Neuronal Organoid Engineering and Disease-Focused High-Throughput Neuropharmacology: Advances, Limitations, and...

Although animal models offer the physiology of the entire organism, various cell populations, and circuit-level behaviors, their predictive ability for polygenic neuropsychiatric disorders may be limited by species-specific neurodevelopment and genetics. Consequently, despite decades of neuropharmacological research, many CNS-targeted drug candidates still fail in late-stage clinical trials. This review summarizes how neuronal-engineering platforms, especially patient-derived induced pluripotent stem-cell (iPSC) organoids and neuron-glia cocultures, enable high-throughput screening (HTS) pipelines with greater clinical fidelity. This review focuses explicitly on neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar disorder, and anxiety, and emphasizes human cell-derived organoid and neuron-glia coculture models tailored to their circuit-level pathophysiology. Organoid-enabled HTS couples human genetics with automated phenotyping, accelerating identification of circuit-level drug effects while reducing animal use. The remaining issues are integrating multiomics data, vascularization, and batch variability. These gaps will be filled, and precision psychiatry will become attainable with the continued advancements in biomaterials, single-cell analytics, and machine learning, by highlighting how human iPSC-derived organoids and advanced neuronal engineering recapitulate pathology and enable scalable drug screening. This review addresses a critical bottleneck in psychiatric drug development and outlines how these innovations can help close the bench-to-bedside gap in neuropsychiatric drug discovery.