Schizophrenia: Viral Hypotheses, Immune Dysfunction, Pathophysiology

Viral Hypotheses

Two lines of evidence that have provoked the most interest in the possibility that viral infections are causative of schizophreniaare an increase in birth during influenza epidemics of individu-als who subsequently develop schizophrenia and an increase in winter births among patients with schizophrenia because of the higher rate of viral infections in winter months. However, nega-tive results from multiple studies have raised serious questions about this theory. Several studies have demonstrated an excess of winter births among patients with schizophrenia. Although sta-tistically significant, the association between winter births and schizophrenia appears relatively small, occurring in less than 10% of cases. Thus, season of birth remains an interesting (and unresolved) research issue but has little use as a risk factor for the illness from a clinical perspective. Exposure to influenza in utero and excess winter births are interesting although indirect lines of evidence for a viral cause of schizophrenia. To date, there has been no direct confirmation for any viral agent causing this ill-ness, such as viral isolates or consistent findings of specific viral antibodies. Advances in neurovirology, however, are providing new insights into the role of viruses in brain diseases, leading to new hypotheses about schizophrenia. One area involves the search for neurotropic retroviruses.

Immune Dysfunction

Several research groups are exploring the possibility that schiz-ophrenia may be associated with impaired immune function including alterations in autoimmunity. Anticardiolipin antibody and antinuclear antibody, two autoantibodies that are used as markers of autoimmune vulnerability, have been shown to be in-creased in patients with schizophrenia in some but not all stud-ies of this illness. Two other markers relevant to autoimmune function, impaired T lymphocyte proliferative response to the mitogen phytohemagglutinin and impaired interleukin-2 pro-duction, have shown more consistent alterations in patients with schizophrenia than in control populations. Some of the most in-triguing work in this area is focused on finding autoantibodies to brain tissue.

Birth Complications

Numerous studies have reported a higher rate of pregnancy and birth complications in patients with schizophrenia than in control populations. The complication rates vary widely among studies, probably because of the inherent difficulties in obtaining reliable and valid retrospective data in this area. In one study, two-thirds of schizophrenia patients and less than one-third of control sub-jects had histories of obstetrical complications. Hypoxia is one possible result of pregnancy and birth complications that has been shown to disrupt brain development. The hippocampus and some neocortical regions are particularly sensitive to shortfalls in oxygen. Thus, one proposed mechanism for a role of pregnancy and birth complications in the cause of schizophrenia involves hypoxia-mediated damage to these areas. Interestingly, some studies suggest that the rate of obstetric complications are higher in early-onset schizophrenia, occur more often in males, in peo-ple with prominent negative symptoms, and no family history of schizophrenia.

Pathophysiology

Whereas etiology refers to the cause of an illness, pathophysiol-ogy refers to the abnormal processes that mediate the clinical manifestation of the illness. As was the case with etiology, thebrain processes that give rise to schizophrenia are currently not known. However, rapidly converging bodies of neuroanatomical and neurochemical data appear to be closing in on defining the pathophysiology of this illness.