Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence From Preclinical Models and Clinical Studies

International Journal of
Molecular Sciences
Review
Therapeutic Potential of TAAR1 Agonists in Schizophrenia:
Evidence from Preclinical Models and Clinical Studies
Nina Dedic 1, *, Heather Dworak 1 , Courtney Zeni 1 , Grazia Rutigliano 2,3 and Oliver D. Howes 3,4,5
1 Sunovion Pharmaceuticals, Marlborough, MA 01752, USA; [email protected] (H.D.);

[email protected] (C.Z.)
2 Department of Pathology, University of Pisa, via Savi 10, 56126 Pisa, Italy; [email protected]
3 Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK;
[email protected]
4 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, Kings College London,
London SE5 8AF, UK
5 Psychiatric Imaging Group, Medical Research Council, London Institute of Medical Sciences,
Hammersmith Hospital, London W12 0NN, UK
* Correspondence: [email protected]
Abstract: Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target
for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic
neurotransmission. In particular, agonist compounds have generated interest as potential treatments
for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone.
Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit
biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in
glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative
Citation: Dedic, N.; Dworak, H.; and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted
Zeni, C.; Rutigliano, G.; Howes, O.D. with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development
Therapeutic Potential of TAAR1 of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties,
Agonists in Schizophrenia: Evidence as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and
from Preclinical Models and Clinical non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled
Studies. Int. J. Mol. Sci. 2021, 22,
clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront,
13185. https://doi.org/10.3390/
is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings,
ijms222413185
this provides a rationale for further investigation and development of this new pharmacological class
for the treatment of schizophrenia and other psychiatric disorders.
Academic Editor: Yukihiro Ohno
Received: 27 October 2021

Keywords: trace amines; trace amine-associated receptor 1 (TAAR1); schizophrenia; psychosis;
Accepted: 1 December 2021 dopamine; serotonin; glutamate; neurocognition
Published: 7 December 2021
Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in 1. Introduction
published maps and institutional affil- 1.1. Schizophrenia: A Severe Psychiatric Disease with Significant Unmet Needs
iations. Schizophrenia is a severe, chronic, and often disabling psychiatric disorder affecting
nearly 20 million people worldwide [1]. It is characterized by symptoms grouped into
positive, negative, and cognitive domains with patients experiencing varying levels of each
(Table 1).
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Int. J. Mol. Sci. 2021, 22, 13185. https://doi.org/10.3390/ijms222413185 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021, 22, 13185 2 of 22
Table 1. Schizophrenia is characterized by symptoms that can be grouped into positive, negative, and cognitive do-
mains [2,3].
Positive Symptoms Negative Symptoms Cognitive Symptoms-Impairments in:

• Delusions • Blunted affect, diminished
- Fixed, false belief facial/vocal expression • Speed of processing
• Hallucinations
- Auditory
- Visual • Avolition, emotional withdrawal • Attention/vigilance
- Tactile
- Olfactory
• Asociality, social isolation • Working memory
• Anhedonia, difficulty anticipating
• Disorganized thinking • Verbal and visual learning
pleasurable activities
• Disorganized behavior
• Alogia, few words and avoidance • Reasoning and problem solving
of communication • Social cognition
Schizophrenia remains one of the most challenging diseases to treat, as significant

heterogeneity exists within the illness and with regard to treatment response. For most
patients, the first episode of psychosis occurs in late adolescence or early adulthood, and is
frequently preceded by a prodromal phase comprised of cognitive and social deficits or
challenges [4]. In general, positive symptoms occur in a relapsing–remitting fashion, while
negative and cognitive symptoms tend to be more chronic with an increasing impact on
social functioning.
Over half (56.0%) of individuals with schizophrenia have co-occurring mental and/or
behavioral health disorders (including drug abuse/dependency (29.0%), depression (27.7%),
alcohol abuse/dependency (24.6%), and anxiety disorder (13.6%)) leading to additional
treatment challenges, increased rates of functional impairment, and rates of unemployment
above 75% [5–7]. Schizophrenia is also associated with an increased risk of premature
mortality (>10-year reduction in average life expectancy), primarily due to increased car-
diovascular disease and increased suicide rates [8–10]. The diagnosis of schizophrenia
is associated with an increase in cardiovascular risk factors (e.g., obesity, hypertension,
diabetes, dyslipidemia), likely attributable not only to an unhealthy and sedentary lifestyle,
but also to the adverse effects of some antipsychotic medication on weight and metabolic
parameters [11,12].
Whether a single unifying pathophysiological process is shared across patients or
different independent disease processes lead to a similar clinical syndrome remains a
crucial focus of research [13]. Several etiological hypotheses of schizophrenia have been
proposed based on evidence for the contribution of genetic risk factors [14], neurodevel-
opmental alterations [15], immune disturbances and inflammation [16–19], trauma [20],
socioeconomic status and urbanization [21,22], and last but not least, dysfunction in several
neurotransmitter and neuropeptide systems (reviewed by Kaar et al.) [23].
For many years, the prevailing neurotransmitter-based theory of schizophrenia has
centered on the dopamine (DA) hypothesis, linking psychotic symptoms to hyperactivity
of the DA mesolimbic system. The DA hypothesis arose in the 1960s after studies showed
that antipsychotics block dopamine D2 -receptors. This, together with the observation
that drugs that potentiate dopamine neurotransmission, such as amphetamine, can mimic
psychotic symptoms in healthy individuals [24], solidified the basis for much of the DA
hypothesis. More recently, neuroimaging studies have shown increased presynaptic DA
synthesis capacity in the striatum of patients with schizophrenia, which also correlates with
psychotic symptom severity [25–28]. In addition to dopaminergic dysfunction, changes in
serotonin (5-hydroxytryptamine [5-HT]), glutamate, and other neurotransmitters have also
been associated with the pathophysiology of schizophrenia [29,30]. In particular, cortical
Int. J. Mol. Sci. 2021, 22, 13185 3 of 22
N-Methyl-D-aspartic acid (NMDA) receptor hypofunction [31–33] as well as serotonin

5-HT2A hyperfunction [34,35] has been linked to psychosis. Although initially investigated
separately, the outlined hypotheses are becoming increasingly integrated, including evi-
dence that glutamatergic dysregulation in cortical regions can lead to striatal dopamine
dysfunction, and ultimately to the development of psychosis [36].
1.2. Current Pharmacologic Treatments

Antipsychotics are the pharmacological standard of care for schizophrenia
globally [37–39]. Despite the complexity of the disease, current drug treatments primarily
rely on one mechanism of action: dopamine D2 receptor blockade. First-generation an-
tipsychotics, discovered initially in the 1950s, exert their action predominantly through
dopamine D2 receptor antagonism. While D2 receptor antagonism accounts for the ther-
apeutic efficacy of these agents, it is also associated with adverse side effects including
hyperprolactinemia and extrapyramidal symptoms (EPS) including tardive dyskinesia,
acute dystonias, parkinsonism, and akathisia [37,38]. Second-generation antipsychotics,
largely introduced into the clinic in the 1990s, often exert additional antagonism at other
receptors such as 5-HT2A [23]. This receptor profile coupled with dosing to avoid un-
necessarily high D2 occupancy has resulted in lower overall risk for hyperprolactinemia
and EPS [40], as demonstrated for agents such as clozapine, olanzapine, quetiapine, arip-
iprazole and lurasidone relative to first generation antipsychotics. Most antipsychotics
exhibit a dose-dependent relationship between D2 receptor occupancy and their therapeu-
tic effects [23]. Several antipsychotics also demonstrate additional activity at adrenergic,
cholinergic, histaminergic and/or other serotonergic receptors. Although these additional
targets may confer therapeutic effects, they may also contribute to aspects of their side
effect profiles. For example, adrenergic (α1) receptor antagonism is associated with ortho-
static hypotension, blockade of histamine (H1 ) receptors is linked to sedation and weight
gain, and muscarinic (M1 ) receptor blockade is associated with dry mouth, blurred vision
and constipation [23,38,41]. While variable among antipsychotics, metabolic dysregula-
tion (including body weight gain) is highly prevalent [11,42,43]. The underlying cause
remains largely elusive, with activity at several targets being implicated in antipsychotic-
induced weight gain and disruption of glucose/insulin homeostasis, including serotonin
5-HT2C /5-HT2A , histamine H1 , dopamine D1 /D2 /D3 , adrenergic α1 and muscarinic M3
receptors [44–46].
Currently available antipsychotic agents are effective in treating the positive symptoms
of schizophrenia (e.g., hallucinations, delusions, and disorganized thinking), however, they
largely leave the negative (e.g., anhedonia, alogia, and avolition) and cognitive symptom
domains (e.g., problems with verbal and visual learning, problem solving, and attention)
untreated [47–51]. Although negative symptom prevalence varies across studies and
definitions, up to 60% of patients have been categorized as having prominent or predom-
inant negative symptoms that require treatment [48]. While several antipsychotics have
demonstrated negative symptom improvement in patients with an acute exacerbation of
schizophrenia, these clinical trials were designed to study patients defined by positive
symptoms, and therefore treatment response cannot be easily teased apart from secondary
negative symptom improvement as a result of improvement in other domains [48]. Strate-
gies to combat this deficit in pharmacologic treatment, such as combining antipsychotics or
adding other types of adjunctive agents, have largely been unsuccessful.
Comparative effectiveness studies such as CATIE, CUTLASS and EUFEST have shown
a large degree of similarity between older and newer antipsychotic agents, with side
effects being the greatest discriminating factor [52–54]. The only exception was clozapine,
which to this day is considered the “gold standard” in terms of efficacy [55]. However,
the underlying mechanism for clozapine’s superior efficacy remains largely unknown
and its clinical use is limited by the risk of developing agranulocytosis (observed in
~1% of patients) [56]. Notably, even though antipsychotics target positive symptoms,
non-response of positive symptoms to antipsychotic treatment is common. For example,
Int. J. Mol. Sci. 2021, 22, 13185 4 of 22
treatment-resistant schizophrenia (non-response to ≥2 medications) occurs in up to 34% of

patients [57]. In addition, relapse of illness is common and occurs in approximately 30% of
patients within a year of their first episode of psychosis, and in up to 80% of patients over
the course of 5 years [58].
The urgency to develop new medications that treat the spectrum of schizophrenia
symptoms with improved safety and tolerability is apparent [38,39]. In the last two decades,
substantial investments have been directed towards the discovery and development of treat-
ments with non-D2 receptor-based mechanisms of action, including candidate medicines
with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, other
dopaminergic (i.e., D1 , D3 ), metabolic, histaminergic, infection/inflammation-based, and
other mechanisms (reviewed in Girgis et al.) [59]. Despite several promising targets (e.g.,
allosteric modulation of NMDA receptor and ongoing work with muscarinic M1 and
M4 receptor agonists), none of these mechanisms have yet yielded new medicines for
schizophrenia patients.
In recent years, substantial evidence has accrued, and two compounds have entered
clinical development centered around a novel therapeutic target: trace amine-associated
receptor 1 (TAAR1). In view of these new developments, we review TAAR1 pharmacology,
candidate ligands in clinical development and the rationale for TAAR1 as a promising
therapeutic target for neuropsychiatric disorders, focusing on schizophrenia.
2. TAAR1 As a Novel Therapeutic Target for the Treatment of Schizophrenia

2.1. Trace Amines and TAAR1
Trace amines (TAs) are a group of endogenous chemical messengers closely related
to the biogenic amine neurotransmitters dopamine (DA), serotonin (5-HT) and nore-
pinephrine (NE). TAs are found in both invertebrate and vertebrate species and are clas-
sically regarded as comprising β-phenylethylamine (β-PEA), p-tyramine, tryptamine,
p-octopamine, and some of their metabolites (Figure 1) [60]. As suggested by their name,
TA concentrations in the central nervous system are low, in fact, several hundred-fold
lower than those of classical monoamine neurotransmitters [60,61].
Since the discovery of the first vertebrate trace amine-associated receptor, TAAR1,
in 2001 [62,63], there has been an increasing interest in this G-protein coupled receptor
as a novel target for the pharmacotherapy of various disorders including psychiatric
illness [64–66]. This is largely attributed to TAAR10 s ability to modulate monoaminergic
neurotransmission and behavior in rodents. In addition to the traditional TAs, TAAR1
is also activated by an array of other endogenous compounds including the monoamine
neurotransmitters dopamine, serotonin, norepinephrine and some of their metabolites
(Figure 1) [64,65].
The TAAR family consist of 6 functional members in humans, with TAAR1 being the
most studied [67,68]. All human TAAR genes cluster to a small genomic region of 108 kb
located in chromosome 6q23, which has been consistently identified as a susceptibility locus
for schizophrenia and affective disorders [69]. Although several groups have attempted to
identify susceptibility loci for mental disorders in TAARs, none of the reports received suf-
ficient replication and the detected variants were not genome-wide significant. In contrast,
several rare variants in TAAR genes (particularly TAAR1) have been detected in patients
with mental and metabolic disorders (reviewed by Rutigliano and Zucchi) [66]. Some of the
variants have demonstrated altered receptor function in vitro [69,70], warranting further
assessment of naturally occurring TAAR1 variants in both brain and metabolic disorders.
Int. J. Mol. Sci. 2021, 22, 13185 5 of 22
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 6 of 23
Figure
Figure 1. Structures
1. Structures ofofnotable
notableendogenous
endogenous and
andsynthetic
syntheticTAAR1
TAAR1ligands.
ligands.
TheEndogenous
regional and TAscell
exert effects at targets
type-specific other than
expression TAAR1,isincluding
of TAAR1 an on-goingaminergic
topic and
of debate
non-GPRC
given receptors
its generally lowasendogenous
well as transporters [65,86,97].
expression levelsThus,
in the thebrain,
development
and theoflack selective,
of suitable,
small molecule
commercially TAAR1
available ligands
tools was crucial
for labeling, suchtoasadvance
specificour understanding
antibodies of specific,
[71]. Notwithstanding
TAAR1-mediated biological effects (Figure 1 and Table 2). This was
this, in rodents, TAAR1 mRNA and protein expression has been reported in monoaminergic initially explored by
Hoffmann–La Roche, resulting in the development of highly selective, TAAR1 full and
nuclei of the brain including the ventral tegmental area (VTA), substantial nigra (SN),
partial agonists based on different chemical scaffolds [98–100]. To date, five selective
and dorsal raphe nucleus (DRN) [62,72]. Receptor expression has also been detected in
TAAR1 agonists have been extensively profiled preclinically (RO5166017, RO5073012,
limbic areas (e.g.,
RO5256390, amygdala,
RO5203648 subiculum),
and RO5263397) basal
(Table ganglia,
2 and Figuresand 1 andthe PFC. Thus,
2). These compoundsTAAR1 is
ideally
have demonstrated antipsychotic, anti-addictive, pro-cognitive, antidepressant-like, signaling
positioned to modulate dopaminergic, serotonergic and glutamatergic and
andwake-promoting
consequently regulateeffects in aspects
rodents, of reward-processing,
likely via TAAR1-mediated cognition and mood
modulation relevant to
of dopamin-
schizophrenia and other
ergic, serotonergic metal disorders.
and glutamatergic However,
circuits [64–66].aAcomprehensive
particular challengeassessment
has beenofthe TAAR1
expression
development in the human TAAR1
of selective brain isantagonists,
still lacking. Outside
and so far onlytheoneCNS, TAAR1
compound expression
(EPPTB [-N- in
(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide])
rodents and humans has been reported in pancreatic β-cells, the has been identified
stomach, the intestines,
andand characterized
leukocytes [84].further suggesting the potential for TAAR1 as a target in metabolic
[73–83],
and immune disorders. agonists have been studied as both basic research tools and as
The Roche TAAR1
potential
To date, drugthecandidates. The partial
precise synaptic andagonist RO5263397
cellular has progressed
localization of TAAR1 to Phase
is not1 clear,
clin- and
ical trials, however, identification of a population of poor metabolizers of RO52263397 has
additional studies are needed to elucidate both in cell systems and in vivo. Both TAAR1-
slowed further development of this compound [101]. Another partial agonist, ralmitaront
mediated pre- and post-synaptic effects have been observed [84–87], which has complicated
(RO6889450), has completed first-in-human studies and is currently being evaluated for
interpretation of some in vivo findings. Receptor localization has largely been reported
the treatment of schizophrenia in Phase 2 randomized, placebo-controlled clinical trials
intracellularly, with evidence
(ClinicalTrials.gov Identifiers for plasma membrane
NCT03669640 expression
and NCT04512066) following ligand-induced
[102–105].
heterodimerization with other GPCRs [63,67,74,76,88–91].
To date, the only TAAR1 agonist that has progressed to Phase 3 clinical trials is ulota-
Although
ront (SEP-363856;its interaction partners and downstream
Sunovion Pharmaceuticals), targetsBreakthrough
which was granted have not been fully eluci-
Therapy
dated, several from
Designation groups the have provided
U.S. Food and Drugimportant insights
Administration forinto TAAR1-mediated
the treatment signaling
of schizophre-
(reviewed
nia (Table in2Berry et al.,1).
and Figure 2017; Gainetdinov
Ulotaront et al., 2018.;
was discovered through Rutigliano
a unique, et al., 2020) [64–66].
target-agnostic
approach
TAAR1 is a that was optimized
Gαs-coupled to identify
receptor thatdrug candidates
promotes cAMPthat production
lack D2 and 5-HT receptor
via 2Astimulation of
antagonism
adenylyl cyclasewhile demonstrating
[62,63,67], whichan in in
can, vivo phenotypic
turn, promoteantipsychotic-like
protein kinase A profile
(PKA) [106].
and pro-
teinAlthough
kinase Cthe ulotaront’s
(PKC) mechanism of[92].
phosphorylation action has notactivation
TAAR1 been fully elucidated,
is also ablesubsequent
to stimulate G
in vitro and in vivo studies demonstrated that full agonism at TAAR1 and partial agonism
protein-coupled inwardly rectifying potassium channels, which is proposed to underly
at 5-HT1A receptors are integral to its efficacy [106]. In addition, ulotaront shows partial
TAAR1-mediated reduction in VTA dopaminergic neuron firing [84,86]. In addition, TAAR1
can signal via a G-protein independent, SS-arrestin2-mediated pathway [91], which ap-
pears most pronounced upon heterodimerization with D2 receptors. Differential signaling
through physical interaction (i.e., heterodimerization) between TAAR1 and other GPCRs
has been proposed. This includes interactions with 5-HT1B [93], α2A [94], potentially 5-
HT1A [86], and most prominently D2 receptors [87,90,91]. The interaction of TAAR1 and
Int. J. Mol. Sci. 2021, 22, 13185 6 of 22
D2 receptors has been shown to exert functional effects both pre- and post-synaptically
(reviewed in Gainetdinov et al., 2018; Berry et al., 2017; Rutigliano et al., 2020) [64–66].
Interestingly, heterodimerization of TAAR1 and D2 enhances the TAAR1-SS-arrestin2 in-
teraction which ultimately results in reduced GSK3SS activation [91]. The proposed shift
from cAMP accumulation to β-arrestin2 recruitment could have important pharmacolog-
ical implications given that the AKT/GSK3β pathway is increasingly implicated in the
pathophysiology of schizophrenia, bipolar disorder, and depression [65].
2.2. Development of Synthetic TAAR1 Ligands

A challenge associated with the study of TAAR1 is its very broad ligand tuning [64,65].
As mentioned earlier, notable endogenous ligands of TAAR1 include the trace amines
β-phenylethylamine (PEA), p-tyramine (TYR), and tryptamine as well as monoamine
neurotransmitters dopamine, serotonin, and norepinephrine (Figure 1) [60,62,63,95]. In
addition, various synthetic compounds are also reported to activate TAAR1 including
psychoactive substances (e.g., amphetamine-like compounds, psilocin, etc.), apomorphine,
and clonidine. Importantly, species differences with respect to potency and efficacy have
been described for several of the mentioned synthetic ligands [63,96].
Endogenous TAs exert effects at targets other than TAAR1, including aminergic and
non-GPRC receptors as well as transporters [65,86,97]. Thus, the development of selec-
tive, small molecule TAAR1 ligands was crucial to advance our understanding of specific,
TAAR1-mediated biological effects (Figure 1 and Table 2). This was initially explored
by Hoffmann–La Roche, resulting in the development of highly selective, TAAR1 full
and partial agonists based on different chemical scaffolds [98–100]. To date, five selec-
tive TAAR1 agonists have been extensively profiled preclinically (RO5166017, RO5073012,
RO5256390, RO5203648 and RO5263397) (Table 2 and Figures 1 and 2). These compounds
have demonstrated antipsychotic, anti-addictive, pro-cognitive, antidepressant-like, and
wake-promoting effects in rodents, likely via TAAR1-mediated modulation of dopaminer-
gic, serotonergic and glutamatergic circuits [64–66]. A particular challenge has been the
development of selective TAAR1 antagonists, and so far only one compound (EPPTB
[-N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide]) has been identi-
fied and characterized [84].
The Roche TAAR1 agonists have been studied as both basic research tools and as
potential drug candidates. The partial agonist RO5263397 has progressed to Phase 1 clinical
trials, however, identification of a population of poor metabolizers of RO52263397 has
slowed further development of this compound [101]. Another partial agonist, ralmitaront
(RO6889450), has completed first-in-human studies and is currently being evaluated for
the treatment of schizophrenia in Phase 2 randomized, placebo-controlled clinical trials
(ClinicalTrials.gov Identifiers NCT03669640 and NCT04512066) [102–105].
To date, the only TAAR1 agonist that has progressed to Phase 3 clinical trials is
ulotaront (SEP-363856; Sunovion Pharmaceuticals), which was granted Breakthrough
Therapy Designation from the U.S. Food and Drug Administration for the treatment
of schizophrenia (Table 2 and Figure 1). Ulotaront was discovered through a unique,
target-agnostic approach that was optimized to identify drug candidates that lack D2 and
5-HT2A receptor antagonism while demonstrating an in vivo phenotypic antipsychotic-like
profile [106]. Although the ulotaront’s mechanism of action has not been fully elucidated,
subsequent in vitro and in vivo studies demonstrated that full agonism at TAAR1 and
partial agonism at 5-HT1A receptors are integral to its efficacy [106]. In addition, ulotaront
shows partial agonism at 5-HT1D and weak functional activity at 5-HT7 receptors. The
fact that an independent, target-agnostic approach also identified TAAR1 agonism as an
antipsychotic-like mechanism is further validation of TAAR1 as a promising therapeutic
target for schizophrenia.
neurons, but also by reducing glutamatergic, excitatory inputs to DA neurons [121]. Intri-
guingly, TAAR1 has also been shown to impact pre- and post-synaptic glutamatergic neu-
rotransmission in the striatum of rodent Parkinson’s disease models [144]. The ability to
regulate corticostriatal crosstalk is not only of relevance to Parkinson’s disease, but also
schizophrenia and other psychiatric disorders [145]. Moreover, TAAR1 may participate in
Int. J. Mol. Sci. 2021, 22, 13185 7 of 22
glutamate clearance via modulation of the excitatory amino acid transporter 2 (EAAT2)
[146,147].
Figure
Figure2. 2.TAAR1-mediated
TAAR1-mediated modulation
modulation of ofmonoaminergic
monoaminergic and and glutamatergic
glutamatergic circuits.
circuits. Simplified
Simplified schematic
schematic of keyof key sero-
serotoner-
tonergic, dopaminergic,
gic, dopaminergic, and and glutamatergic
glutamatergic pathways
pathways in the in the rodent
rodent brain including
brain including evidenceevidence fromwith
from studies studies with ligands
synthetic synthetic
ligands and TAAR1-KO mice. ↑, increase; ↓, decrease; (−), no change. Abbreviations: 5-HT (serotonin),
and TAAR1-KO mice. ↑, increase; ↓, decrease; (−), no change. Abbreviations: 5-HT (serotonin), AMPH (amphetamine), AMPH (ampheta-
mine),
AmyAmy (amygdala),
(amygdala), dSTRdSTR (dorsal
(dorsal striatum/caudoputamen),
striatum/caudoputamen), DA (dopamine),
DA (dopamine), Hip (hippocampus),
Hip (hippocampus), LC (locus
LC (locus ceruleus),
ceruleus), m
m (mouse),
(mouse),MDMA MDMA(3,4-Methylenedioxymethamphetamine),
(3,4-Methylenedioxymethamphetamine), NA (noradrenalin), NAc (nucleus accumbens),
NA (noradrenalin), NAc (nucleus accumbens), PFC (prefrontalPFC (pre-
frontal cortex), r (rat), SN (substantia nigra), VTA (ventral tegmental area).
cortex), r (rat), SN (substantia nigra), VTA (ventral tegmental area).
4. Additional
Table Considerations
2. Pharmacological for TAAR1
effects of TAAR1 agonistsAgonists as species.
in preclinical Therapeutic Agents for Schizo-
phrenia
Behavioral Effects in Preclinical Models &Assays
Clinical Trials in
Compound (Company) In contrast
Human Receptor Profile to antipsychotics, and
Relevant to Positive, consistent
Negative with the lack ofSchizophrenia
and Cognitive D2 receptor activity, nei-
Patients
Symptoms of Schizophrenia
ther RO5256390, RO5263397 nor ulotaront induced catalepsy in rodents [74,106]. On the
• ↓ L-687,414-induced hyperactivity (mouse) [86]
contrary, RO5263397 • even partially hyperactivity
↓ cocaine-induced prevented haloperidol-induced
(mouse) [86] catalepsy, suggesting
• ↓ hyperactivity in DAT-KO mice [86]
RO5166017 that TAAR1 partial
TAAR1 Full Agonist [86] •
activation may mitigate
↓ cocaine-induced CPP (rat) [107]
EPS caused by neuroleptics [74]. Interestingly,
N/A
F. Hoffmann-La Roche
the same authors also • showed
↓ cue- and that TAAR1reinstatement
priming-induced agonism can of potentiate the antipsychotic prop-
cocaine-seeking (rat) [108]
erties of olanzapine• and risperidone,
anxiolytic effect in SIHhighlighting
(mouse) [86] the potential of TAAR1 agonists as ad-
junctive treatments • to↓ L-687,414-induced
current antipsychotics [74].
hyperactivity (mouse) [74] Thus, although TAAR1 agonists
• ↓ PCP-induced hyperactivity (mouse) [74]
demonstrate antipsychotic-like
• efficacy
↓ cocaine-induced in schizophrenia
hyperactivity (mouse and models, they are unlikely to
rat) [74]
cause extrapyramidal •
side effects (EPS, movement disorders), which are a well-known
pro-cognitive effect in attentional set-shifting
RO5256390 side effect of current antipsychotics. This
(rat) and object retrieval is(monkey)
tasks also supported
[74] by recent clinical results with
TAAR1 Full Agonist [74] • antidepressant-like effect in differential N/A
F. Hoffmann-La Roche ulotaront (discussed inreinforcement
detail below). While encouraging, further validation of these find-
of low-rate behavior
ings is required. • (monkey) [74]
↓ context-induced cocaine relapse (rat) [109]
• no antidepressant- or anxiolytic-like effects in
FST & defensive withdrawal test (rat) [74,110]
• ↓ haloperidol-induced catalepsy (rat) [74]
Int. J. Mol. Sci. 2021, 22, 13185 8 of 22
Table 2. Cont.
Behavioral Effects in Preclinical Models &Assays

Clinical Trials in
Compound (Company) Human Receptor Profile Relevant to Positive, Negative and Cognitive
Schizophrenia Patients
Symptoms of Schizophrenia
• ↓ cocaine-induced hyperactivity,
self-administration & relapse
(mouse/rat) [110,111]
• ↓ d-AMPH-induced hyperactivity in rats, no
effect in mice [112]
• ↓ mAMPH-induced hyperactivity and
self-administration (rat) [112]
RO5203648 • ↓ hyperactivity in DAT-KO mice and
TAAR1 Partial Agonist [111] N/A
F. Hoffmann-La Roche rats [109,113]
• ↓ hyperactivity in NR1-KD mice [111]
• pro-cognitive effect in object retrieval tasks
(monkey) [111]
• antidepressant-like effect in FST (rat) and
differential reinforcement of low-rate behavior
(monkey) [111]
• modest anxiolytic effect in SIH (mouse) [111]
• ↓ PCP-induced hyperactivity (mouse) [74]
• ↓ cocaine-induced hyperactivity (mouse) [74]
• ↓ abuse-related effects of cocaine, mAMPH,
nicotine and morphine (rat) [107,114–117]
• ↓ cocaine-induced ICSS (rat) [118]
• reversed chronic stress-induced cognitive and
RO5263397 social interactions deficits without producing
F. Hoffmann-La Roche effects on anxiety in the EPM (mice) [119]
• ↑ mismatch negativity (rat) [120]
• pro-cognitive effect the object retrieval task
(monkey) [74]
• antidepressant-like effect in FST (rat) and
differential reinforcement of low-rate behavior
(monkey) [74]
RO5073012 • ↓ AMPH-induced hyperactivity in Taar1
F. Hoffmann-La Roche overexpressing mice–no effect in WT mice [121]
• Two Phase 2 studies ongoing
• DB, pbo-controlled in patients
with an acute exacerbation of
schizophrenia or schizoaffective
Ralmitaront (RO6889450)
TAAR1 Partial Agonist N/A disorder (NCT04512066) [102]
F. Hoffmann-La Roche
with negative symptoms of
schizophrenia
(NCT03669640) [103]
• Two Phase 2 studies completed:
• antipsychotic-like behavioral profile in the
with an acute exacerbation of
SmartCube platform (mouse) [106]
schizophrenia demonstrated
• ↓ PCP-induced hyperactivity
efficacy and good tolerability [123]
(mouse/rat) [106,122]
• 26-week open-label extension
• no effect on AMPH-induced hyperactivity
study demonstrated continued
(rat) [122]
effectiveness and long-term
Ulotaront • ↓ PCP-induced social interaction deficits
TAAR1 Full Agonist and tolerability [124]
(SEP-363856) (rat) [106]
5-HT1A Partial Agonist [106] • Four Phase 3 studies ongoing:
Sunovion Pharmaceuticals • ↑ prepulse inhibition (mouse) [106]
• Two DB, pbo-controlled studies in
• improved object recognition memory in
patients with an acute
subchronic PCP-treated rats [122]
exacerbation of
• ↓ ketamine-induced increase in striatal
schizophrenia [125,126]
dopamine synthesis capacity (mouse) [36]
• 52-week open-label extension
• modest antidepressant effects in the mouse
study [127]
FST [106]
• 52-week long-term safety
study [128]
Abbreviations: (↑) increase and (↓) decrease relative to vehicle control. Amphetamine (AMPH), double-blind (DB), conditioned place-
preference (CPP), dopamine transporter knockout (DAK-KO), elevated plus-maze (EPM), forced swim test (FST), placebo (pbo), intracranial
self-stimulation (ICSS), methamphetamine (mAMPH), not available (N/A), phencyclidine (PCP), stress-induced hyperthermia (SIH),
subchronic (sc), wild-type (WT).
3. Preclinical Evidence for TAAR1 as a Therapeutic Target for Schizophrenia

In this section, we summarize preclinical evidence supporting TAAR1 agonists as a
potential therapeutic candidate in schizophrenia that may offer differentiation from antipsy-
chotics, which are limited to the efficacy and associated safety profile of D2 antagonism.
We provide an overview of TAAR10 s role in regulating monoaminergic and glutamatergic
Int. J. Mol. Sci. 2021, 22, 13185 9 of 22
circuits implicated in schizophrenia pathophysiology, and discuss the potential for TAAR1
agonists in psychosis, negative symptomatology, cognition, mood, and anxiety as they
relate to schizophrenia.
3.1. Role of TAAR1 in Psychosis and Dopaminergic Tone

Since the first studies in TAAR1-knockout (KO) mice [72,129] and initial findings
that selective TAAR1 agonism exerts inhibitory effects on dopaminergic and serotonergic
neuronal activity [86], there has been a growing body of research characterizing the role of
TAAR1 in the modulation of monoaminergic circuits (Figure 2). Particularly the ability of
TAAR1 to regulate dopaminergic tone has been of interest in the context of schizophrenia
and psychosis in general. In brain slices, selective, full TAAR1 agonists suppress VTA
neuronal firing [74,86] and inhibit electrically evoked dopamine release in the nucleus
accumbens (NAc) [85]. Similarly, ulotaront (TAAR1 agonist with 5-HT1A agonist activity)
was found to decrease VTA neuronal firing, although this was only observed in a subset
of neurons [106]. Consistent with this, the firing rate of dopaminergic VTA neurons is
increased in TAAR1-KO mice and enhanced by the TAAR1 antagonist EPPTB [72,84]. In-
terestingly, the partial agonists RO5203648 and RO5263397 also increase VTA DA neuron
firing suggesting that, in vitro, TAAR1 is constitutively active and/or tonically activated
by endogenous agonists, a situation where partial agonism produces a net antagonistic
effect [74,111]. The extent to which such differential effects occur in vivo remains to be de-
termined. While the molecular mechanism has not been fully elucidated, the effects on DA
neuron firing may result from TAAR1 activation of inwardly rectifying K+ channels [84,86].
In addition, the full agonist RO5166017 was shown to decrease miniature excitatory post
synaptic current (mEPSC) frequency in the VTA without altering the amplitude [121]. This
suggests that TAAR1 is present in the pre-synaptic compartment of excitatory inputs to
DA neurons and participates in agonist-mediated reduction of VTA DA neuron firing.
Although TAAR1 ligands exert prominent effects on DA neuron firing in brain slices,
less clarity exists on how this ultimately affects DA release in the striatum and other
brain regions (Figure 2). Fast scan cyclic voltammetry (FSCV) experiments with selective
agonists have demonstrated attenuation of electrically evoked DA release in brain slices in
the NAc and dorsal striatum of mice [85], and in vivo in the NAc of rats [130]. On the other
hand, in vivo microdialysis studies revealed no effects on baseline striatal DA release with
ulotaront and inconsistent observations are reported in TAAR1-KO mice [72,85,106,131].
Prominent changes in monoaminergic neurotransmission were also observed in TAAR1
overexpressing mice although these effects are difficult to interpret due to the largely
ectopic expression of the receptor [121]. In addition, Leo et al., showed that lack of TAAR1
leads to increased DA release predominately in the NAc, suggesting that TAAR1 may exert
differential regulatory effects in the NAc compared to the dorsal striatum [85,121]. Further
studies, particularly in the substantia nigra and PFC are required to decipher potential
differences in TAAR1-mediated modulation of mesolimbic, mesocortical, and nigrostriatal
dopaminergic circuits. The mechanism of TAAR1-dependent regulation of DA release is
not fully understood but may involve physical interaction with presynaptic D2 receptors
resulting in the modulation of autoinhibition [85,89,90,132].
While TAAR1 partial and full agonists can differentially modulate baseline DA neu-
ron firing, consistent antipsychotic-like effects of both partial and full agonists have
been reported in several rodent models of schizophrenia (Table 2). TAAR1 agonists
robustly block hyperactivity induced by cocaine, amphetamine, PCP and L-687,414 in
rodents [74,86,106,111,112,122], likely through direct effects on DA neurotransmission
and/or upstream modulation of glutamatergic activity. Thus, various TAAR1 agonist
profiles are effective in paradigms based on hyperdopaminergic activity (i.e., cocaine, am-
phetamine) and NMDA receptor hypofunction (PCP, L-687,414), similar to antipsychotics.
Importantly, the antipsychotic-like efficacy of selective agonists was absent in TAAR1-KO
mice, confirming the contribution of the receptor to the behavioral effects [74,86]. On
the other hand, an exaggerated response to the dopaminergic stimulant amphetamine
Int. J. Mol. Sci. 2021, 22, 13185 10 of 22
was observed in TAAR1-KO mice, both in terms of hyperlocomotor activity and striatal
dopamine release [72,129], indicative of a schizophrenia-like dopamine phenotype. Fur-
thermore, TAAR1 agonists inhibit dopamine-dependent hyperactivity in DAT-KO mice and
rats [86,111,113,121] and prevent cocaine-induced dopamine overflow in the NAc [109].
In addition, the TAAR1 full agonist RO5256390 blocks cocaine-induced inhibition of DA
clearance in slices of the NAc. This was dependent on simultaneous D2 autoreceptor acti-
vation and associated downstream GSK-3SS signaling, likely facilitated through TAAR1-D2
heterodimerization [132]. In light of the current data, TAAR1-mediated suppression of DA
neurotransmission appears to be most prominent under hyperdopaminergic conditions.
This is further supported by recent results showing that ulotaront attenuates the ketamine-
induced increase in striatal dopamine synthesis capacity without producing an effect in
naïve mice [36]. This is relevant considering that elevated dopamine synthesis capacity has
been reported in schizophrenia patients and is not targeted by current antipsychotic treat-
ments [25,27,133,134]. Whether ulotaront’s effects on DA synthesis capacity are mediated
through direct action on dopaminergic neurons, or occur further upstream, remains to be
elucidated. Notwithstanding this, the preclinical evidence to date suggests that TAAR1
agonism may represent a unique approach to modulate the presynaptic DA dysfunction
observed in psychosis.
3.2. Role of TAAR1 in Cognition, Negative Symptoms, Mood and Anxiety

As described above, cognitive deficits, negative symptoms, and affective symptoms
of schizophrenia are poorly treated by current antipsychotic medications. While the
pathophysiology underlying these symptoms is not fully understood, hypofunctioning of
the PFC is thought to contribute to them [135]. Several preclinical studies have investigated
the role of TAAR1 in PFC functioning as well as the effect of TAAR1 modulation on
cognition, mood- and anxiety-related behaviors (Table 2 and Figure 2). In non-human
primates (NHPs), TAAR1 agonists have been reported to increase accuracy in the object
retrieval task indicative of improved cognitive performance [74,111]. Further pro-cognitive
effects were shown for RO5256390, which reversed PCP-induced deficits in executive
function in the rat attention set shift task [74]. In addition, RO5263397 improved chronic
stress-induced deficits in cognitive function as well as the associated changes in dendritic
arborization and synapse number in the PFC [119]. Interestingly, specific deletion of TAAR1
in the mPFC mimicked some of the cognitive deficits induced by chronic stress [119]. In
contrast, no pronounced alterations in cognitive performance were reported for TAAR1-KO
mice, although aberrant perseverative and impulsive behaviors were observed [129,136].
The discrepancy is likely caused by differences in temporal and spatial specificity of receptor
deletion (selective receptor ablation during adulthood vs. global deletion embryonic
development). Thus, compensatory developmental effects cannot be excluded in TAAR1-
KO mice. Additional support for antipsychotic and pro-cognitive effects of TAAR1 agonists
comes from studies assessing prepulse inhibition (PPI) and mismatch negativity (MMN).
Impairments in PPI and MMN have repeatedly been observed in schizophrenia patients
and are considered a potential biomarker of the disease [137–142]. Particularly deficits in
MMN are believed to reflect cognitive decline and have been associated with glutamatergic
NMDA receptor alterations [139,142]. In naïve mice, ulotaront and RO5263397 increase PPI
and MMN, respectively [120]. Whether TAAR1 agonists can reverse impairments in PPI
and MMN (e.g., in rodent models of schizophrenia) remains to be investigated.
In contrast to positive and cognitive symptoms, negative and affective symptoms
of schizophrenia are more difficult to model in animals. Thus far, only a few studies
have investigated the role of TAAR1 in social, anxiety and depression-related behavior.
Ulotaront reversed PCP-induced social interaction deficits in rats, suggesting potential
benefits against some of the negative symptoms of schizophrenia, such as social with-
drawal [106]. TAAR1 agonists have also been assessed for antidepressant-like activity in
the classical forced swim test (FST). While partial agonists RO5263397 and RO5203648
decreased immobility in the rat FST, no effect was observed with the full TAAR1 agonist
Int. J. Mol. Sci. 2021, 22, 13185 11 of 22
RO5256390 [74,110,111]. In contrast, modest activity was reported for the full TAAR1
agonist ulotaront in the mouse FST, although a contribution of 5-HT1A agonism to this
effect cannot be excluded [106]. Positive effects of TAAR1 agonists were also observed
on Differential Reinforcement of Low-Rate Behavior (DRL) in NHPs, an antidepressant-
sensitive paradigm that engages PFC and hippocampus activity [74,111]. In addition,
TAAR1 activation in mice attenuates stress-induced hyperthermia [86,111] and improves
chronic stress-induced social avoidance [119], suggesting potential antidepressant and/or
anti-anxiety effects. In contrast, no effects of TAAR1 activation on anxiety-related behav-
ior were reported in the defensive withdrawal test in naïve rats [110] or in the elevated
plus-maze in chronically stressed mice [119].
The above studies encourage further assessment of pro-cognitive, and putative anx-
iolytic and antidepressant-like properties of TAAR1 agonists, not only in the context of
negative symptoms of schizophrenia, but also other psychiatric disorders.
3.3. TAAR1 Effects on Serotonergic, Noradrenergic and Glutamatergic Systems

Effects of TAAR1 agonists on serotonergic and glutamatergic systems have been re-
ported (Figure 2), although the underlying molecular mechanisms have not been explored
in detail. Similar to the findings in the VTA, full and partial agonists increase and decrease
serotonergic neuronal firing in the DRN, respectively [74,86]. These effects were TAAR1-
dependent as they were not observed in TAAR1-KO mice and reversed by the antagonist
EPPTB [74,86]. Although ulotaront was also reported to decrease firing in the DRN in vitro
and in vivo, these effects were largely attributed to 5-HT1A receptor activation [106]. Inter-
estingly, ulotaront did not alter baseline extracellular serotonin levels in the striatum and
PFC of rats [106]. Whether selective TAAR1 agonists modulate serotonin release in vivo
remains to be determined. Compared to wild-type controls, TAAR1-KO mice exhibit
increased spontaneous firing of DRN neurons and enhanced striatal serotonin release in
response to an amphetamine challenge [72,74,86]. However, no significant changes in
baseline serotonin release were detected in the dorsal striatum, NAc or PFC of TAAR1-KO
mice [131]. Notably, Revel and colleagues reported that TAAR1 activation increases agonist
potency at 5-HT1A receptors in brain slices of the DRN. In addition, TAAR1 is required for
the desensitization of 5-HT1A autoreceptors [86]. Given that desensitization of the 5-HT1A
autoreceptor has been linked to the efficacy of antidepressants, co-treatment with TAAR1
agonists might further improve the therapeutic effects of these agents. Although additional
studies are necessary to further elucidate the potential interaction between TAAR1 and
5-HT1A in vitro and in vivo, compounds with dual TAAR1/5-HT1A activity may provide
additional benefits in the treatment of psychosis, mood and anxiety.
Currently, there is little evidence for TAAR1-mediated modulation of the noradrener-
gic system. In contrast to its effect in the VTA and DRN, the full agonist RO5166017 did
not alter the firing frequency of noradrenergic neurons of the locus coeruleus [86]. This
is in agreement with the reported absence of detectable TAAR1 expression in the locus
coeruleus [72], although a more recent study suggests that TAAR1 may regulate glutamate
signaling in cultured noradrenergic neurons [143]. Studies in TAAR1-KO mice reported
no changes in noradrenergic neuron firing or baseline noradrenaline levels in the PFC,
dorsal striatum and NAc compared to wild type controls [86,131]. However, TAAR1-KO
mice exhibit enhanced striatal noradrenaline release in response to an amphetamine chal-
lenge [72]. Thus, in summary, evidence is mixed, and additional studies are needed to
further elucidate whether TAAR1 can directly regulate noradrenergic activity.
As previously described, TAAR1 agonists can attenuate the behavioral deficits induced
by NMDA receptor antagonists PCP, L-687,414 and ketamine [74,86,106,111]. The molecular
basis of this is not well understood and may involve direct modulation of glutamatergic
neurotransmission, or downstream effects on dopaminergic circuits. TAAR1-mediated
modulation of cortical glutamatergic transmission has been of particular interest as its
deficiency is implicated in the pathophysiology of schizophrenia [30]. As mentioned,
TAAR1 agonism can attenuate chronic stress-induced cognitive impairments possibly by
Int. J. Mol. Sci. 2021, 22, 13185 12 of 22
restoring excitatory/inhibitory imbalance and structural alterations in the mPFC [119].

Along these lines, TAAR1-KO mice exhibit reduced NMDA receptor activity in the mPFC
layer V neurons, as suggested by alterations in evoked EPSC kinetics and receptor subunit
composition, as well as reduced mEPSC amplitude and frequency [136]. The observed
glutamate transmission deficits could be a direct consequence of the absence of cortical
TAAR1 and/or may be secondary to alterations in the cortical dopamine system [136]. The
ability to impact the interaction between glutamatergic and dopaminergic circuits may
underlie the beneficial behavioral effects of TAAR1 agonists in rodent models of psychiatric
disorders. This is supported by slice electrophysiology experiments, suggesting that TAAR1
can decrease VTA neuron firing not only through direct action on DA neurons, but also by
reducing glutamatergic, excitatory inputs to DA neurons [121]. Intriguingly, TAAR1 has
also been shown to impact pre- and post-synaptic glutamatergic neurotransmission in the
striatum of rodent Parkinson’s disease models [144]. The ability to regulate corticostriatal
crosstalk is not only of relevance to Parkinson’s disease, but also schizophrenia and other
psychiatric disorders [145]. Moreover, TAAR1 may participate in glutamate clearance via
modulation of the excitatory amino acid transporter 2 (EAAT2) [146,147].
4. Additional Considerations for TAAR1 Agonists as Therapeutic Agents

for Schizophrenia
In contrast to antipsychotics, and consistent with the lack of D2 receptor activity,
neither RO5256390, RO5263397 nor ulotaront induced catalepsy in rodents [74,106]. On the
contrary, RO5263397 even partially prevented haloperidol-induced catalepsy, suggesting
that TAAR1 partial activation may mitigate EPS caused by neuroleptics [74]. Interestingly,
the same authors also showed that TAAR1 agonism can potentiate the antipsychotic
properties of olanzapine and risperidone, highlighting the potential of TAAR1 agonists
as adjunctive treatments to current antipsychotics [74]. Thus, although TAAR1 agonists
demonstrate antipsychotic-like efficacy in schizophrenia models, they are unlikely to cause
extrapyramidal side effects (EPS, movement disorders), which are a well-known side
effect of current antipsychotics. This is also supported by recent clinical results with
ulotaront (discussed in detail below). While encouraging, further validation of these
findings is required.
Importantly, a growing body of evidence implicates TAAR1 in the regulation of
metabolic function and food reward behavior, which has been extensively reviewed else-
where [65,66,148]. This is of significant relevance considering that weight gain and al-
tered levels of several metabolic parameters constitute major side effects of antipsychotic
medication [42]. As noted, antipsychotic-induced weight gain can increase the risk of
cardiovascular side effects and diabetes and result in treatment discontinuation and overall
reduced quality of life [149,150]. In contrast to current antipsychotics, TAAR1 agonists do
not increase body weight in naïve rodents, but rather tend to decrease it [74,76]. In addition,
TAAR1 agonists were shown to prevent olanzapine-induced weight gain in rats [74] and
reduce food intake and excess body weight in diet-induced obese mice [76]. Further studies
in rodent models of type 2 diabetes mellitus revealed improved glucose tolerance and
insulin sensitivity, as well as reduced plasma and liver triglyceride levels [76]. The ob-
served metabolic effects are likely mediated by peripheral TAAR1 activation in pancreatic
SS-cells and enteroendocrine cells of the intestine. On the other hand, TAAR1-mediated
regulation of food intake and food-reward behavior has been linked to its central effects,
predominately dopaminergic and/or glutamatergic in origin [148,151]. This is supported
by the initial work of Ferragud and colleagues demonstrating that the TAAR1 agonist
RO5256390 (administered systemically or microinfused in the mPFC) prevents binge-like
eating of palatable food in rats [110].
Taken together, the current preclinical data suggest that TAAR1 agonists have the
potential to improve several symptom domains of schizophrenia without causing ad-
verse effects such as motor impairments or weight gain. Furthermore, the beneficial
metabolic and antidiabetic effects of TAAR1 agonists raise the question of whether these
Int. J. Mol. Sci. 2021, 22, 13185 13 of 22
agents may be uniquely positioned to improve comorbid metabolic disorders in patients

with schizophrenia.
5. Clinical Evidence for TAAR1 Agonists for the Treatment of Schizophrenia

Two TAAR1 agonists have advanced to clinical trials in patients with schizophrenia:
ulotaront and ralmitaront (Table 2; Figure 1). Pharmacokinetic (PK) studies in humans
have been completed with both agents, but results are available only for ulotaront. In
population PK analyses at dose levels ranging from 10–100 mg, ulotaront is well-absorbed
and exhibits linear PK dose-proportionality with a median Tmax of 2.8 h and an effective
half-life of 7 h [152].
Ralmitaront is currently in Phase 2 development with two double-blind, placebo-
controlled clinical studies examining the efficacy and safety of ralmitaront in patients with
schizophrenia. One study is designed to evaluate two doses of ralmitaront in patients aged
18 to 45 with an acute exacerbation of schizophrenia or schizoaffective disorder over 4
and 12 weeks (NCT04512066), while the other aims to assess one dose of ralmitaront over
12 weeks in patients aged 18 to 55 with negative symptoms of schizophrenia as both a
monotherapy and as adjunctive therapy to D2 antagonists or D2 /5HT2A dual antagonists
(NCT03669640) [102,103].
Ulotaront has progressed to Phase 3 development after favorable efficacy and tolera-
bility data from two completed Phase 2 trials. The ongoing Phase 3 studies include two
double-blind, placebo-controlled studies, one enrolling patients aged 12–65 and the other
18–65, which each aim to assess the efficacy and safety of fixed doses of ulotaront in patients
with an acute exacerbation of schizophrenia (NCT04072354 and NCT04092686) [125,126],
a 52-week, open-label, flexible-dose extension study, (NCT04109950) [127] and another
52-week study evaluating ulotaront compared to quetiapine XR in patients with stable
schizophrenia (NCT04115319) [128].
The completed Phase 2 studies included a 4-week, randomized, double-blind, placebo-
controlled study evaluating efficacy and safety of flexibly dosed ulotaront (50 to 75 mg/day)
in patients aged 18–40 with an acute exacerbation of schizophrenia [123], and a 26-week,
open-label extension study in patients completing the 4-week double-blind study [124].
The dose selection for Phase 2 clinical trials was guided by an initial study in healthy male
volunteers demonstrating robust REM sleep-suppressing effects of ulotaront at 50 mg [153].
In the 4-week, double-blind, placebo-controlled study, treatment with ulotaront re-
sulted in a significantly greater reduction from baseline in the Positive and Negative
Syndrome Scale (PANSS) total score for ulotaront than placebo at Week 4 (Least-Squares
Mean change from Baseline to Week 4 [SE]: −17.2 [1.7] vs. −9.7 [1.6]; p = 0.001; effect
size [ES] = 0.45). Robust improvements relative to placebo were also observed on the
PANSS positive, negative, and general psychopathology subscale scores as well as other
secondary endpoints including the Clinical Global Impression of Severity (CGI-S) score, the
Montgomery-Asberg Depression Rating Scale (MADRS) total score and the Brief Negative
Syndrome Scale (BNSS) total score, a scale designed to specifically assess the negative
symptoms of schizophrenia. Effects on several of the BNSS subscale scores at Week 4
were also observed, including on the Alogia, Asociality, Anhedonia, Avolition and Blunted
Affect subscales and on the negative symptom factors of the Uncorrelated PANSS Score
Matrix transformation of the PANSS (UPSM-PANSS) [154,155]. The UPSM-PANSS factors
have been shown to have low levels of between-factor correlation across multiple clinical
trials in schizophrenia [156]. This suggests that these UPSM factors are detecting a true
negative symptom treatment effect for ulotaront and not a nonspecific effect secondary to
improvement in correlated PANSS items. Thus, these findings suggest potential benefits of
TAAR1 agonists for negative symptoms.
In the 26-week open-label extension study [124] where all patients received flexi-
bly dosed ulotaront (25 to 75 mg/day), continued improvement across a broad array of
schizophrenia symptoms was observed, as measured by the PANSS total score and subscale
scores (positive, negative and general psychopathology), CGI-S score, MADRS total score
Int. J. Mol. Sci. 2021, 22, 13185 14 of 22
and BNSS total score. Furthermore, treatment response rates at Week 26 (as measured by a
≥30% reduction in PANSS total score from the baseline of the double-blind study) were
high (94.1% for patients who received ulotaront in the double-blind study and continued
ulotaront treatment in the extension study, and 92.5% for patients who initially received
placebo in the double-blind study and were switched to ulotaront in the extension study
[observed cases]). Of the 156 patients who received ulotaront in the extension study, 67%
completed 26 weeks of treatment, a rate notably higher than 37–49% attrition rate reported
previously in 6-month extension studies of many current antipsychotics [54,157].
The completed Phase 2 studies with ulotaront suggest that it is effective in treating
the symptoms of schizophrenia with a clinical safety and tolerability profile that lacks the
class-related side effects of currently marketed antipsychotics. In the 4-week, double-blind
study, the safety and tolerability of ulotaront was shown to be similar to the placebo.
The incidence of adverse events (AEs) was generally similar in the ulotaront and placebo
groups, with the only AEs reported in ≥2% of the ulotaront group and twice the rate of
the placebo group being diarrhea (2.5% in ulotaront and 0.8% in placebo) and dyspepsia
(2.5% in ulotaront and 0 in placebo). Notably, treatment with ulotaront was not associated
with EPS or other movement disorders, supporting its lack of D2 blockade. Percentages
of patients reporting EPS AEs (3.3% ulotaront; 3.2% placebo) and results on scales used
to measure motor impairments (AIMS, BARS, SAS) were similar between groups. Mean
changes in metabolic laboratory parameters and prolactin were also similar to placebo and
there were no clinically significant ECG findings. The results of the 26-week extension
study were consistent with these results. Overall, there was a low incidence of AEs. AEs
related to EPS were few and there were no clinically meaningful changes on scales used to
measure the degree of motor symptoms. In addition, ulotaront had no clinically meaningful
effects on weight, lipids, glycemic indices, prolactin, or ECG parameters (including no
evidence for prolongation of the QTc interval)—all hallmark side effects associated with
antipsychotics that work via D2 receptor antagonism. Taken together, these results suggest
a generally well-tolerated safety profile for ulotaront that is consistent with the absence of
D2 -receptor blockade and supportive of a novel mechanism of action and a new drug class
for the treatment of schizophrenia.
6. Conclusions
Foundational preclinical research and recent clinical evidence demonstrate the promise
of TAAR1 agonists to be the first novel drug class for the treatment of schizophrenia
in almost 70 years. Ulotaront recently reached recommended status for its proposed
International Nonproprietary Name (INN), joining TAAR1 partial agonist ralmitaront
in this class with the designated stem “-taront” [158]. These recent developments have
ignited further interest in TAAR1 biology. Preclinical data suggest TAAR1 agonists may be
uniquely positioned to target the presynaptic mechanisms underlying dopamine synthesis
capacity dysfunction in psychosis and modulate glutamatergic circuit alterations associated
with core symptoms of schizophrenia. Thus, increasing our knowledge of TAAR1 and its
ability to modulate monoaminergic and glutamatergic circuits is not only important for the
development of future TAAR1 agonists and their potential therapeutic effects, but possibly
also to our understanding of the pathophysiology of schizophrenia. Future work should
be aimed at pinpointing the precise cellular and subcellular localization of TAAR1 and
increasing our understanding of its signal transductions and molecular interactions.
The potential for a non-D2 -based approach to offset the last 70 years of treatment with
antipsychotics is promising and underscores the need for treatments with broad-spectrum
efficacy and improved safety and tolerability compared to current antipsychotics. To date,
treatments indicated for schizophrenia have been restricted to drugs that primarily act
via antagonism at D2 and/or 5-HT2A receptors. Ongoing Phase 2 and 3 clinical trials
will determine whether TAAR1 agonists can circumvent the fate of prior, non-D2 receptor
experimental drugs to become the first novel mechanism for the treatment of schizophrenia.
Int. J. Mol. Sci. 2021, 22, 13185 15 of 22
Although initial clinical results with ulotaront are encouraging, these findings will need to
be replicated in additional clinical studies.
Most currently available antipsychotics are associated with significant side effects,
with EPS and cardiometabolic disturbances considered to be the most troublesome. Preclin-
ical and clinical data to date suggest that TAAR1 agonists may improve several symptom
domains of schizophrenia without causing debilitating motor impairments or metabolic
syndrome. The availability of a treatment with a novel safety profile therefore becomes an
attractive option.
In general, the reduction of positive symptoms serves as a marker of currently defined
treatment success with antipsychotics; however, other important symptoms of schizophre-
nia and comorbidities are often ignored or undertreated. Both preclinical and clinical
studies and analyses support the hypothesis that TAAR1 agonists may be effective in
treating the negative symptoms of schizophrenia. Moreover, studies in rodents and non-
human primates have demonstrated pro-cognitive effects of TAAR1 agonists. The potential
availability of an agent able to address negative and cognitive symptoms (notably present
in the prodromal period) may enable earlier intervention especially if a differentiated
risk-benefit profile vs. antipsychotics can be demonstrated. This notion however needs
to be thoroughly explored, as these scenarios have not been investigated in clinical trials.
Future studies examining the consequences of earlier intervention with TAAR1 agonists
would be of interest.
TAAR1 may be a valuable therapeutic target in areas beyond schizophrenia and psy-
chosis. A considerable body of preclinical evidence supports TAAR1 as a promising target
for the treatment of metabolic syndrome and obesity, substance abuse, sleep disorders
characterized by changes in REM sleep, and potentially mood and anxiety disorders. Con-
sidering that many of these represent comorbidities of schizophrenia, future studies should
assess whether TAAR1 agonists have the potential to treat a spectrum of largely unad-
dressed schizophrenia symptoms which would otherwise require combination treatments
and polypharmacy.
In the foreseeable future, findings from ongoing clinical trials with ralmitaront and
ulotaront will be fundamental to elucidate the therapeutic utility of TAAR1 agonists, which
hold great promise as a new drug class for the treatment of schizophrenia.
Funding: Manuscript development was supported by Sunovion Pharmaceuticals Inc. (Marlborough,

MA, USA).
Acknowledgments: We thank all the researchers, patients, investigators, who were a part of the
summarized research. Thank you to Edward Schweizer for providing editorial assistance (funded
by Sunovion Pharmaceuticals). Sunovion discovered ulotaront in collaboration with Psycho-Genics
based in part on a mechanism-independent approach using the in vivo phenotypic SmartCube®
platform and associated artificial intelligence algorithms.
Conflicts of Interest: N.D., H.D. and C.Z. are employees of Sunovion Pharmaceuticals. G.R. is
supported by the European Union’s Horizon 2020 research and innovation program under the MSC
grant agreement n◦ 101026235. O.D.H. is funded by the UK Medical Research Council and the NIHR
Bio-medical Research Centre at South London and Maudsley NHS Foundation Trust and King’s
College London. ODH is a part-time employee of H. Lundbeck A/S and has received investigator-
initiated research funding from and/or participated in advisory/speaker meetings organized by
Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, In-
vicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche and Viatris/Mylan.
Neither Howes or his family have holdings/a financial stake in any pharmaceutical company.
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International Journal of

1 Sunovion Pharmaceuticals, Marlborough, MA 01752, USA; [email protected] (H.D.);

Received: 27 October 2021

Publisher’s Note: MDPI stays neutral

Int. J. Mol. Sci. 2021, 22, 13185. https://doi.org/10.3390/ijms222413185 https://www.mdpi.com/journal/ijms

Positive Symptoms Negative Symptoms Cognitive Symptoms-Impairments in:

Schizophrenia remains one of the most challenging diseases to treat, as significant

N-Methyl-D-aspartic acid (NMDA) receptor hypofunction [31–33] as well as serotonin

1.2. Current Pharmacologic Treatments

treatment-resistant schizophrenia (non-response to ≥2 medications) occurs in up to 34% of

2. TAAR1 As a Novel Therapeutic Target for the Treatment of Schizophrenia

2.2. Development of Synthetic TAAR1 Ligands

Behavioral Effects in Preclinical Models &Assays

3. Preclinical Evidence for TAAR1 as a Therapeutic Target for Schizophrenia

3.1. Role of TAAR1 in Psychosis and Dopaminergic Tone

3.2. Role of TAAR1 in Cognition, Negative Symptoms, Mood and Anxiety

3.3. TAAR1 Effects on Serotonergic, Noradrenergic and Glutamatergic Systems

restoring excitatory/inhibitory imbalance and structural alterations in the mPFC [119].

4. Additional Considerations for TAAR1 Agonists as Therapeutic Agents

agents may be uniquely positioned to improve comorbid metabolic disorders in patients

5. Clinical Evidence for TAAR1 Agonists for the Treatment of Schizophrenia

Funding: Manuscript development was supported by Sunovion Pharmaceuticals Inc. (Marlborough,

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