Trace Amine-Associated Receptor 1 (TAAR1): Molecular and Clinical Insights for the Treatment of Schizophrenia and Related Comorbidities

Abstract

Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D₂-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.

Schizophrenia is a severe mental illness with a lifetime prevalence of about 1%, reducing life expectancy and accounting for significant healthcare burden.¹ High overall costs of the illness are attributable to a typically early adulthood onset, relatively high rates of hospitalization, and long-term impairments in social and occupational functioning. Schizophrenia is characterized by a broad array of symptoms including positive symptoms (delusions and hallucinations), negative symptoms (amotivation, social withdrawal, and reduced emotional expression), and cognitive impairments (impaired working memory, verbal memory, and executive functioning).¹ The mainstay of current treatments involves targeting the dopamine D₂-receptor or modulating dopaminergic neurotransmission.² While these medications have some impact upon positive symptoms, there is little or no clinical impact on negative symptoms and cognitive impairment.²

Chlorpromazine (Figure 1), the first antipsychotic medication identified in 1952, was initially used as an anesthetic agent.² The multiple antipsychotics developed since 1952 are all primarily dopamine D₂-receptor antagonists; however, only ∼70% of patients respond to these medicines.^1,2 Older generation antipsychotic medications (typical antipsychotics, e.g., chlorpromazine, zulopenthixol, haloperidol) (Figure 1) have significant neurological side effects (tardive dyskinesia, dystonia, and akathisia).^1,2 Newer generation “atypical antipsychotic” medications (e.g., olanzapine, quetiapine, risperidone, ziprasidone) (Figure 1) have reduced neurological side effects, thought to be due to adding 5HT_2A-receptor antagonism to dopamine D₂-receptor blockade.² However, atypical antipsychotics yield similar efficacy, with ∼30% of patients remaining treatment-resistant, and present an increased risk of metabolic syndrome (weight gain, increased triglycerides and cholesterol). The generalized lack of efficacy of dopamine D₂-receptor blockade in treatment-resistant schizophrenia (TRS) is perhaps unsurprising, given the unchanged presynaptic dopamine synthesis capacity in these patients, unlike treatment-responsive patients.^3,4 In this context, clozapine (Figure 1) stands apart as the only atypical antipsychotic medication effective in TRS.^1,2 Even so, the clozapine response rate in the setting of TRS is only ∼40–60% and causes significant weight gain and the rare risk of life-threatening agranulocytosis.^1,2 There remains a need for medications effective in the TRS patient population with reduced propensity for side effects.

Figure 1.

Chemical structures of (A) typical and (B) atypical antipsychotics, TAAR1 agonists, (C) endogenous trace-amines, and (D) drug candidates in clinical trials.

Another concern in relation to long-term administration of dopamine D₂-receptor blocking medications is the risk of dopamine supersensitivity psychosis due to dopamine D₂-receptor upregulation.⁵ The potential clinical consequence of dopamine supersensitivity psychosis is that antipsychotic medication may progressively lose effectiveness in treating the schizophrenia, necessitating increasingly higher antipsychotic doses over time, with attendant increased side-effect burden.⁵ Ultimately, dopamine supersensitivity psychosis may progress to treatment-resistant schizophrenia.⁵ Medications that do not lead to dopamine supersensitivity psychosis may lead to better long-term clinical outcomes and reduced rates of TRS.

There are also some concerns that the dopamine D₂-receptor blockade can lead to neuronal atrophy and reduction of cortical volume.⁵ In this context, antipsychotic medication in preclinical studies impairs memory-related task performance as well as spatial and working memory.⁵ Therefore, cognitive impairment associated with schizophrenia may in part be linked to antipsychotic-induced cortical volume loss. Thus, developing an effective nondopamine D₂-receptor-targeting drug for the treatment of schizophrenia with minimal off-target side-effects is of significant importance.

The dopamine hypothesis in schizophrenia has dominated the field for more than five decades; however, emerging evidence suggests that contributing factors for schizophrenia may lie outside the dopaminergic system.⁶⁻⁸ Despite numerous past failures, hope remains that targeting nondopaminergic systems could be beneficial for the treatment of schizophrenia to better address all three symptom domains. Trace-amine-associated receptor 1 (TAAR1) is one such newly identified receptor system under active investigation for the treatment of schizophrenia and showing promising initial clinical trial results.^2,8 Some of the potential benefits of using TAAR1 agonists over other antipsychotics are highlighted in Table 1.

Table 1. Antipsychotic Medication versus TAAR1 Agonists.

conventional antipsychotics	TAAR1 agonists
can lead to dopamine supersensitivity psychosis	will likely not cause dopamine supersensitivity psychosis
can induce tardive dyskinesia/tardive dystonia/akathisia	likely no induction of tardive dyskinesia/tardive dystonia/akathisia
can cause metabolic syndrome	likely no induction of metabolic syndrome, and may be able to treat metabolic syndrome
no effect for treating substance abuse	may be able to reduce craving for substance abuse
not useful in treatment-resistant schizophrenia (except clozapine)	may help for patients who do not respond to current antipsychotic medications
have little impact on negative symptoms and cognition	effect on negative symptoms and cognition is currently unknown

Trace Amine-Associated Receptor 1 (TAAR1)

Trace amines (TAs) are endogenous metabolites of amino acids structurally similar to biogenic amines. TAs (e.g., p-tyramine, β-phenylethylamine, and tryptamine) (Figure 1) occur at low levels (100 ng/g tissue), are degraded by monoamine oxidase with a rapid turnover rate, and selectively activate a family of G protein-coupled receptors (GPCRs) generally referred to as TAARs (TAAR1 is officially designated TA₁ by NC-IUPHAR). The TAAR1 gene was mapped to chromosome 6q23.2, coinciding with a potential susceptibility locus for schizophrenia and bipolar disorder.⁹⁻¹² TAAR1 is widely distributed throughout the brain including the dopamine-rich regions such as ventral tegmental area (VTA), substantia nigra, and serotonin-rich regions such as dorsal raphe nucleus (DRN) (Figure 2).^11,12 TAAR1 expression in different zones in the brain modulates dopaminergic, glutamatergic, and serotonergic neurons.^11,12 Thus, TAAR1 plays an essential role in the regulation of reward circuits, cognitive processes, and mood states, physiological processes disrupted in schizophrenia.

Figure 2.

(A) Key regions of TAAR1 expression in the brain associated with pathophysiology of schizophrenia and other neuropsychiatric disorders, (B) TAAR1 homology model, (C) close-up view of the binding interactions between ulotaront and TAAR1 from MD simulations. TAAR1 is shown as cartoon (white), key amino acids are shown as sticks (green), and ulotaront is shown as ball and sticks (C, N, O, and S atom(s) are in magenta, blue, red, and yellow, respectively).

TAAR1-mediated regulation of dopamine D₂-receptor expression and activity was demonstrated in several in vitro and in vivo studies;^13,14 subsequently, it was shown that the two receptors form heterodimers.¹⁴ In striatal tissues from Taar1^–/– mice, there is increased dopamine D₂-receptor expression and enhanced signaling via the protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) pathway.¹⁵ The AKT/GSK3β pathway is increasingly connected to the etiology of schizophrenia and other mental health disorders.^11,12 Targeting AKT/GSK3β signaling is an exciting prospect for future research in the mental health space.

Schizophrenia, Substance Abuse, and TAAR1

Patients with schizophrenia have high rates of substance abuse comorbidity with about half of patients having serious problems with drug or alcohol misuse during their lifetime compared with 16% of the general population.¹⁶ Substance abuse comorbidity in schizophrenia is associated with increased rates of relapse, rehospitalization, noncompliance with treatment, poor global functioning, violence, and suicide.¹⁶ There are varying hypotheses explaining the association between substance abuse and schizophrenia including the diathesis-stress model (poverty, victimization, and deviant social environments) and self-medication hypothesis (use of substances to reduce symptoms or side-effect burden of antipsychotic medication).¹⁶ Alternative biologically-based theories propose that schizophrenia and substance abuse disorders share a common pathophysiology in overlapping neural circuits related to possible dysfunction in “brain reward” circuits.¹⁶ Most antipsychotic medications do not lessen substance abuse in schizophrenia, with the only exception being clozapine.¹⁶ Since multiple psychotropic agents including amphetamines, methamphetamine, and methylenedioxymethamphetamine (MDMA) are potent human TAAR1 agonists, there is significant interest in determining the role TAAR1 agonists might play to reduce drug craving and other addictive behaviors.^11,12 This potential anticraving role relates to specific TAAR1 localization within central dopamine reward center pathways and regulation of dopamine D₂-receptor signaling.^11,12 There have been no human clinical trials of TAAR1 agonists for drug addiction, but these trials are now anticipated in light of recent clinical data.¹¹ In this context, patients with schizophrenia and comorbid substance abuse (amphetamine, cocaine, alcohol, etc.) may specifically benefit from TAAR1 agonists (Table 1). On a related note, TAAR1-selective agonists decrease methamphetamine self-administration, reinstatement, behavioral sensitization, and motivation to seek amphetamine.¹¹ Therefore, TAAR1 agonists may also be beneficial treatments for patients with amphetamine-induced psychosis.

Schizophrenia, Metabolic Syndrome, and TAAR1

Patients with schizophrenia have high rates of metabolic syndrome, which may only be partially related to the effects of atypical antipsychotic medication. TAAR1 is also expressed on the insulin-producing beta-cells of the pancreas, the stomach, and the intestines.¹¹ Selective TAAR1 agonists dose-dependently enhance glucose-stimulated insulin secretion in human islets,¹¹ and the TAAR1 partial agonist, R05263397, prevented olanzapine-induced weight gain in patients with schizophrenia.¹¹ TAAR1 has been identified in brain areas (hypothalamus, limbic system, and cortex) specifically associated with regulation of nutrient intake, storage, and processing.¹¹ Central and peripheral actions of TAAR1 agonists offer promise for treating metabolic dysfunction in patients with schizophrenia.

TAAR1 Agonists in Development

Because of an intimate link between TAAR1 and dopamine D₂ receptors as well as involvement in brain circuitry relevant to schizophrenia and reward, there has been significant interest in developing TAAR1 agonists. Several promising drug candidates have been developed by both pharmaceutical companies (e.g., F. Hoffmann-La Roche, Purdue Pharma LP) and academic groups. The most advanced of these, ulotaront (SEP-363856), was granted a Breakthrough Therapy Designation by the U.S. Food Drug Administration in 2019 and has markedly smaller size and lower molecular weight compared with other antipsychotics (Figure 1).

A recent clinical trial study by Sunovion Pharmaceuticals evaluated ulotaront as a potential monotherapy treatment for acute schizophrenia. Ulotaront binds with high affinity to TAAR1 and 5-HT_1A receptors but not to dopamine D₂/5-HT_2A receptors.^8,17 The 4-week randomized placebo-controlled trial resulted in a significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo. The effect size for ulotaront compared to placebo was 0.45, which compared favorably with second-generation atypical antipsychotic drugs (viz. 0.51). Metabolic and neurological adverse event rates for ulotaront were similar to placebo, with increased somnolence and gastrointestinal symptoms suggesting that ulotaront may have a lower side-effect profile when compared with atypical antipsychotic medication.⁸ Currently, 12 clinical trials of ulotaront are registered for schizophrenia including two large multicenter efficacy studies. The results of these studies in patients with schizophrenia will be important to replicate the initial promising findings of Koblan and colleagues. Another structurally distinct TAAR1 agonist, ralmitaront (RO6889450) (Figure 1), developed by Hoffmann-La Roche, is currently in two phase 2 trials for the treatment of patients with schizophrenia or schizoaffective disorder and negative symptoms; these studies are expected to be completed by April 2023.

Explorations into Ulotaront Binding to TAAR1

Currently, there are no experimental structures of TAAR1 to definitively map the binding pockets. However, theoretical models of both human and mammalian (rat and mouse) TAAR1 have provided some insights into how different agonists interact with this receptor.^18,19 Early homology models of rat and mouse TAAR1 predicted some agonists are bound in different orientations despite a high (93%) sequence similarity between these species.¹⁸ A human TAAR1 structural model was combined with static molecular docking to investigate the binding interactions of three different agonists (RO516607, β-phenylethylamine, and 3-iodothyronamine).¹⁹ Recently, we developed a TAAR1 homology model (Figure 2) combined with molecular dynamics (MD) simulations to probe ulotaront binding to TAAR1.⁷ Residues in TM3 were predicted to form a salt bridge (Asp103^3.32), hydrogen bonding (Ser107^3.36), and hydrophobic (Ile104^3.33) interactions with ulotaront; the ligand mainly formed aromatic contacts with TM5 (Phe195^5.44 and Phe199^5.47) and TM6 (Phe268^6.52).⁷ Consistent with earlier studies, ulotaront is proposed to recognize the conserved orthosteric binding site within class A GPCRs. Further, two residues, Phe186^ECL2 and Phe195^5.44 unique to TAAR1, may play a prominent role in the selective binding of ulotaront to TAAR1 relative to other aminergic receptors (viz. 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2C, 5-HT₇, α_2A, α_2B, dopamine D₂). In particular, given its reported dual receptor pharmacology, this study examined the residue composition of the ulotaront binding site across TAAR1 and 5-HT_1A, suggesting the former interacted with ulotaront with a greater number of aromatic contacts. Elucidating structures of TAAR1 bound to ulotaront or site-directed mutagenesis studies may provide further insights into the role of residues involved in ulotaront binding to both TAAR1 and 5-HT_1A and inform future rational TAAR1 drug discovery efforts.

Conclusion and Future Perspectives

The potential benefits of TAAR1 agonists for schizophrenia are multifold, ranging from reduction in metabolic syndrome to decreased drug craving/substance abuse. Continued efforts to decipher the molecular basis of TAAR1 agonist binding, the contribution of TAAR1 and D₂-receptor dimerization, and the myriad of downstream functional consequences of TAAR1 activation remain highly significant. Molecular-level insights are needed to inform structure-guided discovery of novel TAAR1 agonists with the capacity to optimally fine-tune cellular activity. In this respect, unravelling species and cell-type differences in TAAR1 signaling and agonist pharmacology will be critical to aid translation. Furthermore, since ulotaront and similar molecules do not directly engage dopamine D₂-receptors, TAAR1 agonists are predicted to be less likely to induce dopamine supersensitivity and may have potential in the treatment of TRS patients. Ultimately, future clinical trial data will inform about the benefits of TAAR1 agonists over existing antipsychotics and whether TAAR1 agonists have the potential to supersede current antipsychotics. Also, the ongoing and future clinical trials will unravel the prospects of TAAR1 agonists in the treatment of multiple disease states including bipolar disorder, depression, stress, sleep disorders, substance abuse disorders, and Parkinson’s disease.

The authors declare no competing financial interest.