Environmental Risk Factors for Schizophrenia
Although genetic risk factors clearly play a role in the etiology of schizophrenia, there is an abundant literature on the importance of non-genetic risk factors (Table 1). For example, a large population–based study indicates that urban birth and late-winter/early-spring birth are much more closely associated with schizophrenia than is having an affected first-degree relative. Similarly, most other reported environmental risk factors, such as maternal stress and prenatal malnutrition, likely alter pre- and perinatal brain development.
A variety of maternal infections have been implicated in the risk for schizophrenia, and it has been proposed that inflammatory responses to infection, especially responses that involve cytokines generated by the mother, placenta, or fetus, represent a common mechanism (29). Inflammatory cytokines generated in response to maternal infection can have a neurotoxic effect on developing neurons (30, 31), and cytokines regulate neurodevelopmental processes implicated in schizophrenia, such as programmed cell death and synapse development.
A recent meta-analysis of prospective, population-based studies has demonstrated that three groups of obstetric complications are significantly related to schizophrenia: a) complications of pregnancy (e.g., bleeding, preeclampsia, diabetes, and rhesus incompatibility); b) abnormal fetal growth and development (e.g., premature birth or low birth weight, congenital malformations, small head circumference); and c) complications of delivery (e.g., uterine atony, asphyxia, emergency cesarean section) [for review, see (32) ].
Fetal hypoxic or ischemic damage to the developing brain may be a common mechanism for complications associated with preeclampsia, uterine atony, asphyxia, and emergency Cesarean section (33), although clinical and subclinical infections are associated with these complications as well. Intriguingly, premature cortical synaptic pruning has been implicated in fetal hypoxia associated with brain structural abnormalities among patients with early-onset schizophrenia (34). In addition, hypoxia or ischemia in preterm babies may cause intra- and periventricular hemorrhage, and the long-term consequences of the latter include ventricular enlargement, smaller hippocampal volumes (35), and corpus callosal abnormalities. It should be noted, however, that current methods of studying obstetric complications in schizophrenia may be reaching the limit of their usefulness (32), particularly given the generally small quantitative nature of obstetric effects.
It was recently reported that the cerebrospinal fluid of twenty-nine percent of patients with recent-onset schizophrenia or schizoaffective disorder contain human endogenous retroviral sequence [(HERV)-W], the transcription of which is up-regulated in the frontal cortex of postmortem brains of schizophrenic patients (36). This report supports previous speculation as to a viral etiology of schizophrenia, and the results suggest that the onset of the illness in some patients may be related to the transcriptional activation of certain retroviral elements in the brain.
Epidemiological studies have indicated an increased incidence of schizophrenia in the offspring of women who had been subjected to irradiation in their first trimester (37, 38). Rhesus monkeys irradiated during the period of thalamic neurogenesis in utero demonstrate neuronal losses in specific thalamic nuclei as well as decreases in cortical neuropil and, in adulthood, exhibit the deformation and loss of thalamic tissue (39) characteristic of schizophrenic brains (40, 41). It is notable that, prior to puberty, the fetally irradiated monkeys perform normally on working memory tasks, but, as adults, show deficits similar to those exhibited in schizophrenia (39). Other environmental risk factors for schizophrenia are shown in Table 1.