Drug discovery in psychopharmacology: from 2D models to cerebral organoids

Abstract

Psychiatric disorders are a heterogeneous group of mental illnesses associated with a high social and economic burden on patients and society. The complex symptomatology of these disorders, coupled with our limited understanding of the structural and functional abnormalities affecting the brains of neuropsychiatric patients, has made it difficult to develop effective medical treatment strategies. With the advent of reprogramming technologies and recent developments in induced pluripotent stem (iPS) cell-based protocols for differentiation into defined neuronal cultures and 3-dimensional cerebral organoids, a new era of preclinical disease modeling has begun which could revolutionize drug discovery in psychiatry. This review provides an overview of iPS cell-based disease models in psychiatry and how these models contribute to our understanding of pharmacological drug action. We also propose a refined iPSC-based drug discovery pipeline, ranging from cell-based stratification of patients through improved screening and validation steps to more precise psychopharmacology.