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Book Forum: Schizophrenia and Other Severe Mental Illnesses   |    
Prenatal Exposures in Schizophrenia
JEAN-PIERRE LINDENMAYER, M.D.
Am J Psychiatry 2001;158:831-a-832. doi:10.1176/appi.ajp.158.5.831-a
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Edited by Ezra S. Susser, M.D., Dr.P.H., Alan S. Brown, M.D., and Jack M. Gorman, M.D. Washington, D.C., American Psychiatric Press, 1999, 352 pp., $38.00.

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The goal of this edited book is to present an up-to-date review of prenatal factors that may interact with genetic factors in mediating schizophrenic illness. From the outset, the editors stipulate that it is clear that schizophrenia is an inherited disorder. However, they recognize that other factors such as environmental influences, must be at work in turning on susceptibility genes. Three types of prenatal factors are the focus of the book: prenatal infections, prenatal nutritional deficiency exposure, and prenatal immunological exposures.

Waddington and colleagues lay the groundwork by systematically reviewing all neurodevelopmental abnormalities that have been postulated to relate to early intrauterine adversity. Their review is very comprehensive, leading them to propose that schizophrenia is a neurodevelopmental disorder leading to a "static encephalopathy." However, they find that adult disease progression does not contradict a static concept of the disease. They are critical of the traditional multifactorial polygenic model according to which environmental factors are thought to act as additive sources of risk. They suggest that "the gene(s) predisposing to schizophrenia both code for dysgenesis and confer on individuals some varying epigenetic susceptibility to other prenatally dysgenic factors." Such factors could be prenatal infections, prenatal nutritional disorders, or immunological insults. These environmental factors may be responsible for the higher risk for schizophrenia in a given population of individuals who share the same environmental factor. This is an excellent introductory chapter that sets the tone and conceptual framework for the other contributions.

One chapter on interaction of genes and prenatal exposures presents a short review of the different classical genetic models and a more in-depth set of models of multifactorial causation. The additive effects model, synergistic effects model, mediating effects model, and multiplicative effects model receive excellent discussions. It would have been helpful to have more examples for each model as well as shorter versions of the well-known family, adoption, and high-risk studies.

Nowakowski’s treatment of the prenatal development of the brain is a thorough primer in neurodevelopmental anatomy and focuses particularly on the migratory process of developing neurons and its disruption. Neuronal cells go through developmental stages of cell proliferation, neuronal migration, and neuronal differentiation throughout pregnancy. Studies are reviewed that have found evidence of arrested cell migration in schizophrenia. For example, such a disruption could be caused by maternal influenza immunoglobulin G antibodies.

Murray’s group carefully reviews the complex data on a possible association of prenatal gestational influenza infection with schizophrenia. They conclude that prenatal influenza does increase the risk of schizophrenia and that the maximum risk is in the second trimester but the overall effect is small. The main weakness of this link is the lack, as of yet, of consistent evidence of elevated maternal and proband immunogens.

An interesting suggestive finding is the fact that rheumatoid arthritis is rare in schizophrenia and is associated with human lymphocyte antigen (HLA) DR4. Wright and colleagues found a lower rate of HLA DR4 in patients with schizophrenia, which may suggest that the presence of HLA DR4 may be protective of schizophrenia.

Another prenatal viral infection reviewed is rubella, which together with cytomegalovirus and herpes simplex virus is associated with central nervous system teratogenicity. This is a thought-provoking chapter, particularly in its attempt to explore the more likely indirect pathogenetic mechanisms of prenatal viral infections in relation to schizophrenia. The possible role of concomitant antiviral medications used during gestational viral infections, the effects of hyperthermia in secondary infections, and the effects of concurrent nutritional deprivation are explored. The Dutch famine and its association with schizophrenia in the exposed birth cohort is a classic example of the role of nutritional deprivation in the greater risk of schizophrenia. This chapter is one of the best in the book.

An area of further necessary research is that of the interaction of the risk due to nutritional deficits with the effects of parental genetic loading for schizophrenia. There is a chapter dealing with the possible underlying mechanisms of the effects of protein and calorie deprivation on neural development that suggests possibilities for pathophysiologic models for schizophrenia. One issue that is not addressed, however, is the fact that these nutritional deprivations were rather extreme and probably not typical in the prenatal development of most present-day individuals with schizophrenia.

One chapter on the role of Rhesus factor incompatibility and risk for schizophrenia is provocative, although the supporting data are limited. In particular, there may have been a selection bias to find more Rhesus-incompatible and problematic gestational outcomes, which could have increased the number of individuals with schizophrenia in the Rhesus-incompatible group.

The emerging role of antibodies to a heat shock protein (HSP60), which are found in more patients with schizophrenia than in comparison subjects, is discussed in a final chapter. These autoantibodies may be markers of neuronal damage rather than the cause of such damage. Heat shock proteins are induced in response to a variety of stressful stimuli and conceivably could reflect neuronal injury due to a viral infection. However, this finding needs to be more widely replicated.

Wyatt’s concluding chapter reviews the implications of this emerging set of data for prevention of schizophrenia. He argues that the results of genetic and epidemiological research should be used to develop preventive interventions for the disorder. At present, most efforts are focused on minimizing the effects of chronicity and deterioration of an established illness. Wyatt argues that primary prevention could use data from the incompatibility studies and aggressively administer anti-D gamma globulin after delivery of a Rhesus-incompatible pregnancy or could consider a more active anti-influenza immunization program for women of childbearing age. He correctly suggests the need for a shift in paradigm: to emphasize research in primary and secondary prevention of schizophrenia, which in turn would make research in rehabilitation and improved treatments less necessary.

Overall, this is a timely and well-edited book. It is comprehensive and as up-to-date as books on ongoing research can be. It primarily addresses the schizophrenia researcher but provides an in-depth summary of this area for the general reader as well.

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