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

To date, the pathogenesis of schizophrenia remains poorly under stood. However, neurodevelopmental theories have been used to explain this complex disorder, as converging lines of evi dence 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. What are the differences between men and women? The incidence of schizophrenia in men is approximately 40% higher than in women, 2 and men have an earlier peak age at onset. 3 Sex differences are especially relevant in LOS. Manfred Bleuler first described LOS in 1943, and it remains distinct in its clinical profile compared with EOS. 3 Late-onset schizophrenia has a 1-year prevalence rate of 0.6% when accounting for patients in whom the disorder is diagnosed after age 45, and it is reported that 23% of patients with schizophrenia had an onset of symptoms after age 40. The second peak of incidence in women: Is it so obvious? A meta-analysis conducted by Kirkbride and colleagues 7 compiling schizophrenia incidence rates over a 6-year period in England noted a "secondary peak" of incidence in women near the age of 45 years. This concept has also been discussed in other reports. 8 However, consideration o