The design of multi-target ligands and their role in schizophrenia therapy: an update

INTRODUCTION: Schizophrenia is a complex psychiatric disorder with a partially understood pathophysiology involving multiple neurotransmitter systems and receptor families in its onset and progression. Modern therapeutic approaches for effective schizophrenia treatment require multi-target drug actions that exert therapeutic effects through interactions with various neurotransmitter systems. AREAS COVERED: This review provides an updated overview of schizophrenia pathophysiology, focusing on current dopaminergic, serotonergic, and glutamatergic hypotheses, with particular attention to multi-target antipsychotics and the rationale for their development. The literature was searched using relevant online scientific journal databases. For the overview of recent advances and novel multi-target ligands, studies published primarily between 2020 and 2026 were included. State-of-the-art strategies for designing multi-target ligands, including molecular modeling and computer-aided drug design approaches, are discussed, along with the opportunities and limitations associated with multifunctional compounds. EXPERT OPINION: Advancing schizophrenia treatment depends on the ongoing development of well-balanced multi-target ligands, which require careful adjustment of affinities across multiple neurotransmitter systems and receptor families while avoiding off-target interactions and maintaining optimal physicochemical and pharmacokinetic properties. Nevertheless, multi-target antipsychotics offer substantial advantages in therapy, positioning them as a transformative direction in antipsychotic drug discovery.