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.
Highlights
The proposed shift from cAMP accumulation to β-arrestin2 recruitment could have important pharmacological implications given that the AKT/GSK3β pathway is increasingly implicated in the pathophysiology of schizophrenia, bipolar disorder, and depression [65]
We provide an overview of Trace amine-associated receptor 1 (TAAR1) s role in regulating monoaminergic and glutamatergic 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
Ulotaront had no clinically meaningful effects on weight, lipids, glycemic indices, prolactin, or ECG parameters—all hallmark side effects associated with antipsychotics that work via D2 receptor antagonism
Summary
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). 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% [5,6,7]. 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 outlined hypotheses are becoming increasingly integrated, including evidence that glutamatergic dysregulation in cortical regions can lead to striatal dopamine dysfunction, and to the development of psychosis [36]
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