront in healthy volunteers on sleep parameters (Hopkins, Dedic, and Koblan 2021) or fMRI tasks (Perini et al. 2023). Hopkins, Dedic, and Koblan (2021) included two cohorts of crossover studies comparing two single doses of ulotaront with placebo. (Perini et al. 2023) was a parallel trial comparing ulotaront to placebo or the antipsychotic amisulpride on fMRI tasks relevant to reward, working memory and emotion processing in volunteers with high or low schizotypy traits. One study examined two single doses of ulotaront in adults with narcolepsy-cateplexy compared to placebo using a three-period crossover design (Szabo et al. 2023).

Data from the following studies were unavailable: One study examined the efficacy and safety of ulotaront in comparison to placebo in adolescents with an acute episode schizophrenia (NCT04072354). This study had two parts with adults and adolescents. This study has been recently completed, and although some usable data in the adult population are available (see above), these are not available for the adolescents. One study examined the long-term efficacy and safety of ulotaront in comparison to the antipsychotic quetiapine in adults with clinically stable schizophrenia (NCT04115319). The study should have been completed in 12.2022, but there are currently no usable data available. One study examined monotherapy or add-on treatment with ralmitaront in comparison to placebo in adults with schizophrenia or schizoaffective disorder and predominant negative symptoms (NCT03669640). The study has been recently completed in 05.2023, and it has been reported to be failed, yet no usable data were available. Nine studies examined pharmacokinetics and safety of single or few multiple doses of ulotaront or ralmitaront in healthy volunteers (Fowler 2015, JapicCTI-194581, NCT02699372, SEP361-101, DA801002, NCT01940159, Koblan 2016, NCT04325737, NCT04865835).

The following studies are ongoing: - One study is examining the efficacy and safety of two ulotaront doses of 50mg/d and 75mg/d in comparison to placebo in adults with an acute episode of schizophrenia (NCT04825860). The study is expected to be completed in 06.2025. - Two studies are examining the efficacy and safety of ulotaront compared to placebo in other mental health conditions, i.e., adults with major depression (NCT05593029) and generalized anxiety disorder (NCT05729373). These trials are expected to be completed in 2025, and their safety data are relevant for this review.

The studies used to describe mechanistic insights are provided in the relevant section below. It should be noted that the findings from an additional single-arm molecular neuroimaging are described in this section (Sumitomo Pharma America 2023a), which was uncontrolled and formally excluded from this iteration of the review. The characteristics of this study and its findings are described in the “mechanistic insights” section.

2.4 Risk of bias assessment

The risk of bias of the studies was examined using the RoB2 tool (Sterne et al. 2019) for parallel and crossover studies for all outcomes. Here, we present the risk of bias of using the worst judgement of a domain across outcomes. It should be noted that when there were some concerns in only one of the domains, we assigned an overall low risk of bias according to our protocol.

Figure 2 Risk of bias of studies with usable data

All the studies were double-blind randomized controlled studies, with a low risk of bias in most cases in their respective domains of biases due to randomization, deviations from intended interventions, and outcome measurement. There were also no indications of selectively reported results; thus, the studies had a low risk of bias in their respective domains. Most of the studies had missing outcome data, but there was no clear indication that the missingness depended on the true value of the effects for most of the outcomes. Therefore, there were some concerns, except for Isaacson et al. (2023), which had a high risk of bias for efficacy outcomes but not for adverse events and other outcomes. Additionally, there were few differences in this domain across outcomes, such as a low risk for the outcome of dropouts. In terms of the three crossover studies, there was a low risk of bias in period and carry-over effects, except for some concerns in the three-period crossover study of Tsukada et al. (2023) . Few differences across outcomes can be found in the overall judgment of the risk of bias for each study per outcome in the respective forest plots below.

It should be noted that the x-axis in the figures below, which present dichotomous outcomes using odds ratios, is logarithmically scaled. When the forest plots present only the effect sizes, there were crossover studies in which variances were corrected assuming a correlation of 0.2.

2.5 Comparison 1: TAAR1 agonist vs placebo

2.5.1 Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Figure 3a Forest plot for overall symptoms (primary outcome, measured with PANSS total) for the comparison of TAAR1 agonist vs. placebo in people with acute episode of schizophrenia at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Figure 3b Forest plot for overall symptoms (primary outcome, measured with the NPI total score) for the comparison of TAAR1 agonist vs. placebo in people with Parkinson’s disease psychosis at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.2 Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 4a Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. placebo in people with acute episode of schizophrenia (measured with PANSS positive) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Figure 4b Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. placebo in people with Parkinson’s disease psychosis (measured with SAPS-PD) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.3 Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 5 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. placebo (measured with PANSS negative) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.4 Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 6 Forest plot for depressive symptoms for the comparison of TAAR1 agonist vs. placebo (measured with PANSS anxiety/depression factor) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.5 Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 7 Forest plot for cognitive impairment for the comparison of TAAR1 agonist vs. placebo (measured with MMSE) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD:Standardized mean difference, 95%CI: 95% confidence intervals, SD: Standard deviation.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.6 Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.7 Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.8 Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 8a Forest plot for response (>50% or 20% symptom reduction in PANSS total from baseline) for the comparison of TAAR1 agonist vs. placebo in people with acute episode of schizophrenia at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Figure 8b Forest plot for response (>50% symptom reduction in SAPS-PD from baseline) for the comparison of TAAR1 agonist vs. placebo in people with Parkinson’s disease psychosis at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.9 Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.10 Summary outcome plot: Efficacy outcomes

Figure 9 Summary plot for efficacy outcomes at 4-6 weeks for the comparison of TAAR1 agonists vs. placebo in the two populations of patients with an acute episode of schizophrenia and Parkinson’s disease psychosis. There were only available data for the timepoint of 3-13 weeks. The size of the points are proportional to the number of participants used in the analysis. SMD>0 correspond to more symptom improvement by TAAR1 agonists compared to placebo. The findings of the random-effects model are presented. SMD: Standardized mean difference, 95%CI: 95% confidence interval. N=number of studies, n=number of participants.

2.5.11 Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Figure 10 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 11 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.12 Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

Figure 12 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 13 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.13 Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

Figure 14 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 15 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.14 Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

There were available usable data from four studies (i.e., (Hopkins, Dedic, and Koblan 2021; Perini et al. 2023; Szabo et al. 2023; Tsukada et al. 2023)) but all of them reported 0 deaths so that could not provide estimable effect sizes with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 16 Forest plot for death for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). Studies with 0 events in both arms could not provide estimable effect sizes with the current approach. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.15 Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

Figure 17 Forest plot for any adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals

Timepoint 2: 3 weeks - 13 weeks

Figure 18 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.16 Secondary outcome: Anticholinergic symptoms

Timepoint 1: 1 day - 2 weeks

Figure 19 Forest plot for anticholinergic side-effects (i.e., dry mouth in this study) for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.17 Secondary outcome: Hypotension

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 20 Forest plot for hypotension for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.18 Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

Figure 21 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 22 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.19 Secondary outcome: Nausea or vomiting

Timepoint 1: 1 day - 2 weeks

Figure 23 Forest plot for nausea or vomiting for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 24 Forest plot for nausea or vomiting for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

It should be noted that there appears to be some heterogeneity in the findings between ulotaront and ralmitaront. This heterogeneity may potentially be driven by the fact that ulotaront is also a 5-HT1A receptor partial agonist, which is associated with gastrointestinal symptoms.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.20 Secondary outcome: QTc prolongation

Timepoint 1: 1 day - 2 weeks

Figure 25 Forest plot for QTc prolongation for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with not estimable effect sizes had 0 events in both groups. The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

There were available data in Koblan et al. (2020) , which reported 0 events in both groups, so that an effect size cannot be estimated with the current approach.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.21 Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

Figure 26 Forest plot for QTc interval in msec for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. The overall risk of bias of the studies for this outcome is presented. MD:Mean difference, 95%CI: 95% confidence intervals

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.22 Secondary outcome: Weight increased

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 27 Forest plot for weight gain for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR=Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.23 Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 28 Forest plot for weight change in kg for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. MD:Mean difference, SD: standard deviation, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.24 Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

There were available data from one study (Hopkins, Dedic, and Koblan 2021) reporting 0 events in both arms so that an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.25 Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 29 Forest plot for prolactin levels in ng/ml for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). SD was imputed from the dataset of antipsychotic trials in Huhn et al 2021. The overall risk of bias of the studies for this outcome is presented. MD:Mean difference, SD=Standard deviation, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.26 Secondary outcome: Akathisia

Terms considered included: restlessness (when was used to describe akathisia)

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 30 Forest plot for akathisia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.27 Secondary outcome: Extrapyramidal symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 31 Forest plot for extrapyramidal side effects (use of antiparkinsonian medication as a proxy) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. MD:Mean difference, SD: standard deviation, 95%CI: 95% confidence intervals. Furthermore, there were narrative descriptions from a conference abstract (“ACNP 62(nd) Annual Meeting: Poster Abstracts P251 - P500” 2023) that ulotaront did not differ from placebo in extrapyramidal symptoms with low absolute frequencies in two unpublished phase III trials (Sumitomo Pharma America 2023b, 2023c). Moreover, ulotaront was reported not to deteriorate movement symptoms in participants with Parkinson’s disease psychosis as measured with the Unified Parkinson Disease Rating Scale Part III (Isaacson et al. 2023).

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.28 Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

There were usable data for one study (Perini et al. 2023), which reported 0 events in both groups so that an effect size could not be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 32 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.29 Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 33 Forest plot for agitation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.30 Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Figure 34 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 35 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.31 Secondary outcome: Sedation

Terms that were considered as reported in the trials: fatigue, sedation, somnolence

Timepoint 1: 1 day - 2 weeks

Figure 36 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 2: 3 weeks - 13 weeks

Figure 37 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.32 Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 38 Forest plot for insomnia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. The overall risk of bias of the studies for this outcome is presented. OR:Odds ratio, 95%CI: 95% confidence intervals.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.5.33 Summary outcome plot: Dropouts and side-effects

Figure 39 Summary forest plot for dropouts and side-effects for the comparison of TAAR1 agonists compared to placebo and for the two timepoints with usable data. It should be noted that different populations have been pooled in the analysis of dropouts and adverse events including schizophrenia, Parkinson’s disease psychosis, narcolepsy-cateplexy and healthy volunteers. The size is proportional to the number of participants in the analysis. The findings of the random-effects model are presented. OR>1 corresponds to more events with TAAR1 agonists compared to placebo. OR: Odds ratio, 95%CI: 95% confidence intervals. N=number of studies, n=number of participants.

2.6 Comparison 2: TAAR1 agonist vs antipsychotic

2.6.1 Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Figure 40 Forest plot for overall symptoms (primary outcome, measureed with PANSS total) for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD: Standardized mean difference, SD: Standard deviation, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.2 Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 41 Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. antipsychotics (measured with PANSS positive) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD: Standardized mean difference, SD: Standard deviation, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.3 Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 42 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. antipsychotics (measured with PANSS negative) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD: Standardized mean difference, SD: Standard deviation, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.4 Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 43 Forest plot for depression symptoms for the comparison of TAAR1 agonist vs. antipsychotics (measured with PANSS anxiety/depression factor) at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. SMD: Standardized mean difference, SD: Standard deviation, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.5 Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.6 Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.7 Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.8 Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 44 Forest plot for response to treatment (>50% symptom reduction in PANSS total from baseline) for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.9 Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.10 Summary outcome plot: Efficacy outcomes

Figure 45 Summary plot for efficacy outcomes at 4 weeks for the comparison of TAAR1 agonists versus antipscyhotcs in patients with an acute episode of schizophrenia. There were only data for the timepoint of 3-13 weeks. There were only data for ralmitaront as TAAR1 agonist and risperidone as control group. SMD>0 correspond to more symptom improvement by TAAR1 agonists compared to antipsychotic. SMD: Standardized mean difference, 95%CI: 95% confidence interval. N=number of studies, n=number of participants.

2.6.11 Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Figure 46 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 47 Forest plot for dropouts due to any reason for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.12 Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

There were usable data in (Perini et al. 2023), whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

Figure 48 Forest plot for dropouts due to adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.13 Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

Figure 49 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 50 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.14 Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

There were usable data in (Perini et al. 2023), whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 2: 3 weeks - 13 weeks

There were usable data in (Roche 2022), whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.15 Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

Figure 51 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 52 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.16 Secondary outcome: Anticholinergic symptoms

Timepoint 1: 1 day - 2 weeks

Figure 53 Forest plot for anticholinergic side effects (e.g., dry mouth in this study) for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.17 Secondary outcome: Hypotension

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.18 Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

Figure 54 Forest plot for dizziness for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.19 Secondary outcome: Nausea or vomiting

Terms that were considered as reported in the trials: nausea, vomiting, emesis

Timepoint 1: 1 day - 2 weeks

Figure 55 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.It should be noted that the study (Perini et al. 2023) examined ulotaront that is also a partial agonsit of 5-HT1A causing potentially gastrointestinal side-effects. In comparison, ralmitaront is not a partial agonist of the 5-HT1A receptor. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 56 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). It should be noted that the study (Roche 2022) examined ralmitaront, which compared to ulotaront is not a partial agonist of the 5-HT1A receptor that can be associated with gastrointestinal side effects. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.20 Secondary outcome: QTc prolongation

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.21 Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.22 Secondary outcome: Weight increased

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 57 Forest plot for weight increase for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.23 Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.24 Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.25 Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.26 Secondary outcome: Akathisia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.27 Secondary outcome: Exrapyramidal symptoms

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.28 Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

Figure 58 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 59 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.29 Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 60 Forest plot for agitation for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.30 Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Figure 61 Forest plot for headache as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

Figure 62 Forest plot for headache for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.31 Secondary outcome: Sedation

Timepoint 1: 1 day - 2 weeks

Figure 63 Forest plot for sedation for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks. The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 2: 3 weeks - 13 weeks

No usable data available from RCT.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.32 Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No usable data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Figure 64 Forest plot for insomnia for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint). The overall risk of bias of the studies for this outcome is presented. OR: Odds ratio, 95%CI: 95% confidence interval.

Timepoint 3: > 13 weeks

No usable data available from RCT.

2.6.33 Summary outcome plot: Dropouts and side-effects

Figure 65 Summary forest plot for dropouts and side-effects for the comparison of TAAR1 agonists compared to antipsychotics and for the two timepoints with usable data. There were data for single doses of ralmitaront versus amisulpride in healthy volunteers at 1 day, and ulotaront versus risperidone in acute schizophrenia or schizoaffective disorder at 4 weeks. The size of the points is proportional to the number of participants. OR>1 corresponds to more events with TAAR1 agonists compared to antipsychotics. OR: Odds ratio, 95%CI: 95% confidence interval. N=number of studies, n=number of participants.

2.7 Mechanistic insights into the effects of TAAR1 agonism for psychosis

There were no usable data available from RCTs on neurobiological measures relevant to psychosis and neurotransmitter signalling that could be analyzed as secondary outcomes of this review. Therefore, to be able to provide additional insights into the mechanism of TAAR1 agonism for psychosis, we sought to describe any potentially available data from both controlled and uncontrolled studies, irrespective of whether they have been included or not in the review (see above).

Additional evidence from two neuroimaging studies (Perini et al. 2023; Sumitomo Pharma America 2023a) generally supports the notion that TAAR1 agonists can ameliorate the elevated striatal dopamine synthesis and release capacity that is considered central in the development of symptoms of psychosis (Howes and Shatalina 2022).

Perini et al. (2023) was double-blind, three-arm parallel RCT examining the effects of a single dose of ulotaront 50mg compared to placebo and amisulpride 400mg on fMRI blood oxygen level-dependent (BOLD) striatal responses to reward processing, as measured during the anticipation phase of the Monetary Incentive Delay (MID) task (primary outcome). BOLD striatal responses to reward during the anticipatory phase of MID were selected as the primary outcome due to their potential relation to increased dopamine release in the striatum. The study enrolled 96 healthy volunteers, 51 with low schizotypy traits and 45 with high, as measured with the Schizotypal Personality Questionnaire (scores <10 indicate low schizotypy traits, >=40 high schizotypy traits) to examine interactions due to the potential shared increased striatal activity between positive symptoms and schizotypal traits. The interventions were administered 2 hours before the fMRI. Moreover, the study measured responses to other brain regions, the outcome phase of MID, BOLD responses to the N-back task for working memory, responses to an emotional test battery, resting state connectivity, and arterial spin labelling.

The findings of the primary outcome of this study are reported here as they were deemed most relevant to dopaminergic signalling. Ulotaront appeared to be associated with smaller BOLD striatal responses compared to placebo (left striatum: -0.13%, p=0.03, SMD=-0.55, 95%CI: -1.05, -0.05; right striatum: -0.12%, p=0.06, SMD=-0.44, 95%CI: -0.94, 0.06) but not to amisulpride (left: -0.07%, p=0.38, SMD=-0.22, 95%CI: -0.71, 0.27; right: -0.03%, p=0.66, SMD: -0.11, 95%CI: -0.60, 0.38) in the anticipation of loss, and did not differ from both placebo (left: -0.07%, p=0.30, SMD=-0.25, 95%CI: -0.75, 0.25; right: -0.07%, p=0.27, SMD=-0.25, 95%CI: -0.75, 0.25) and amisulpride (left: -0.03%, p=0.65, SMD=-0.11, 95%CI: -0.60, 0.38; right: -0.02%, p=0.74, SMD=-0.08, 95%CI: -0.57, 0.41) in the anticipation of win in the MID task. There were also no differences in BOLD insular responses (anticipation of loss - ulotaront vs. placebo left 0.00%, p=0.99, SMD=0.00, 95%CI: -0.50, 0.50 and right -0.10%, p=0.16 SMD=-0.36, 95%CI:-0.86, 0.14. ulotaront vs. amisulpride left 0.01%, p=0.94, SMD=0.02, 95%CI: -0.48, 0.52 and right -0.08%, p=0.42, SMD=-0.20, 95%CI: -0.70, 0.30; anticipation of win - ulotaront vs. placebo left: 0.08%, p=0.18, SMD=0.34, 95%CI: -0.16, 0.84, and right -0.01%, p=0.90, SMD=-0.04, 95%CI: -0.54, 0.46, ulotaront vs. amisulpride left 0.02%, p=0.84, SMD=0.05, 95%CI: -0.45, 0.55, and right 0.03%, p=0.72, SMD=0.09, 95%CI: -0.40, 0.58), but ulotaront seemed to increase BOLD responses in the medial orbital frontal cortex in anticipation of loss compared to placebo (left: 0.19%, p=0.07, SMD=0.44, 95%CI: -0.06, 0.94; right: 0.17%, p=0.10, SMD=0.43, 95%CI: -0.07, 0.93) and amisulpride (left: 0.25%, p=0.03, SMD=0.56, 95%CI: 0.06, 1.06; right: 0.22%, p=0.05, SMD=0.50, 95%CI: 0.00, 1.00) and in anticipation of win compared to placebo (left: 0.25%, p=0.01, SMD=0.64, 95%CI: 0.14, 1.14; right: 0.24%, p=0.01, SMD=0.68, 95%CI: 0.18, 1.18), but not clearly to amisulpride (left: 0.10%, p=0.30, SMD=0.26, 95%CI: -0.24, 0.76; right: 0.11%, p=0.19, SMD=0.33, 95%CI: -0.16, 0.82). Interactions with schizotypy traits were not reported for the primary outcome, but ulotaront was reported to reverse in comparison to placebo the aberrant increased BOLD response in the right insula observed in participants with high schizotypy traits but not in those with low schizotypy traits.

However, it is unclear if the primary outcome was selected a priori or a posteriori, as no primary outcome was reported in the registration of the study on clinicaltrials.gov, thus biases due to seletected reported outcomes cannot be excluded. There were also differences between the interventions in some of the other measures, with ulotaront being reported as associated with the modification of signals in brain regions associated with cognitive symptoms in schizophrenia. Moreover, ulotaront was associated with sedation in 60% of the participants, more frequently than placebo (see Figure 36) and amisulpride (see Figure 63) that impaired reaction times in the tasks but was not correlated with BOLD responses. Nevertheless, the impact of this sedative effect on these findings is unclear.

In conclusion, this study suggests that ulotaront might be able to reduce dopamine release in situations that are increased, like the anticipatory phase of MID, and potentially in psychosis.

Sumitomo Pharma America (2023a) was an open-label single-arm trial examining the effects of a 2-week treatment with ulotaront (50-75mg/d) as an add-on to antipsychotic treatment on dopamine synthesis capacity in clinically stable patients with schizophrenia (an uncontrolled study that was not included in this meta-analysis, with available data from a conference abstract in ACNP 2024 (“ACNP 62(nd) Annual Meeting: Poster Abstracts P251 - P500” 2023)]). This study included 14 men and 5 women (aged 18-45 years, mean age 32.9 years) with clinically stable schizophrenia (DSM-5) on a stable dose of antipsychotics for at least 3 weeks before screening. Three additional patients were enrolled but did not complete the baseline scan, so they were excluded from the study. The patients underwent an F-DOPA PET scan both at baseline and after 2 weeks of treatment with ulotaront (50-75mg/d) as an add-on to antipsychotic treatment. At baseline, the patients had a mean PANSS total score of 79.3 (SD=7.3), PANSS positive subscale of 19.2 (SD=4.6), PANSS Marder positive factor of 24.3 (SD=4.6), and CGI-S of 4.2 (SD=0.6), indicating that the patients had on average symptoms of moderate severity.

After 2 weeks of treatment with add-on ulotaront, there was a decrease in dopamine synthesis capacity in the striatum as indicated by the F-DOPA PET scan by -3.98% from baseline (95% CI: -8.68%, 0.72%), with the 95% CI not excluding the null effect, and the striatal subregions ranging from -3.38% in the associative striatum, -3.89% in the sensorimotor striatum, to -5.79% in the limbic striatum. This reduction was considered to be clinically meaningful, and although it was not correlated with the relative reduction in PANSS total scores (r=0.19, p>0.05), it was correlated with improvements in the PANSS Marder positive factor (r=0.49, p<0.05).

The study can be considered to have a high risk of bias due to the single-arm design, lack of control conditions, and the absence of blinding, yet the measurement of the outcome can be considered objective.

In conclusion, this study suggests that ulotaront may be able to reduce the dopamine synthesis capacity in clinically stable, but still symptomatic, people with schizophrenia, and the decrease in dopamine synthesis could be associated with the improvement of symptoms.

No other controlled or uncontrolled study (see included and excluded studies in the supplementary files of the review) reported any neurobiological measure. It should be noted that another study, i.e., NCT02699372, consisting of double-blind trials examining single and multiple ascending doses of ralmitaront compared to placebo in healthy volunteers (see Table 1), utilized neuropsychological tasks but did not couple them with neuroimaging or other neurobiological measures to provide further insights. There were no usable data for this study for any of the outcomes; only brief and narrative descriptions of the findings of these tasks were available in the study protocol of Halff et al. (2023) . These findings describe that ralmitaront improved reward-related behavioral tasks compared to placebo but lacked additional information.

2.8 Subgroup analyses and meta-regressions

There were less than 5 studies available for the analyses of the primary outcome, precluding the exploration of potential reasons of heterogeneity with subgroup analyses and meta-regressions.

Nevertheless, we explored potential differences between ulotaront and ralmitaront in improving overall symptoms of acute schizophrenia, and potential dose-effects by plotting the effect sizes for each fixed-dose level of TAAR1 agonist compared to placebo. However, we did not conduct any formal subgroup test or dose-response meta-analysis due to the limited number of studies.

Moreover, it should be noted that we presented the effect sizes in each specific subgroup of participants for all outcomes, but we did not perform a formal subgroup test

2.8.1 Exploration of differences between ulotaront and ralmitaront in their effects on overall symptoms of acute schizophrenia

Figure 66 Forest plot presenting the effects of ulotaront and ralmitaront compared to placebo on overall symptoms in acute schizophrenia (measured with PANSS total) at 4-6 weeks separately. SMD: Standardized mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.

2.8.2 Exploration of dose-effects of ulotaront and ralmitaront on overall symptoms of acute schizophrenia

Figure 67 Effect sizes for each dose level of ulotaront and ralmitaront compared to placebo in improving overall symptoms of acute schizophrenia at 4-6 weeks are presented separately. The findings of each study are presented separately, and the effect sizes were corrected for using the same control condition in each study. It should be noted that Koblan et al. (2020) was a two-arm flexible-dosing study, and its effect size is placed in the middle of the range of the administered dose (50mg/d to 75mg/d). SMD: Standardized mean difference, 95%CI: 95% confidence intervals.

In the fixed-dosing studies (Sumitomo Pharma America 2023b, 2023c; Roche 2022), higher doses (i.e., ulotaront 100mg/d and ralmitaront 150mg/d) may be associated with more improvement compared to smaller doses. However, the effect sizes at these high doses still appear to be small, with a standardized mean difference (SMD) of approximately 0.2. In the flexible dosing study by Koblan et al. (2020) , which utilized doses of ulotaront up to 75mg/d, small-to-medium effect sizes were observed. Importantly, the available data are limited. Therefore, the findings are inconclusive.

2.9 Sensitivity analyses

We did not conduct the following sensitivity analyses for the primary outcome due to the limited data: 1) Restricting the analysis to studies with low risk of bias, since there were 4 studies with low risk of bias in acute schizophrenia (Koblan et al. 2020; Sumitomo Pharma America 2023b, 2023c; Roche 2022), and 1 study with high risk of bias in Parkinson’s disease psychosis (1 study with high risk of bias) (Isaacson et al. 2023). 2) Excluding imputed data, since no imputed data were used in the analysis of the primary outcome. There were no imputed data in the analysis of the primary outcome.

Due to the limited number of studies, we also presented a fixed-effects model for all outcomes in addition to the random-effects model to assess the robustness of the findings. The findings were robust in the majority of cases. For the primary outcome in the meta-analysis of 4 studies in acute schizophrenia (Koblan et al. 2020; Sumitomo Pharma America 2023b, 2023c; Roche 2022), the point estimate of the effect sizes did not differ between random- and fixed-effects (SMD:0.15 and 0.13, respectively), but the 95% CI in the fixed-effects model was narrower, excluding the null effect (95% CI: -0.05, 0.34, and 0.02, 0.05, respectively). Nonetheless, the interpretation of the findings that TAAR1 agonists have little to no effect compared to placebo in improving overall symptoms does not change

2.10 Reporting bias

Reporting bias was evaluated using the ROB-ME tool (Matthew J. Page et al. 2023), taking into account the usable data from the eligible studies identified in the search, the comprehensiveness of the search, and potential patterns of missingness and small-study effects. We followed the algorithm to assign a low or high risk of reporting bias, or to express some concerns, by answering signalling questions related to the domains mentioned above.

2.10.1 Results matrix

We identified the total number of eligible and completed studies, with or without usable data, that could contribute to dropout and safety data for each comparison (as shown in Table 1 and Table 2): 1) There were 12 studies with 626 participants for the comparison of TAAR1 agonists versus placebo over a period of 1 day to 2 weeks. 2) There were 2 studies with 100 participants for the comparison of TAAR1 agonists versus placebo over the same duration. 3) For the comparison of TAAR1 agonists versus placebo over 3-13 weeks, there were 6 studies involving 1550 participants, including also 1 study (NCT03669640) focusing predominantly on negative symptoms. 4) Finally, it should be noted that one study (NCT04115319) with 475 participants could contribute to the comparison of TAAR1 agonists versus other antipsychotics for periods exceeding 13 weeks. However, no usable data for this analysis were available from any other study.

The results matrix for the eligible studies, which were identified in the search, for all outcomes with usable data from at least one study, can be found below in Table 2.

Timepoint	Study name	Population	Comparison	Sample size	Overall symptoms	Response	Positive symptoms	Negative symptoms	Depressive symptoms	Cognitive impairment	Dropouts due to any reason	Dropouts due to adverse events	Any adverse event	Serious adverse event	Mortality due to any cause	Nausea or vomiting	Weight change (kg)	Weight increase (dichotomous)	Prolactin levels (ng/ml)	Prolactin (dichotomous)	Extrapyramidal side-effects	Akathisia	Agitation	Anxiety	Sedation	Insomnia	Headache	QTc interval (msec)	QTc prolongtion (dichotomous)	Hypotension	Dizziness	Anticholinergic
1 day to 2 weeks	DA801002 (in Galluppi et al. 2021)	Volunteers	TAAR1 agonists vs. placebo	16	na	na	na	na	na	na	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	na	na	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks	Fowler et al. 2015	Volunteers	TAAR1 agonists vs. placebo	49	na	na	na	na	na	na	? (reported as well tolerated without relevant findings, no further information)	? (reported as well tolerated without relevant findings, no further information)	? (reported as well tolerated without relevant findings, no further information)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	na	na	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks	Hopkins et al. 2021	Volunteers	TAAR1 agonists vs. placebo	24	na	na	na	na	na	na	✓	✓	✓	✓	✓	✓	na	na	~ (prolactin elevation as dichotomous outcome)	✓	? (reported as generally safe and well tolerated)	? (reported as generally safe and well tolerated)	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	✓	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	~ (reported as dichotomous outcome)	✓	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)	? (reported as generally safe and well tolerated, no changes in vital signs or physical examination)
1 day to 2 weeks	JapicCTI-194581	Volunteers	TAAR1 agonists vs. placebo	64	na	na	na	na	na	na	?	?	?	?	?	?	na	na	?	?	?	?	?	?	?	?	?	?	?	?	?	?
1 day to 2 weeks	Koblan et al. 2016	Schizophrenia (clinically stable)	TAAR1 agonists vs. placebo	48	na	na	na	na	na	na	?	?	?	?	?	?	na	na	?	?	?	?	?	?	?	?	?	?	?	?	?	?
1 day to 2 weeks	NCT01940159	Schizophrenia (clinically stable)	TAAR1 agonists vs. placebo	48	na	na	na	na	na	na	?	?	?	?	?	?	na	na	?	?	?	?	?	?	?	?	?	?	?	?	?	?
1 day to 2 weeks	NCT02699372	Volunteers	TAAR1 agonists vs. placebo	164	na	na	na	na	na	na	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)
1 day to 2 weeks	NCT04325737	Schizophrenia (clinically stable)	TAAR1 agonists vs. placebo	13	na	na	na	na	na	na	?	?	?	?	?	?	na	na	?	?	?	?	?	?	?	?	?	?	?	?	?	?
1 day to 2 weeks	Perini et al. 2023	Volunteers	TAAR1 agonists vs.placebo vs. antipsychotics	105	na	na	na	na	na	na	✓	✓	✓	✓	✓	✓	na	na	? (no clinically meaningful changes in safety parameters, unclear if measured)	? (no clinically meaningful changes in safety parameters, unclear if measured)	? (no clinically meaningful changes in safety parameters)	? (no clinically meaningful changes in safety parameters)	? (no clinically meaningful changes in safety parameters)	? (no clinically meaningful changes in safety parameters)	✓	? (no clinically meaningful changes in safety parameters)	✓	? (no clinically meaningful changes in safety parameters, unclear if measured)	? (no clinically meaningful changes in safety parameters, unclear if measured)	? (no clinically meaningful changes in safety parameters)	✓	✓
1 day to 2 weeks	SEP361-101 (in Galluppi et al. 2021 and Chen et al. 2022)	Volunteers	TAAR1 agonists vs. placebo	52	na	na	na	na	na	na	? (reported as well tolerated without relevant findings, no further information)	? (reported as well tolerated without relevant findings, no further information)	? (reported as well tolerated without relevant findings, no further information)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	na	na	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)	? (no information, single dose study focusing on pharmacokinetics)
1 day to 2 weeks	Szabo (2023)	Narcolepsy-cataplexy	TAAR1 agonists vs. placebo	18	na	na	na	na	na	na	? (no clearly described under which treatments)	? (2 patients had dropped out due to nausea, but uclear under which treatment)	✓	✓	✓	? (4 patients had nausea but uclear under which treatment)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (well tolerated, no clinically significant or relevant abnormalities in ECG, blood pressure measurement, laboratory safety parameters)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (2 patients had somnolence but uclear under which treatment)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)	? (no clinically significant findings in laboratory parameters, vital signs, ECG, physical or neurological examinations)
1 day to 2 weeks	Tsukada et al. 2023	Schizophrenia (clinically stable)	TAAR1 agonists vs. placebo	68	na	na	na	na	na	na	? (no clearly described under which treatments)	✓	✓	✓	✓	✓	na	na	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	✓	? (no changes in vital signs, ulotaront well-tolerated)	? (no changes in vital signs, ulotaront well-tolerated)	✓	✓	? (no changes in vital signs, ulotaront well-tolerated)	✓	? (no changes in vital signs, ulotaront well-tolerated)
1 day to 2 weeks	NCT05402111	Schizophrenia (clinically stable)	TAAR1 agonists vs. antipsychotics	36	na	na	na	na	na	na	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?
3-13 weeks	Isaacson et al. 2023	Parkinson’s disease psychosis	TAAR1 agonists vs. placebo	39	✓	✓	✓	~ (probably not measured)	~ (probably not measured)	✓	✓	✓	✓	✓	✓	✓	? (no information, no clinically meaningful changes in ECG, laboratory values)	? (no information, no clinically meaningful changes in ECG, laboratory values)	? (no information, no clinically meaningful changes in ECG, laboratory values)	NA	~ (measured with UPDRS paRT III scale, no differences with placebo)	~ (measured with UPDRS paRT III scale, no differences with placebo)	? (neuropsychiatric events seemed to more frequent in ulotaront vs. placebo, including hallucinations and confusational state)	? (neuropsychiatric events seemed to more frequent in ulotaront vs. placebo, including hallucinations and confusational state)	✓	✓	?	? (no information, no clinically meaningful changes in ECG, laboratory values)	? (no information, no clinically meaningful changes in ECG, laboratory values)	✓	✓	?
3-13 weeks	Koblan et al. 2020	Schizophrenia (acute)	TAAR1 agonists vs. placebo	245	✓	✓	✓	✓	✓	? (probably not measured at the randomized phase)	✓	✓	✓	✓	✓	✓	✓	✓	✓	~ (reported as continuous)	✓	✓	✓	✓	✓	✓	✓	~ (reported as dichotomous outcome)	✓	?	?	?
3-13 weeks	NCT04072354	Schizophrenia (acute)	TAAR1 agonists vs. placebo	463	✓	✓	X	X	X	? (probably not measured)	✓	?	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	~ (frequency of extapyramidal side-effects was low and similar to placebo)	< (frequency of extapyramidal side-effects was low and similar to placebo)	? (no information, NNH for all adverse events >=10)	? (reported as common, NNH>=10)	NA	? (reported as common, NNH>=10)	? (reported as common, NNH>=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)
3-13 weeks	NCT04092686	Schizophrenia (acute)	TAAR1 agonists vs. placebo	462	✓ (adult) / ? (adolescent)	✓	X	X	X	? (probably not measured)	✓	?	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	NA	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	< (frequency of extapyramidal side-effects was low and similar to placebo)	< (frequency of extapyramidal side-effects was low and similar to placebo)	? (no information, NNH for all adverse events >=10)	? (reported as common, NNH>=10)	NA	? (reported as common, NNH>=10)	? (reported as common, NNH>=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)	? (no information, NNH for all adverse events >=10)
3-13 weeks	NCT04512066	Schizophrenia or schizoaffective disorder (acute)	TAAR1 agonists vs.placebo vs. antipsychotics	287	✓	✓	✓	✓	✓	?	✓	✓	✓	✓	✓	✓	< (reported as dichotomous outcome)	✓	?	?	?	?	✓	✓	?	✓	✓	?	?	?	?	?
3-13 weeks	NCT03669640	Schizophrenia (negative symptoms)	TAAR1 agonists vs. placebo	128	?	?	?	X (failed trial focusing on negative symptoms)	?	? (probably not measured)	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?
> 13 weeks	NCT04115319	Schizophrenia (clinically stable)	TAAR1 agonists vs. antipsychotics	475	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?	?

Table 2 Results matrix for the primary outcome. ✓: A study result is available for inclusion in the meta-analysis.; ~:No study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result.; ?: Unclear whether an eligible study result was generated or unclear reason of missing evidence. Narrative descriptions of the effects of drugs as reported in the studies are mentioned here to facilitate the judgement of regarding the reason of missingness. * Sumitomo Pharma America (2023b) included two parts, i.e., adults (sample size 435) and adolescents (sample size unclear but it was probably 28; planned 90). It should be noted that all of the other studies included adult populations. na: not applicable for this outcome (e.g., efficacy outcomes in healthy volunteers or after a single dose in stable patients).

2.10.2 Funnel plots and examination of small-study effects

There were insufficient data for the primary outcome but also other outcomes (i.e., fewer than 10 studies) to examine small-study effects with funnel plots. Thus, we cannot explore the pattern of missing evidence or conduct sensitivity analysis to explore the potential impact of the missing evidence. Thus, we replied the following signalling questions as ROB-ME-4.7: “probably no” and ROB-ME-4.8: “probably no”.

2.10.3 Coverage of the search strategy

We conducted a comprehensive search for both published and unpublished studies in multiple electronic databases, supplemented by manual searches of the reference lists of included studies and previous reviews. Screening was carried out by at least two independent reviewers. All studies identified in the search were conducted by the pharmaceutical industry. Although we contacted them, we have not received additional data for the first iteration. Considering that all eligible studies are experimental and were conducted recently, it is expected that most, if not all, have been registered, thus facilitating their detection during searches in clinical trial registries. Nonetheless, it’s possible that small phase I studies focusing on pharmacokinetics may not have been registered and could therefore have been overlooked. Consequently, we do not anticipate that our search has missed any major or significant studies (ROB-ME-3.1: “no”, ROB-ME-3.2: “probably yes”, ROB-ME-3.3:“probably yes”, ROB-ME-4.5: “no”).

2.10.4 ROB-ME evaluation

Data were available for all eligible studies concerning the primary outcome, i.e., answers to the ROB-ME signalling question 4.1: “no”, ROB-ME-4.3: “yes” for adolescents, ROB-ME-4.4: “no”, thus leading to low risk of reporting bias - considering also the comprehensiveness of the search.

The results matrix in Table 2 could also apply to the secondary efficacy outcomes in acute psychosis, although some studies did not have usable data for these outcomes. Specifically, the two failed phase III trials, (Sumitomo Pharma America 2023b, 2023c), did not report effects on symptom domains. Consequently, these analyses would be prone to bias due to missing evidence (ROB-ME-4.1: “yes”, ROB-ME-4.2: “yes”, thus leading to high risk of reporting bias).

The reasons for the missingness of data for these outcomes can be unclear, but in most cases, it is due to either not being measured or not reported for reasons other than their P-values, magnitude, and direction of effects, yet this cannot be excluded. Therefore, we employed, as a general rule, the following approach in response to ROB-ME-4.1: “no” (as none was generally considered to have reported usable data for these outcomes due to their P-value, magnitude, or direction), ROB-ME-4.3: ‘yes’, ROB-ME-4.4: ‘’NI” if less than 50% of the participants had usable data, suggesting the possibility that the findings could notably change if the missing data had been added to the analysis. The cut-off of 50% of the participants was selected to balance out that in most cases, the findings were not missing due to unfavorable findings (see Table 2) but also to consider the possibility that the findings may be likely to change with the addition of missing evidence, given the small number of studies and participants in their estimates. In this situation, we assigned some concerns or moderate risk of missing evidence given that ROB-ME-4.5: “no” (see above, 2.10.3), and patterns of missing evidence or sensitivity analyses could not be conducted. However, the impact of this on the magnitude and direction of the findings can be unclear. If there were data from more than 50% of the participants, we responded to ROB-ME-4.4: ’probably no’, leading to low risk given that ROB-ME-4.5: “no” , and patterns of missing evidence or sensitivity analyses could not be conducted.

Finally, low risk of reporting bias was judged for the outcomes used to provide mechanistic insights for the same reasons described above. The search was comprehensive and no other study was found to measure neurobiological outcomes.

2.11 Summary of evidence

2.11.1 Approach to evaluate the confidence in the evidence

For each comparison, outcome and timepoint, we presented the summary of the evidence by presenting the summary of the association, biases due to study limitations, biases due to reporting bias, biases due to indirectness and other biases.

Summary of the association: We presented the number of studies (N), participants (n) contributing to the analysis, the point estimates and 95% confidence intervals for both random- and fixed-effects models. We also made a statement about dose-effects for the primary outcome (Figure 67).

Within-study biases: This refers to the study limitations measured with the risk of bias assessments using RoB2 (Sterne et al. 2019). The majority of the studies had a low risk of bias, or at most, some concerns across domains (mainly in missing outcome data, and also in the randomization process, period, and carry-over effects in Tsukada et al. (2023)) and outcomes, except for one small study (Isaacson et al. 2023) with a high risk of bias due to missing outcome data for the efficacy outcomes. Thus, we assigned “high risk” for within-study biases when the efficacy outcomes were solely based on (Isaacson et al. 2023). On other occasions where studies had a low risk or at most some concerns, mainly in the domain of missing outcome data, we assigned “low risk” of within-study biases when no more than 50% of the studies were rated with some concerns, and “moderate risk” otherwise. In most cases, some concerns were raised due to missing outcome data. A recent meta-epidemiological study suggested that biases due to missing outcome data might underestimate the effects (Wang et al. 2024). In schizophrenia trials, there is evidence that participants who dropped out may have a worse prognosis compared to those who stayed in the trial (Rabinowitz and Davidov 2008). However, there were generally no clear differences in dropouts between TAAR1 agonists and control conditions, although TAAR1 may be associated with higher dropout rates compared to placebo (Figure 11). Therefore, we judged that a high risk of bias due to missing outcome data in efficacy outcomes in Isaacson et al. (2023), could have possibly overestimated the effects of TAAR1 agonists compared to placebo in favor of the former. However, in other cases, when there were some concerns for safety, it is unclear whether missing outcome data could have led to biased findings.

Across-study bias: This is referring to reporting bias, and we used the approach mentioned above to assign “low risk”, “moderate risk” or “high risk”.

Indirectness: We assigned “no concerns” regarding indirectness for the efficacy outcomes, as there were no issues related to population, interventions, control conditions, outcomes, or settings in the clinical trials involving adults with an acute episode of schizophrenia or Parkinson’s disease psychosis. However, potential indirectness in terms of population characteristics may exist in the analysis of other outcomes. This is because we pooled data from diverse populations, including those with schizophrenia spectrum disorders, Parkinson’s disease psychosis, narcolepsy-cataplexy, and healthy volunteers. Although the majority of adverse events might not vary significantly across these groups, we considered “moderate risk” regarding indirectness when the analyses included fewer than 50% of participants with schizophrenia. This is because schizophrenia can be considered the primary population to which these findings would be applied. Nevertheless, the impact on the magnitude and direction of the effects remains unclear.

Other biases: We considered additional biases, such as potential factors that could impact the magnitude and direction of the findings. Specifically, we regarded “moderate risk” for other biases for the primary outcome and response to treatment in adults with an acute episode of schizophrenia due to potential problems in the execution of two phase III trials on ulotaront during COVID-19 (Sumitomo Pharma America 2023b, 2023c). These trials had high placebo effects of about 14 points and 19 points reduction in PANSS total scores (compared to a mean of approximately 6 points in antipsychotic trials, (Stefan Leucht et al. 2018)), suggesting that potential factors associated with placebo effects could have diluted effect sizes and underestimated the effects. A conference abstract at ACNP 2024 (“ACNP 62(nd) Annual Meeting: Poster Abstracts P251 - P500” 2023) reported that pooled analyses of these two trials (Sumitomo Pharma America 2023b, 2023c) using participants enrolled before COVID-19 found effect sizes similar to those in the phase II trial of Koblan et al. (2020) . Potential explanations, among others, could include the pressure for recruitment during the pandemic that might have led to baseline inflation and less careful recruitment, difficulties in the execution and monitoring of the trial such as protocol deviations and co-treatments, or other factors (Stefan Leucht, Heres, and Davis 2013; Stefan Leucht et al. 2019). It should be noted that another trial was conducted during COVID-19 (Roche 2022), but the potential impact of the pandemic on its execution has not been reported. Nonetheless, the possibility that the findings have been underestimated cannot be excluded.

2.11.2 Summary of evidence tables

Summary of evidence table for efficacy outcomes

TAAR1 agonists versus placebo in adults with an acute episode of schizophrenia

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
Overall symptoms (PANSS total) - primary outcome (Figure 3a)	4-6 weeks	N=4, n=1291; Random-effects: SMD=0.15, 95%CI: -0.05, 0.34; Fixed-effects: SMD=0.13, 95%CI: 0.02, 0.25; Dose effects: uncertain/unclear dose-response indication (Figure 67)	Low risk: All studies had overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Moderate risk: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which in some cases could be associated with factors related to smaller effect sizes. Specifically, a pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects of TAAR1 agonists compared to placebo in favor of the latter.
Response to treatment (≥50% or ≥20% reduction in PANSS total) (Figure 8a)	4-6 weeks	N=4, n=1357; Random-effects: 23.7% vs. 18.7%, OR=1.35, 95%CI: 0.86, 2.12; Fixed-effects: OR=1.39, 95%CI: 1.04, 1.86	Low risk: All studies had overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Moderate risk: Three trials were conducted during COVID-19 (2 in ulotaront, 1 in ralmitaront), which in some cases could be associated with factors related to smaller effect sizes. Specifically, a pooled analysis of the two Phase III ulotaront trials, using only the participants enrolled before COVID-19, showed effect sizes like the Phase II ulotaront trial. This may have underestimated the effects of TAAR1 agonists compared to placebo in favor of the latter.
Positive symptoms (PANSS positive subscale/factor) (Figure 4a)	4 weeks	N=2, n=399; Random-effects: SMD=0.23, 95%CI: 0.03, 0.43; Fixed-effects: SMD=0.23, 95%CI: 0.03, 0.43	Low risk: All studies had overall low risk of bias.	High risk. This may have overestimated the effects in favor of TAAR1 agonists.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Negative symptoms (PANSS negative subscale/factor) (Figure 5)	4 weeks	N=2, n=399; Random-effects: SMD=0.23, 95%CI: -0.01, 0.48; Fixed-effects: SMD=0.24, 95%CI: 0.04, 0.44	Low risk: All studies had overall low risk of bias.	High risk. This may have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Depressive symptoms (PANSS anxiety/depression factor) (Figure 6)	4 weeks	N=2, n=399; Random-effects: SMD=0.17, 95%CI: -0.06, 0.39; Fixed-effects: SMD=0.17, 95%CI: -0.03, 0.37	Low risk: All studies had overall low risk of bias.	High risk. This may have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.

Table 3 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in adults with an acute episode of schizophrenia. There were data for ulotaront and ralmitaront. There is an uncertain/unclear dose-response indication (see Figure 67). Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. SMD: Standardized mean difference, OR: Odds ratio, 95%CI: 95% confidence interval.

TAAR1 agonists versus antipsychotics in adults with an acute episode of schizophrenia

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
Overall symptoms (PANSS total) – primary outcome (Figure 40)	4 weeks	N=1, n=156; SMD=-0.53, 95%CI: -0.86, -0.2	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Response to treatment (≥50%reduction in PANSS total) (Figure 44)	4 weeks	N=1, n=214; 7.9% vs. 13.5%, OR=0.55, 95%CI: 0.22, 1.35	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Positive symptoms (PANSS positive subscale/factor) (Figure 41)	4 weeks	N=1, n=156; SMD=-0.55, 95%CI: -0.89, -0.22	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Negative symptoms (PANSS negative subscale/factor) (Figure 42)	4 weeks	N=1, n=156; SMD=-0.13, 95%CI: -0.46, 0.19	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Depressive symptoms (PANSS anxiety/depression factor) (Figure 43)	4 weeks	N=1, n=156; SMD=-0.23, 95%CI: -0.56, 0.1	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.

Table 4 Summary of evidence table for the comparison of TAAR1 agonists versus antipsychotics for efficacy outcomes in adults with an acute episode of schizophrenia. There were data for ralmitaront versus risperidone in a single study (Roche 2022). Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. SMD: Standardized mean difference, OR: Odds ratio, 95%CI: 95% confidence interval.

TAAR1 agonists versus placebo for efficacy outcomes in Parkinson’s disease psychosis

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
Overall symptoms (NPI) (Figure 1b)	6 weeks	N=1, n=37; SMD=-0.28, 95%CI: -0.95, 0.38	High risk: 1 study with overall high risk of bias (due to missing outcome data).This might have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Response to treatment (≥50% in SAPS-PD) (Figure 8b)	6 weeks	N=1, n=39; 24% vs. 21.4%, OR=1.16, 95%CI: 0.24, 5.58	High risk: 1 study with overall high risk of bias (due to missing outcome data).This might have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Positive symptoms (SAPS-PD) (Figure 2b)	6 weeks	N=1, n=38; SMD=0.14, 95%CI: -0.52, 0.8	High risk: 1 study with overall high risk of bias (due to missing outcome data).This might have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Cognitive impairment (MMSE) (Figure 7)	6 weeks	N=1, n=37; SMD=-0.51, 95%CI: -1.18, 0.17	High risk: 1 study with overall high risk of bias (due to missing outcome data).This might have overestimated the effects of TAAR1 agonists compared to placebo in favor of the former.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.

Table 5 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for efficacy outcomes in Parkinson’s disease psychosis. There were data from a single study for ulotaront (Isaacson et al. 2023). Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. SMD: Standardized mean difference, OR: Odds ratio, 95%CI: 95% confidence interval.

Summary of evidence table for dropouts and side-effects

TAAR1 agonists versus placebo for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
Dropouts due to any reason (Figure 10)	1 day	N=2, n=93; 11.7% vs. 4.7%, OR=2.67, 95%CI: 0.48, 14.8 (one study reported 0 events in both arms)	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear, but the number of dropouts in studies examining single doses should be small.	Moderate risk: No usable data from studies in schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dropouts due to any reason (Figure 11)	4-6 weeks	N=5, n=1396; Random-effects: 22.9% vs. 19.6%, OR=1.22, 95%CI: 0.93, 1.60; Fixed-effects: OR=1.22, 95%CI: 0.93, 1.60	Low risk: All studies had overall low risk of bias.	Low risk.	Low risk: 80% studies and 97.2% participants with schizophrenia.	Low risk: No indication of other biases.
Dropouts due to adverse events (Figure 12)	1 day	N=3 n=161; 0.5% vs. 1.6%, OR=0.33, 95%CI: 0.02, 5.72	Low risk: 66.7% had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear, but the number of dropouts in studies examining single doses should be small.	Moderate risk: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dropouts due to adverse events (Figure 13)	4-6 weeks	N=3 n=497; Random-effects: 8.1% vs. 7.1%, OR=1.15, 95%CI: 0.58, 2.29; Fixed-effects: OR=1.19, 95%CI: 0.6, 2.34	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia.	Low risk: No indication of other biases.
Serious adverse events (Figure 14)	1 day to 2 weeks	N=4 n=177; Random-effects: 4.6% vs. 1.6%, OR=3.02, 95%CI: 0.36, 25.76; Fixed-effects: OR=3.02, 95%CI: 0.36, 25.76	Low risk: 75% had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Serious adverse events (Figure 15)	4-6 weeks	N=3 n=497; Random-effects: 2.7% vs. 2.7%, OR=0.97, 95%CI: 0.28, 3.38; Fixed-effects: OR=1.01, 95%CI: 0.32, 3.21	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia	Low risk: No indication of other biases.
Death due to any cause	1 day to 2 weeks	N=4 n=177; not estimable effect size 0 events in both arms	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Death due to any cause (Figure 16)	4-6 weeks	N=3 n=497; 3% vs. 1%, OR=3.15, 95%CI: 0.13, 78.11	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia	Low risk: No indication of other biases.
Any adverse event (Figure 17)	1 day to 2 weeks	N=4 n=177; Random-effects: 52.3% vs. 11.4%, OR=8.49, 95%CI: 1.73, 41.66; Fixed-effects: OR=9.3, 95%CI: 3.92, 22.08	Low risk: 75% had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 25% studies and 38.4% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Any adverse event (Figure 18)	4-6 weeks	N=3 n=497; Random-effects: 48.7% vs. 54.6%, OR=0.79, 95%CI: 0.54, 1.15; Fixed-effects: OR=0.78, 95%CI: 0.54, 1.15	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia	Low risk: No indication of other biases.
Anticholinergic symptom (Figure 19)	1 day	N=1 n=69; 15.3% vs. 1.4%, OR=12.44, 95%CI: 0.66, 234.38	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Hypotension (Figure 20)	6 weeks	N=1 n=39; 52.4% vs. 78.6%, OR=0.3, 95%CI: 0.07, 1.32	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dizziness (Figure 21)	1 day	N=2 n=137; Random-effects: 19.9% vs. 3.5%, OR=6.89, 95%CI: 1.98, 23.92; Fixed-effects: OR=6.89, 95%CI: 1.98, 23.92	Moderate risk: 50% of studies had an overall low risk of bias (some concerns regarding the randomization process, missing outcome data, and period/carryover effects). The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 50% studies and 49.6% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dizziness (Figure 22)	6 weeks	N=1 n=39; 16% vs. 7.1%, OR=2.48, 95%CI: 0.25, 24.65	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Nausea/vomitting (Figure 23)	1 day	N=3 n=161; Random-effects: 19.5% vs. 1.6%, OR=15.14, 95%CI: 3.71, 61.75; Fixed-effects: OR=15.14, 95%CI: 3.71, 61.75	Low risk: 66.7% had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Nausea/vomitting (Figure 24)	4-6 weeks	N=3 n=497; Random-effects: 3.9% vs. 4.4%, OR=0.88, 95%CI: 0.25, 3.15; Fixed-effects: OR=0.92, 95%CI: 0.38, 2.24	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia.	Low risk: No indication of other biases.
QTc prolongation (any cut-off) (Figure 25)	1 day	N=2 n=92; 8.1% vs. 1.6%, OR=5.32, 95%CI: 0.6, 46.78	Moderate risk: 50% of studies had an overall low risk of bias (some concerns regarding the randomization process and missing outcome data). The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 50% studies and 73.9% participants with schizophrenia.	Low risk: No indication of other biases.
QTc prolongation (any cut-off)	4 weeks	N=1 n=245; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
QTc interval (msec) (Figure 26)	1 day	N=1 n=62; MD=1.25, 95%CI: -2.87, 5.37	Moderate risk: 1 study with overall some concerns in risk of bias regarding the randomization process and missing outcome data. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Weight increased (≥7% increase or any cut-off) (Figure 27)	4 weeks	N=2 n=458; Random-effects: 1.1% vs. 1%, OR=1.04, 95%CI: 0.17, 6.47; Fixed-effects: OR=1.04, 95%CI: 0.17, 6.47	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Weight (kg) (Figure 28)	4 weeks	N=1 n=245; MD=0.4, 95%CI: -0.13, 0.93	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Prolactin elevation (any cut-off)	1 day	N=1 n=24; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Prolactin levels (ng/ml) (Figure 29)	4 weeks	N=1 n=227; MD=-0.58, 95%CI: -7.87, 6.7	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Akathisia (Figure 30)	4 weeks	N=1 n=245; 1.2% vs. 0.4%, OR=3.15, 95%CI: 0.13, 78.11	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Extrapyramidal symptoms (Figure 31)	4 weeks	N=1 n=245; 3.3% vs. 3.2%, OR=1.04, 95%CI: 0.25, 4.27	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Anxiety	1 day	N=1 n=69; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Anxiety (Figure 32)	4 weeks	N=2 n=458; Random-effects: 2.6% vs. 7.6%, OR=0.32, 95%CI: 0.12, 0.85; Fixed-effects: OR=0.31, 95%CI: 0.12, 0.8	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Agitation (Figure 33)	4 weeks	N=2 n=458; Random-effects: 5.5% vs. 4.2%, OR=1.35, 95%CI: 0.53, 3.43; Fixed-effects: OR=1.38, 95%CI: 0.56, 3.45	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Headache (Figure 33)	1 day	N=1 n=69; 11.5% vs. 20.6%, OR=0.5, 95%CI: 0.13, 1.89	Low risk: 1 study with an overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Headache (Figure 34)	4 weeks	N=2 n=458; Random-effects: 7.9% vs. 9%, OR=0.86, 95%CI: 0.43, 1.69; Fixed-effects: OR=0.86, 95%CI: 0.44, 1.68	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.
Sedation (Figure 36)	1 day	N=3 n=161; Random-effects: 28.8% vs. 4.1%, OR=9.55, 95%CI: 3.5, 26.09; Fixed-effects: OR=9.55, 95%CI: 3.5, 26.09	Low risk: 66.7% had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: 33.3% studies and 42.2% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Sedation (Figure 37)	4-6 weeks	N=2 n=284; Random-effects: 8.1% vs. 7.2%, OR=1.14, 95%CI: 0.44, 3; Fixed-effects: OR=1.15, 95%CI: 0.44, 2.99	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 50% studies and 86.3% participants with schizophrenia.	Low risk: No indication of other biases.
Insomnia (Figure 38)	4 weeks	N=3 n=497; Random-effects: 5.6% vs. 6%, OR=0.93, 95%CI: 0.17, 5.06; Fixed-effects: OR=0.71, 95%CI: 0.32, 1.55	Low risk: All studies had overall low risk of bias.	Moderate risk: The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: 66.7% studies and 92.2% participants with schizophrenia.	Low risk: No indication of other biases.

Table 6 Summary of evidence table for the comparison of TAAR1 agonists versus placebo for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers. There were data for ulotaront and ralmitaront. Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. MD: Mean difference, OR: Odds ratio, 95%CI: 95% confidence interval.

TAAR1 agonists versus antipsychotics for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
Dropouts due to any reason (Figure 46)	1 day	N=1 n=71; 14.3% vs. 5.6%, OR=2.83, 95%CI: 0.51, 15.69	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dropouts due to any reason (Figure 47)	4 weeks	N=1 n=214; 22.9% vs. 18.9%, OR=1.27, 95%CI: 0.63, 2.56	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Dropouts due to adverse events	1 day	N=1 n=71; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dropouts due to adverse events (Figure 48)	4 weeks	N=1 n=214; 6.4% vs. 1.4%, OR=5.02, 95%CI: 0.62, 40.38	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Serious adverse events (Figure 49)	1 day	N=1 n=71; 4.2% vs. 1.4%, OR=3.17, 95%CI: 0.13, 80.58	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Serious adverse events (Figure 50)	4 weeks	N=1 n=214; 2.5% vs. 0.7%, OR=3.79, 95%CI: 0.19, 74.42	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Death due to any cause	1 day	N=1 n=71; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Death due to any cause	4 weeks	N=1 n=214; not estimable effect size 0 events in both arms	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Any adverse event (Figure 51)	1 day	N=1 n=71; 97.1% vs. 41.7%, OR=47.6, 95%CI: 5.85, 387.2	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Any adverse event (Figure 52)	4 weeks	N=1 n=214; 26.5% vs. 48.6%, OR=0.38, 95%CI: 0.21, 0.68	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Anticholinergic symptom (Figure 53)	1 day	N=1 n=71; 15.3% vs. 1.4%, OR=13.16, 95%CI: 0.7, 247.71	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Dizziness (Figure 54)	1 day	N=1 n=71; 28.6% vs. 2.8%, OR=14, 95%CI: 1.68, 116.49	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Nausea/vomiting (Figure 55)	1 day	N=1 n=71; 34.7% vs. 1.4%, OR=38.83, 95%CI: 2.19, 687.51	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Nausea/vomiting (Figure 56)	4 weeks	N=1 n=214; 1.4% vs. 8.1%, OR=0.16, 95%CI: 0.03, 0.84	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Weight increased (any cut-off) (Figure 57)	4 weeks	N=1 n=214; 1.4% vs. 10.8%, OR=0.12, 95%CI: 0.02, 0.58	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Anxiety (Figure 58)	1 day	N=1 n=71; 1.2% vs. 8.3%, OR=0.13, 95%CI: 0.01, 2.71	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Anxiety (Figure 59)	4 weeks	N=1 n=214; 3.6% vs. 6.8%, OR=0.51, 95%CI: 0.14, 1.83	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Agitation (Figure 60)	4 weeks	N=1 n=214; 6% vs. 0.7%, OR=9.56, 95%CI: 0.54, 167.96	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Headache (Figure 61)	1 day	N=1 n=71; 11.4% vs. 2.8%, OR=4.52, 95%CI: 0.48, 42.59	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Headache (Figure 62)	4 weeks	N=1 n=214; 6.4% vs. 8.1%, OR=0.78, 95%CI: 0.27, 2.28	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.
Sedation (Figure 63)	1 day	N=1 n=71; 60% vs. 13.9%, OR=9.3, 95%CI: 2.91, 29.72	Low risk: 1 study with an overall low risk of bias.	Low risk.	Moderate risk: 0% studies and 0% participants with schizophrenia. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Low risk: No indication of other biases.
Insomnia (Figure 64)	4 weeks	N=1 n=214; 5.7% vs. 6.8%, OR=0.84, 95%CI: 0.26, 2.65	Low risk: 1 study with an overall low risk of bias.	Low risk.	Low risk: No clear indication of indirectness	Low risk: No indication of other biases.

Table 7 Summary of evidence table for the comparison of TAAR1 agonists versus antipsychotics for dropouts and side-effects in adults with psychosis, other mental health conditions and healthy volunteers. There were data from two studies, one for ulotaront vs. amisulpride (single dose) (Perini et al. 2023), and one for ralmitaront vs. risperidone (4 weeks) (Roche 2022). Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. OR: Odds ratio, 95%CI: 95% confidence interval.

Summary of evidence table for the mechanistic insights of TAAR1 agonism for psychosis

Evidence from two neuroimaging studies (Perini et al. 2023; Sumitomo Pharma America 2023a) generally supports the notion that TAAR1 agonists can ameliorate the elevated striatal dopamine synthesis and release capacity that is considered central in the development of symptoms of psychosis (Howes and Shatalina 2022). The summary of the evidence of these studies is presented below.

Outcome	Timepoint	Summary of the association	Within-study biases	Across-studies biases	Indirectness	Other biases
fMRI of BOLD striatal responses to reward processing, measured during the anticipatory phase of the Monetary Incentive Delay task in healthy volunteers with low or high schizotypy traits, treated with a single dose of ulotaront, placebo, or amisulpride.	2 hours after treatment	N=1, n=96; In anticipation of loss, ulotaront appeared to be associated with smaller BOLD striatal responses compared to placebo (left: SMD=-0.55, 95%CI: -1.05, -0.05; right: SMD=-0.44, 95%CI: -0.94, 0.06) but not to amisulpride (left: SMD=-0.22, 95%CI: -0.71, 0.27; right: SMD: -0.11, 95%CI: -0.60, 0.38). In anticipation of a win, ulotaront did not seem to differ in BOLD striatal responses compared to placebo (left: SMD=-0.25, 95%CI: -0.75, 0.25; right: SMD=-0.25, 95%CI: -0.75, 0.25) and amisulpride (left: SMD=-0.11, 95%CI: -0.60, 0.38; right: SMD=-0.08, 95%CI: -0.57, 0.41). The interaction with schizotypy traits for BOLD striatal responses was not reported. However, it was reported that ulotaront could reverse, in comparison to placebo, the aberrant BOLD right insular responses to anticipation of loss in participants with high schizotypy traits.	Moderate risk: The study had a low risk of bias (Figure 2), but it is unclear whether the selection of the primary outcome reported in this table was determined a priori or a posteriori. The findings from all measured outcomes were reported, but not all those regarding interactions with schizotypy traits. Nevertheless, the possibility of bias due to selectively reported results cannot be excluded. This bias could have exaggerated the findings in favor of TAAR1 agonists.	Low risk.	Moderate risk: The study did not include participants with psychosis, but healthy volunteers with low and high schizotypy traits. The impact of the bias on the magnitude and direction of the effects of TAAR1 agonists is unclear.	Moderate risk: Ulotaront appeared to cause sedation in 60% of the participants, more frequently compared to placebo (Figure 36) and amisulpride (Figure 63). Consequently, ulotaront was associated with decreased performance and accuracy across the different neuropsychological tasks used in the study, but it was not correlated with the BOLD responses and impaired reaction times by <10% in this task. The impact of this bias on the magnitude and direction of the effects of TAAR1 agonists on this outcome is unclear.
Dopamine synthesis capacity in the striatum measured with F-DOPA PET in clinically stable patients with schizophrenia treated with ulotaront as add-on to antipsychotic treatment	2 weeks	N=1, n=22; Reduction of dopamine synthesis capacity in the striatum: -3.98%, 95% CI: -8.68%, 0.72% (reductions in all striatal subregions). This effect was not found to be correlated with improvement in overall symptoms (r=0.19, p>0.05), but it was correlated with reductions in positive symptoms (r=0.49, p<0.05).	High risk: The study was single arm without control conditions, and open label. The outcome measure can be considered objective. Uncontrolled findings may be exaggerated in favor of TAAR1 agonists.	Low risk.	Low risk: No clear indication of indirectness.	Low risk: No indication of other biases.

Table 8 Summary of evidence table for the mechanistic insights of TAAR1 agonism for psychosis. The findings of two studies (Perini et al. 2023; Sumitomo Pharma America 2023a) with available neurobiological measures relevant to psychosis are narratively reported. These include the double-blind randomized controlled trial of Perini et al. (2023) with the fMRI BOLD striatal responses in the anticipatory phase of the Monetary Incentive Delay (MID) task (proxy for increased dopaminergic signalling in the striatum), and the open label single-arm study of Sumitomo Pharma America (2023a) with F-DOPA PET in the striatum. Across-study bias was evaluated using the ROB-ME approach (Matthew J. Page et al. 2023). N=number of studies, n=number of participants. SMD=Standardized mean difference, 95%CI: 95% confidence interval. p-value: p-value for the correlation coefficient.

3. Abbreviations

BOLD: Blood Oxygen Level-Dependent

DB: Double-Blind

DSM-IV-TR/DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision / Fifth Edition

ECG: Electrocardiogram

F-DOPA: Fluorodopa

GAD: Generalized Anxiety Disorder

GRADE approach: Grading of Recommendations Assessment, Development, and Evaluation approach

kg: Kilograms

MDD: Major Depressive Disorder

MD: Mean Difference

MID: Monetary Incentive Delay task

mg: Milligrams

MMSE: Mini-Mental State Examination

msec: Milliseconds

na: Not applicable/available

ng/ml: Nanograms per Milliliter

N: Number of studies

n: Number of participants

NNH: Number Needed to Harm

NPI: Neuropsychiatric Inventory

OR: Odds Ratio

PANSS: Positive and Negative Syndrome Scale

PET: Positron Emission Tomography

REML: Restricted Maximum Likelihood

RCT: Randomized Controlled Trial

RoB2: Risk of Bias 2

ROB-ME: Risk Of Bias due to Missing Evidence

SAPS-PD: Scale for the Assessment of Positive Symptoms in Parkinson’s Disease

SD: Standard Deviation

SMD: Standardized Mean Difference

TAAR1: Trace amine-associated receptor 1

4. References

We used R version 4.3.2 (R Core Team 2023) and the following R packages: devtools v. 2.4.5 (Wickham et al. 2022), kableExtra v. 1.3.9.9001 (Zhu 2023), knitr v. 1.45 (Xie 2014, 2015, 2023), Matrix v. 1.6.1.1 (Bates, Maechler, and Jagan 2023), meta v. 6.5.0 (Balduzzi, Rücker, and Schwarzer 2019), metadat v. 1.2.0 (White et al. 2022), metafor v. 4.2.0 (Viechtbauer 2010), netmeta v. 2.8.2 (Balduzzi et al. 2023), numDeriv v. 2016.8.1.1 (Gilbert and Varadhan 2019), PRISMA2020 v. 1.1.1 (Haddaway et al. 2022), robvis v. 0.3.0.900 (McGuinness and Higgins 2020), tidyverse v. 2.0.0 (Wickham et al. 2019), usethis v. 2.2.0 (Wickham et al. 2023), writexl v. 1.4.2 (Ooms 2023).

“ACNP 62(nd) Annual Meeting: Poster Abstracts P251 - P500.” 2023. Journal Article. Neuropsychopharmacology 48 (Suppl 1): 211–354. https://doi.org/10.1038/s41386-023-01756-4.

Balduzzi, Sara, Gerta Rücker, Adriani Nikolakopoulou, Theodoros Papakonstantinou, Georgia Salanti, Orestis Efthimiou, and Guido Schwarzer. 2023. “netmeta: An R Package for Network Meta-Analysis Using Frequentist Methods.” Journal of Statistical Software 106 (2): 1–40. https://doi.org/10.18637/jss.v106.i02.

Balduzzi, Sara, Gerta Rücker, and Guido Schwarzer. 2019. “How to Perform a Meta-Analysis with R: A Practical Tutorial.” Evidence-Based Mental Health, no. 22: 153–60.

Bates, Douglas, Martin Maechler, and Mikael Jagan. 2023. Matrix: Sparse and Dense Matrix Classes and Methods. https://CRAN.R-project.org/package=Matrix.

Chiou, W. L. 1978. “Critical Evaluation of the Potential Error in Pharmacokinetic Studies of Using the Linear Trapezoidal Rule Method for the Calculation of the Area Under the Plasma Level–Time Curve.” Journal Article. J Pharmacokinet Biopharm 6 (6): 539–46. https://doi.org/10.1007/bf01062108.

Elbourne, Diana R, Douglas G Altman, Julian PT Higgins, Francois Curtin, Helen V Worthington, and Andy Vail. 2002. “Meta-Analyses Involving Cross-over Trials: Methodological Issues.” International Journal of Epidemiology 31 (1): 140149.

Gilbert, Paul, and Ravi Varadhan. 2019. numDeriv: Accurate Numerical Derivatives. https://CRAN.R-project.org/package=numDeriv.

Haddaway, Neal R, Matthew J Page, Chris C Pritchard, and Luke A McGuinness. 2022. “PRISMA2020: An r Package and Shiny App for Producing PRISMA 2020-Compliant Flow Diagrams, with Interactivity for Optimised Digital Transparency and Open Synthesis.” Campbell Systematic Reviews 18 (2): e1230. https://doi.org/10.1002/cl2.1230.

Halff, E. F., G. Rutigliano, A. Garcia-Hidalgo, and O. D. Howes. 2023. “Trace Amine-Associated Receptor 1 (TAAR1) Agonism as a New Treatment Strategy for Schizophrenia and Related Disorders.” Journal Article. Trends Neurosci 46 (1): 60–74. https://doi.org/10.1016/j.tins.2022.10.010.

Higgins, Julian P. T., James Thomas, Jacqueline Chandler, Miranda Cumpston, Tianjing Li, Matthew J. Page, and Vivian A. Welch. 2019. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons.

Hopkins, Seth C., Nina Dedic, and Kenneth S. Koblan. 2021. “Effect of TAAR1/5-HT1A Agonist SEP-363856 on REM Sleep in Humans.” Journal Article. Translational Psychiatry 11 (1): 228. https://doi.org/10.1038/s41398-021-01331-9.

Howes, Oliver D, and Ekaterina Shatalina. 2022. “Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance.” Biological Psychiatry 92 (6): 501513.

Huhn, M., A. Nikolakopoulou, J. Schneider-Thoma, M. Krause, M. Samara, N. Peter, T. Arndt, et al. 2019. “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.” Journal Article. Lancet 394 (10202): 939–51. https://doi.org/10.1016/s0140-6736(19)31135-3.

IntHout, Joanna, John P. A. Ioannidis, and George F. Borm. 2014. “The Hartung-Knapp-Sidik-Jonkman Method for Random Effects Meta-Analysis Is Straightforward and Considerably Outperforms the Standard DerSimonian-Laird Method.” Journal Article. BMC Medical Research Methodology 14 (1): 25. https://doi.org/10.1186/1471-2288-14-25.

Isaacson, S. H., M. Goldstein, R. Pahwa, C. Singer, K. Klos, M. Pucci, Y. Zhang, D. Crandall, K. S. Koblan, and B. Navia. 2023. “Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT(1A) Agonist, in Patients with Parkinson Disease Psychosis: A Pilot Study.” Journal Article. Neurol Clin Pract 13 (4): e200175. https://doi.org/10.1212/cpj.0000000000200175.

Koblan, K. S., J. Kent, S. C. Hopkins, J. H. Krystal, H. Cheng, R. Goldman, and A. Loebel. 2020. “A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.” Journal Article. N Engl J Med 382 (16): 1497–1506. https://doi.org/10.1056/NEJMoa1911772.

Leucht, S., S. Siafis, R. R. Engel, J. Schneider-Thoma, I. Bighelli, A. Cipriani, T. A. Furukawa, and J. M. Davis. 2022. “How Efficacious Are Antipsychotic Drugs for Schizophrenia? An Interpretation Based on 13 Effect Size Indices.” Journal Article. Schizophr Bull 48 (1): 27–36. https://doi.org/10.1093/schbul/sbab094.

Leucht, Stefan, Anna Chaimani, Claudia Leucht, Maximilian Huhn, Dimitris Mavridis, Bartosz Helfer, Myrto Samara, et al. 2018. “60 Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Meta-Regression of Predictors of Placebo Response.” Schizophrenia Research 201: 315323.

Leucht, Stefan, Anna Chaimani, Dimitris Mavridis, Claudia Leucht, Maximilian Huhn, Bartosz Helfer, Myrto Samara, Andrea Cipriani, John R Geddes, and John M Davis. 2019. “Disconnection of Drug-Response and Placebo-Response in Acute-Phase Antipsychotic Drug Trials on Schizophrenia? Meta-Regression Analysis.” Neuropsychopharmacology 44 (11): 19551966.

Leucht, Stefan, Stephan Heres, and John M Davis. 2013. “Increasing Placebo Response in Antipsychotic Drug Trials: Let’s Stop the Vicious Circle.”

McGuinness, Luke A, and Julian PT Higgins. 2020. “Risk-of-Bias VISualization (Robvis): An r Package and Shiny Web App for Visualizing Risk-of-Bias Assessments.” Research Synthesis Methods. https://doi.org/10.1002/jrsm.1411.

Ooms, Jeroen. 2023. writexl: Export Data Frames to Excel “xlsx” Format. https://CRAN.R-project.org/package=writexl.

Page, Matthew J, Joanne E McKenzie, Patrick M Bossuyt, Isabelle Boutron, Tammy C Hoffmann, Cynthia D Mulrow, Larissa Shamseer, et al. 2021. “The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews.” International Journal of Surgery 88: 105906.

Page, Matthew J., Jonathan A. C. Sterne, Isabelle Boutron, Asbjørn Hróbjartsson, Jamie J. Kirkham, Tianjing Li, Andreas Lundh, Evan Mayo-Wilson, Joanne E. McKenzie, and Lesley A. Stewart. 2023. “ROB-ME: A Tool for Assessing Risk of Bias Due to Missing Evidence in Systematic Reviews with Meta-Analysis.” Bmj 383.

Perini, F., J. M. Nazimek, S. McKie, L. P. Capitão, J. Scaife, D. Pal, M. Browning, et al. 2023. “Effects of Ulotaront on Brain Circuits of Reward, Working Memory, and Emotion Processing in Healthy Volunteers with High or Low Schizotypy.” Journal Article. Schizophrenia (Heidelb) 9 (1): 49. https://doi.org/10.1038/s41537-023-00385-6.

R Core Team. 2023. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing. https://www.R-project.org/.

Rabinowitz, Jonathan, and Ori Davidov. 2008. “The Association of Dropout and Outcome in Trials of Antipsychotic Medication and Its Implications for Dealing with Missing Data.” Schizophrenia Bulletin 34 (2): 286291.

Roche, Hoffmann-La. 2022. “NCT04512066: A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) Vs Placebo in Patients with an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder.” Journal Article. https://www.clinicaltrials.gov/study/NCT04512066.

Schwarzer, Guido, Hiam Chemaitelly, Laith J. Abu-Raddad, and Gerta Rücker. 2019. “Seriously Misleading Results Using Inverse of Freeman-Tukey Double Arcsine Transformation in Meta-Analysis of Single Proportions.” Research Synthesis Methods 10 (3): 476–83.

Siafis, Spyridon, Robert McCutcheon, Virginia Chiocchia, Edoardo G Ostinelli, Simonne Wright, Claire Stansfield, Damian Omari Juma, Ioannis Mantas, Oliver D Howes, and Grazia Rutigliano. 2023. “Trace Amine-Associated Receptor 1 (TAAR1) Agonists for Psychosis: Protocol for a Living Systematic Review and Meta-Analysis of Human and Non-Human Studies.” Wellcome Open Research 8.

Sterne, J. A. C., J. Savović, M. J. Page, R. G. Elbers, N. S. Blencowe, I. Boutron, C. J. Cates, et al. 2019. “RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials.” Journal Article. Bmj 366: l4898. https://doi.org/10.1136/bmj.l4898.

Sumitomo Pharma America. 2023a. “NCT04038957: A Clinical Study to Investigate the Effect of an Investigational Drug as an Added Medication to an Antipsychotic, in Adults with Schizophrenia, as Measured Positron Emission Tomography (PET) Imaging.” Journal Article.

———. 2023b. “NCT04072354: A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People with Schizophrenia.” Journal Article. https://clinicaltrials.gov/study/NCT04072354.

———. 2023c. “NCT04092686: A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People with Schizophrenia.” Journal Article. https://clinicaltrials.gov/study/NCT04092686.

Szabo, S. T., S. C. Hopkins, R. Lew, A. Loebel, T. Roth, and K. S. Koblan. 2023. “A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Phase 1b Crossover Trial Comparing Two Doses of Ulotaront with Placebo in the Treatment of Narcolepsy-Cataplexy.” Journal Article. Sleep Med 107: 202–11. https://doi.org/10.1016/j.sleep.2023.04.019.

Tsukada, H., S. M. Milanovic, B. Darpo, H. Xue, K. Xiong, E. Tripp, L. Lennek, M. Worden, S. C. Hopkins, and G. R. Galluppi. 2023. “A Randomized, Single-Dose, Crossover Study of the Effects of Ulotaront on Electrocardiogram Intervals in Subjects with Schizophrenia.” Journal Article. Clin Transl Sci 16 (6): 1063–74. https://doi.org/10.1111/cts.13512.

Viechtbauer, Wolfgang. 2010. “Conducting Meta-Analyses in R with the metafor Package.” Journal of Statistical Software 36 (3): 1–48. https://doi.org/10.18637/jss.v036.i03.

Wang, Ying, Sameer Parpia, Rachel Couban, Qi Wang, Susan Armijo-Olivo, Dirk Bassler, Matthias Briel, et al. 2024. “Compelling Evidence from Meta-Epidemiological Studies Demonstrates Overestimation of Effects in Randomized Trials That Fail to Optimize Randomization and Blind Patients and Outcome Assessors.” Journal of Clinical Epidemiology 165: 111211.

White, Thomas, Daniel Noble, Alistair Senior, W. Kyle Hamilton, and Wolfgang Viechtbauer. 2022. metadat: Meta-Analysis Datasets. https://CRAN.R-project.org/package=metadat.

Wickham, Hadley, Mara Averick, Jennifer Bryan, Winston Chang, Lucy D’Agostino McGowan, Romain François, Garrett Grolemund, et al. 2019. “Welcome to the tidyverse.” Journal of Open Source Software 4 (43): 1686. https://doi.org/10.21105/joss.01686.

Wickham, Hadley, Jennifer Bryan, Malcolm Barrett, and Andy Teucher. 2023. usethis: Automate Package and Project Setup. https://CRAN.R-project.org/package=usethis.

Wickham, Hadley, Jim Hester, Winston Chang, and Jennifer Bryan. 2022. devtools: Tools to Make Developing r Packages Easier. https://CRAN.R-project.org/package=devtools.

Xie, Yihui. 2014. “knitr: A Comprehensive Tool for Reproducible Research in R.” In Implementing Reproducible Computational Research, edited by Victoria Stodden, Friedrich Leisch, and Roger D. Peng. Chapman; Hall/CRC.

———. 2015. Dynamic Documents with R and Knitr. 2nd ed. Boca Raton, Florida: Chapman; Hall/CRC. https://yihui.org/knitr/.

———. 2023. knitr: A General-Purpose Package for Dynamic Report Generation in r. https://yihui.org/knitr/.

Zhu, Hao. 2023. kableExtra: Construct Complex Table with “kable” and Pipe Syntax. http://haozhu233.github.io/kableExtra/.