Can the neurodevelopmental theory account for sex differences in schizophrenia across the life span?

To date, the pathogenesis of schizophrenia remains poorly understood. However, neurodevelopmental theories have been used to explain this complex disorder, as converging lines of evidence suggest abnormal trajectory of brain development as a key pathological process.1 To understand the pathogenesis through a neurodevelopmental lens, sex differences observed between men and women, including age at onset, prevalence and clinical presentations, are important. This editorial uses the neurodevelopmental hypothesis as the main framework to reflect on and examine the variation of incidence between the sexes across the life span, with some emphasis on late-onset schizophrenia (LOS). We think that the neurodevelopmental theory may prove valuable in accounting for sex differences in early-onset schizophrenia (EOS), as sex differences in early brain development may point to differing ways the brains of women and men handle in-utero insults. However, this theory is limited in accounting for the neurobiological mechanisms underlying sex differences across the entire life span, as it may fail to explain the predominance of women with LOS. We think that the widely discussed role of estrogen in delaying the age of onset of schizophrenia in women may not be restricted to the “estrogen protection” hypothesis; rather, estrogen’s modulation of key brain structures and processes in the adult brain, perhaps through epigenetic changes, may be more intimately connected to LOS in women. Therefore, the classical neurodevelopmental theories may not be sufficient to allow a full understanding of the sex differences in patients with schizophrenia.