Abstract
Since the discovery of chlorpromazine, antagonism of dopamine D2 receptors has been central to the mechanism of antipsychotic drug efficacy. Currently approved antipsychotics effectively manage the positive symptoms of schizophrenia, however, their effects on negative and cognitive symptoms are negligible. Moreover, these drugs are associated with many serious side effects (e.g., motor and endocrine abnormalities, sedation, and weight gain) which negatively impact medication adherence. Researchers have vigorously pursued new therapeutic targets to treat schizophrenia beyond D2 receptor blockade. Recently, trace amine-associated receptor1 (TAAR1) has emerged as a promising new drug target. This review will discuss the current state of research of TAAR1 and will summarize the status of TAAR1 agonists in clinical development and their potential treatments for psychiatric disorders. Ulotaront is a TAAR1 agonist with 5-HT1A agonist activity under investigation for the treatment of schizophrenia. Ulotaront is the first TAAR1 agonist to progress to randomized controlled clinical trials and has demonstrated broad efficacy in animal models of schizophrenia. Unlike all approved antipsychotic drugs, ulotaront does not exert its effects via blockade of dopamine D2 or serotonin 5-HT2A receptors. In a randomized, double-blind, placebo-controlled clinical trial in patients with an acute exacerbation of schizophrenia, ulotaront demonstrated efficacy for both positive and negative symptoms, with continued symptom improvement observed over the course of the optional 6-month open-label extension study. In these studies, ulotaront was generally safe and well-tolerated with a tolerability profile similar to placebo and distinguished from the antipsychotic class, supporting its novel mechanism of action and absence of D2-receptor blockade. Taken together, these results are supportive of the therapeutic potential of TAAR1 agonists as a possible new drug class for the treatment of schizophrenia.
