CLINICAL HANDBOOK OF SCHIZOPHRENIA

72 I. CORE SCIENCE AND BACKGROUND INFORMATIONoccur due to an abnormally aggressive synaptic pruning process, leading to a reduction insynaptic connectivity beyond a psychosis threshold, resulting in a fragmented or disconnectedbrain. This lack of neural connectivity throughout the brain reflects the challengesfaced by patients with schizophrenia, with deficits in most areas, including cognitive,social, emotional, and perceptual difficulties. Moreover, this model is supported by postmortemstudies that have found reduced neuropil without neuronal loss, in which decreasedneuropil represents a loss of connections between neurons.Early environmental insults, such as OCs, would fit within this neurodevelopmentalmodel by reducing the amount of synaptic pruning necessary to cause psychoticsymptomatology. This would lead to an earlier age of onset and possibly portend a worsenedclinical outcome. As we have seen, this is precisely what occurs in individuals with ahistory of hypoxia-associated OCs, who typically have an earlier age of onset and morepronounced neuroanatomical abnormalities.Viewing schizophrenia as a developmental disorder encourages exploration into possibleearly intervention and prevention strategies in individuals who are genetically susceptible.The emergence of candidate disease genes, as well as the advances in mappingout molecular pathways involved in schizophrenia, will likely pave the road to understandingand treating an incredibly serious and debilitating disorder.KEY POINTS• OCs have been found to be repeatedly associated with schizophrenia outcome, occurring inthe histories of 20–30% of patients with schizophrenia and 5–10% of the overall population.• Of the prevailing explanatory models, the majority of evidence supports the gene–environmentinteraction model, which asserts that OCs interact with genes associated with schizophreniato increase risk for the disorder.• Many OCs have been associated with schizophrenia, including complications during pregnancy,fetal and infant underdevelopment, and birth complications.• Lack of oxygen to the fetus, termed fetal hypoxia, likely is involved in many OCs associatedwith schizophrenia.• A history of hypoxia-associated OCs differentiates between patients with schzophrenia andtheir nonschizophrenic siblings, and leads to a form of schizophrenia characterized by earlierage of onset and greater neuroanatomical abnormalities.• Infection during pregnancy has been repeatedly associated with schizophrenia in offspring.More recent studies using serological confirmation of infection have found an associationbetween HSV-2, influenza, genital and reproductive infection, and T. gondii exposure duringpregnancy and schizophrenia spectrum disorders in offspring.• Most prenatal infections do not cross the placenta; therefore, the damaging effects to the fetusseem to be partially related to the mother’s immune response to infection, particularly involvinginflammation.• Genetic polymorphisms that amplify the inflammatory response to infection have beenfound among patients with schizophrenia, suggesting that genetic factors may conferheightened sensitivity to infection and other prenatal insults.• Both infection and proinflammatory cytokines have been linked to increased fetal hypoxia,which has been associated with schizophrenia and many of the brain abnormalities linkedto the disorder.• Some theorists propose that schizophrenia arises due excessive reduction in the connectionsthroughout the brain (synaptic pruning), leading to problems in most areas of functioning.OCs fit within this model by further reducing the amount of connections in the brain,leading to an earlier age of onset and worsened clinical outcome.