Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

Abstract

Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma-2, 5-HT_2A, and α_1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M_1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT_1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics.