Decoding psychotic and other psychiatric disorders through placental organ: From cytoarchitecture to...

Psychosis-defined as a profound disconnection between objective external reality and internal mental representations-represents a critical mental health condition, especially when it emerges for the first time during pregnancy. First-episode psychosis (FEP) in pregnant women (FEP-PW), though rare, presents severe risks for both maternal and fetal health. Despite its clinical significance, the biological mechanisms underlying FEP-PW remain poorly understood. This narrative review investigates the human placenta as a valuable and dynamic organ for decoding psychiatric and psychological disorders, particularly FEP-PW, but also encompassing conditions such as psychological stress, metabolic stress, post-traumatic stress disorder (PTSD), affective disorders, anxiety, schizophrenia, and broader psychotic syndromes. We define FEP and its unique presentation during pregnancy, highlighting clinical aspects and current diagnostic challenges. Central to this review is the evolving recognition of the placenta, not as a mere byproduct of parturition, but as a biologically active interface that influences both maternal mental health and fetal neurodevelopment. We argue for the importance of studying the human placenta directly, given the species-specific nature of genomic imprinting and stress-responsive signaling, which limits the translational power of animal models. Accumulating evidence reveals that maternal psychological and metabolic stressors can alter placental structure and function, with implications for both maternal psychiatric vulnerability and the long-term mental health of the offspring. These findings support the Developmental Origins of Health and Disease (DOHaD) framework and suggest that placental molecular dysregulation may contribute to the intergenerational transmission of psychiatric risk. By integrating diverse biological and clinical perspectives, this review positions the placenta as a critical organ for future research in perinatal psychiatry and mental health. Emerging strategies such as the analysis of placenta-derived extracellular vesicles (EVs) offer a promising, non-invasive avenue to monitor placental molecular activity in real time. By integrating EV-based transcriptomic and proteomic profiling from maternal blood, future research may identify biomarkers of stress-related placental dysfunction linked to maternal psychiatric conditions. This approach holds strong potential to bridge current gaps in perinatal mental health research, aligning with the DOHaD framework to inform early detection and intervention strategies.