Induced pluripotent stem cell-derived neuronal models in psychiatry: Mechanistic insights and translational horizons

Human induced pluripotent stem cell (iPSC)-derived neuronal models have become an important platform for investigating psychiatric disorders by enabling experimental access to human neurons carrying patient-specific genetic risk. Advances in reprogramming, neural differentiation, single-cell profiling, electrophysiology, and genome editing have facilitated the accessibility of knowledge which was once unavailable. Psychiatric disorders pose particular challenges for in vitro modeling due to their polygenic architecture, developmental origins, and clinical heterogeneity. This review summarizes the current state of iPSC-derived neuronal technologies, summarizes key findings across major psychiatric disorders, and discusses methodological limitations and emerging translational directions. We emphasize quantitative functional phenotyping and patient stratification as central principles for future progress in precision psychiatry. The future of precision psychiatry relies on two central principles; analyzing patient specific neuronal characteristics with an objective, comparable readout, and classifying patients into biologically meaningful subgroups which share common features such as mechanism, biomarker profile, or functional and structural signature.

Keywords: Induced pluripotent stem cells; Schizophrenia; Bipolar disorder; Major depressive disorder; Autism spectrum disorder; Attention-deficit hyperactivity disorder; Precision psychiatry; In vitro disease modeling

Core Tip: Human induced pluripotent stem cell-derived neuronal models are transforming psychiatric research by enabling direct investigation of patient-specific neural phenotypes in a human genetic context. Beyond disease modeling, emerging evidence suggests that quantitative functional phenotyping can identify biologically meaningful patient subgroups and treatment-response signatures. This review synthesizes findings across major psychiatric disorders and proposes a conceptual shift from reproducing diagnostic categories in vitro toward mechanism-based stratification. Such approaches may bridge the gap between psychiatric genetics and clinical decision-making, advancing the development of precision psychiatry.undefined