IUPHAR Review - Novel therapeutic targets for schizophrenia treatment: a translational perspective.

Schizophrenia is a severe and debilitating psychiatric disorder that profoundly impacts cognitive, emotional, and social functioning. Despite its devastating personal and societal toll, current treatments often provide only partial relief, underscoring the urgent need for innovative therapeutic strategies. This review explores emerging approaches that target the complex neurobiological underpinnings of schizophrenia, moving beyond traditional dopamine-centric models. Among these, some novel drugs still employ multimodal mechanisms, simultaneously targeting dopaminergic and serotonergic systems to enhance efficacy and tolerability. Given the well-documented excitatory/inhibitory imbalance in schizophrenia, significant efforts have been directed toward addressing NMDA receptor hypofunctionality. However, strategies targeting this pathway have yet to demonstrate consistent clinical efficacy. In contrast, therapies targeting the cholinergic system have shown greater promise. For instance, the xanomeline-trospium combination, which modulates muscarinic receptors, has recently gained approval, and other molecules with similar mechanisms are currently under development. Beyond these approaches, novel strategies are being explored to target innovative pathways, including neuroplasticity, neuroinflammation, and mitochondrial dysfunction. These efforts are often designed as part of a combinatorial strategy to enhance the efficacy of currently available antipsychotic drugs. Despite significant progress, challenges remain in translating experimental discoveries into effective clinical applications. Future research should prioritize biomarker-driven approaches and precision medicine to optimize individualized treatment outcomes. By integrating these emerging therapeutic targets, schizophrenia treatment may evolve toward a more comprehensive and personalized approach, addressing the disorder's full spectrum of symptoms and improving patient quality of life.