Early cerebro-craniofacial dysmorphogenesis in schizophrenia: a lifetime trajectory model from neurodevelopmental basis to 'neuroprogressive' process.

Understanding the temporal origin(s) of schizophrenia, through specifying the earliest identifiable pathology, might indicate when to look for etiological factor(s), what their nature might be, and how course of illness might evolve from these origins. From this premise, earlier formulations are elaborated to offer a rigorously data-driven model that roots schizophrenia in cerebro-craniofacial dysmorphogenesis, particularly along the mid-line but involving other structures, over weeks 9/10 through 14/15 of gestation. However, a brain that has been compromised very early in fetal life is still subject to the normal endogenous programme of developmental, maturational and involutional processes on which a variety of exogenous biological insults and psychosocial stressors can impact adversely over later pregnancy, through infancy and childhood, to maturation and into old age, to sculpt brain structure and function; it should be emphasised that the effects of such endogenous programmes and exogenous insults on such an already developmentally-compromised brain may be different from their effects on a brain whose early fetal origins were unremarkable. From these early origins, a lifetime trajectory model for schizophrenia from developmental basis to 'neuroprogressive' process is constructed. Thereafter, consideration is given to what the model can explain, including cerebral asymmetry and homogeneity, what it cannot explain, what empirical findings would challenge or disprove the model, what cellular and molecular mechanisms might underpin the model, and what are its implications.