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

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 and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

“…8 Symptoms of schizophrenia are classified as positive (e.g., delusions and hallucinations), negative (e.g., lack of motivation and social withdraw), and cognitive (e.g., impaired memory, attention, and problem-solving), and the presence and severity of these symptoms varies between patients. [9][10][11][12] As symptoms typically appear in early adulthood and there is currently no cure for this disease, many patients require lifelong management. [13][14][15] Accordingly, the economic burden of schizophrenia is high.…”

“…22 Current antipsychotic therapies act on dopamine D2 receptors, which produces a clinical response in patients with schizophrenia but also results in metabolic and motor side effects, namely increased prolactin levels, weight gain, and extrapyramidal symptoms (EPSs). 9,10,12,23,24 Second-generation, or atypical, antipsychotic drugs also have activity at 5-hydroxytryptamine 2A receptors, which also contributes to weight gain and metabolic changes. 23,25 Treatment-related side effects are risk factors for poor medication adherence and early death in this patient population, as they may cause patients to experience negative feelings of themselves or lead to the development of comorbid conditions such as diabetes or cardiovascular disease.…”

“…12,22 Additionally, currently available antipsychotic medications are effective in the management of positive symptoms, but there is still an unmet need for treatment options that can improve the negative and cognitive symptoms of schizophrenia. [9][10][11]25 Antipsychotic therapies are effective for positive symptoms in about 70% of patients, the remainder have treatment-resistant disorder. 22 Given these factors, there is a place in therapy for new interventions that do not produce the same side effects associated with current D2-receptor binding drugs and that can also treat the negative and cognitive symptoms of schizophrenia.…”

“…22 Given these factors, there is a place in therapy for new interventions that do not produce the same side effects associated with current D2-receptor binding drugs and that can also treat the negative and cognitive symptoms of schizophrenia. 7,9,10,27 The Technology In recent years, there have been considerable medical advances made with respect to TAAR1, a guanine nucleotide-binding protein-coupled receptor, and its potential role in treating schizophrenia and other psychiatric disorders. 9,15,[28][29][30] TAAR1 is found throughout the central nervous system as well as in peripheral tissues, and its expression in key areas of the brain makes it an attractive target for a number of neurologic disorders.…”

“…7,9,10,27 The Technology In recent years, there have been considerable medical advances made with respect to TAAR1, a guanine nucleotide-binding protein-coupled receptor, and its potential role in treating schizophrenia and other psychiatric disorders. 9,15,[28][29][30] TAAR1 is found throughout the central nervous system as well as in peripheral tissues, and its expression in key areas of the brain makes it an attractive target for a number of neurologic disorders. 28,29,31 TAAR1 agonists represent a novel drug class for treating schizophrenia as they do not block D2 receptors.…”