Early neurodevelopment and psychosis risk: Role of neurohormones and biological sex in modulating genetic, prenatal and sensory processing factors in brain development

Schizophrenia is a psychiatric disorder largely believed to have neurodevelopmental origins with complex polygenic influences (including gene-environment interactions) that modify illness expression, as captured by the diathesis-stress model. It is now well known that the scope of these influences that render individuals vulnerable is broad and not necessarily illness specific, though many are believed to play a role in psychosis risk. Adverse pre-/peri-/post- natal events (e.g., prenatal maternal stress, teratogen exposure, obstetric complications) and genetic factors (e.g., candidate/susceptibility and modifier genes; epigenetics) represent two exemplary risk domains given they exert effects (though not exclusively) during early development (including impacting brain development). Relatively new to this field of study is consideration of sexual dimorphisms and the modulating role of one's biological sex and neurohormones (e.g., byproducts of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes; namely, cortisol and gonadal hormones) across the developmental trajectory in setting the stage for - and later potentiating (or buffering) - underlying vulnerability towards illness manifestation. This holds potential for better understanding etiology of, and risk for, psychosis from a diathesis-stress perspective. This chapter focuses on select early neurodevelopmental risk factors for psychosis, particularly 1) evidence of genetic influences (from linkage to association studies, candidate susceptibility and modifier genes, and epigenetics), 2) pre-/peri- natal risk factors presumed to impact brain development and evidenced to occur in higher rates than normal in psychosis risk (with consideration of gene by environment interactions), and 3) sensory processing/early information-processing deficits (including sensorimotor gating) as an example of a vulnerability indicator; all of which are discussed with respect to hormonal influences and sexual differentiation. While an in-depth discussion of later developmental maturational processes (e.g., during adolescence) is beyond the scope of this paper, we briefly discuss this important developmental period in understanding psychosis risk and respective clinical implications. Throughout the paper, findings (and putative risk factors) are contextualized (and discussed) with respect to sex differences, the potential modulating role of neurohormones, and synergistic effects towards bolstering current theoretical models of psychosis proneness.