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 believed to result from an interaction between genetic susceptibility and environmental stimuli. Although current therapies prescribed for depression can be effective, it will take several weeks to demonstrate their full effectiveness and is often accompanied by side effects and withdrawal symptoms. In this regard, the discovery of new antidepressant drugs with unique, higher curative effects and fewer adverse reactions is the pursuit of pharmaceuticals. Trace amine-associated receptor 1 (TAAR1), a 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, which makes TAAR1 a new drug target for the treatment of dysfunction of monoamine-related disorders. Moreover, TAAR1 agonists have attracted interest as potential treatments for depression due to their role in regulating monoamine neurotransmission. 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, the final results of this Phase 2/3 clinical study have not been announced yet, and the efficacy and safety of Ulotaront in the treatment of depression still need further observation and research. Thus, this article 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.