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

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.

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.

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.