The two-hit hypothesis of schizophrenia suggests that a combination of genetic susceptibility coupled with a distinct developmental insult can prime an individual for a later event that ultimately leads to onset of the full clinical syndrome (). In the case of schizophrenia, multiple genetic liabilities have been suggested to interact with environmental factors, ultimately affecting the development of the central nervous system in a way that creates an abnormal signaling network (). This network, however, may not become abnormal until later in life: schizophrenia tends to first occur in the early and late 20s in males and females, respectively, suggesting that an event in adolescence or post-adolescence may be highly influential in the development of the disorder (this is explored below). A number of structural abnormalities in schizophrenia are associated with symptom development: Gray and white matter alterations, cerebral asymmetries, and ventricular enlargement, accompanied by abnormal neuronal density, size, shape, and migration (for review, see ; ; ; ) A multifactorial conceptualization of psychiatric disease is emerging in which multiple biologically significant events (or “hits”) are temporally distributed across early periods of the overall lifespan, and result in the development of schizophrenia-like diseases (). Until now, genetic abnormalities were viewed as the likely ‘first hit,’ however, as we suggest below, infection and inflammatory processes may also serve this function.
Neuroimaging studies have found significant sex differences in brain development trajectories during childhood and adolescence in healthy participants. Grey matter volumes peak at an earlier age in women than in men, and the pattern is consistent across many brain structures. One interpretation of these differences could be that boys have longer childhood periods of dynamic brain changes. Studies in animal models examining neurodevelopmental trajectories after an in utero immune challenge found that structural abnormalities in brain development showed sex specificity in rats. Therefore, is it possible that there is a higher probability of early insults manifesting as schizophrenia in men due to longer periods of dynamic brain changes during the critical years of brain maturation? Sex differences in neurotransmitters and growth factors that guide neuronal pathways may also have implications for how the developing brain handles environmental insults. For example, dopaminergic neurons migrate and differentiate in early fetal life, and sexual dimorphisms in dopaminergic neurons during rat brain development have been reported. In addition, developmental differences in amino acid neurotransmitter levels in the rat brain have shown sex specificity. These differences are important for neurodevelopment, as glutamate promotes dendritic growth in hippocampal pyramidal neurons and γ-aminobutyric acid increases neuronal migration. Sex differences in the central nervous system colonization and function of microglia may also be a contributing factor to vulnerability windows in neural development. It has been proposed that boys and girls may respond differently to a challenge to the prenatal immune system, as studies found microglia with a more activated phenotype in female rats. Taken together, sex differences in the developing brain may provide plausible explanations for a greater proportion of men affected by EOS due to a greater susceptibility to insults in utero. This may connect sex differences observed in patients with EOS with the neurodevelopmental hypothesis.
the estrogen hypothesis of schizophrenia ..
In summary, there is compelling evidence that gender differences in schizophrenia may be due to differences in hormonal activity. Clinical trials are beginning to show the benefits of estrogen treatment in schizophrenia, and this remains a promising area of study. Investigating the causes of sex differences in schizophrenia may continue to yield important insights into its etiology.