The role of trace amine-associated receptor 1 (TAAR1) in the pathophysiology and treatment of depression

Abstract

Depression is a chronic and recurrent psychiatric condition thought to result from an interaction between genetic susceptibility and environmental stimuli. Even though existing available therapies prescribed for depressed patients are effective, it will take several weeks to demonstrate their full effectiveness, and is often accompanied by side effects and withdrawal symptoms. In this regard, discovery of new antidepressant drug of unique, higher curative effect, and less adverse reaction is the pursuit of pharmaceutical. Trace-amine associated receptor 1 (TAAR1), an intracellular G-protein coupled receptor (GPCR) that is broadly expressed in the mammalian brain, especially within cortical, limbic, and midbrain monoaminergic regions and activated by "trace amines" (TAs). It is allegedly involved in modulating dopaminergic, serotonergic and glutamatergic transmission, makes TAAR1 a new drug target for the treatment of dysfunction of monoamine-related disorders. What's more, agonist compounds of TAAR1 have generated interest as potential treatments for depression due to TAAR1-mediated regulation of monoamine neurotransmitters. In fact, Ulotaront (a TAAR1 agonist) is reported to be currently undergoing phase 2/3 clinical trials in order to test its safety and efficacy in the treatment of major depressive disorder (MDD). However, details of the mechanism of TAAR1 remain elusive. Thus, this paper aims to review evidence of the potential role of TAAR1 in the pathophysiology and treatment of depression. Moreover, we briefly summarize the recent findings in the elucidation of behavioral and physiological properties of TAAR1 agonists both in clinical trials and preclinical animal studies. Collectively, these studies will provide a solid foundation for TAAR1 as a novel therapeutic target for depression.

Keywords: Depression; TAAR1; Antidepressant; Ulotaront; Neuropsychiatric disorders; Signalling pathway.