Gilmore and Murray (2006-"Prenatal and perinatal factors," pages 55-67 in "Textbook of Schizophrenia" edited by Jeffrey Lieberman et al for The American Psychiatric Publishing) noted that twin studies estimate the heritability of schizophrenia to be approximately 80%, with the remaining 20% variance to be attributed to environmental factors. Concordance rates in MZ twins are only in the 40%-45% range, and some researchers have good reason to feel these are inflated figures. The twin methodology, according to Gilmore and Murray, has two major limitations which may lead to overestimating the genetic contribution and underestimating the environmental contribution to schizophrenia. First, heritability estimates assume additive effects of genes and environments and do not allow for gene-environment interactions. Secondly, twin methodology is based on an equal environment assumption, i.e., that MZ and DZ twins share similar prenatal environments. This assumption is false since most MZ twins share a placenta, whereas DZ twins have separate placentas. In addition, MZ twins have lower birth weights, higher rates of premature birth, and more adverse perinatal outcomes than do DZ twins. Gilmore and Murray suggest: “These same pre-and perinatal environmental risk factors also may increase risk for schizophrenia and could therefore lead to higher concordance rates in MZ twins that would be falsely attributed to genetic factors” (p. 55). Some researchers have pointed out that the results of twin studies would be particularly misleading in disorders in which the prenatal environment plays a role in their etiology. Research has demonstrated that this may be the case in schizophrenia. Prenatal stress mediated by corticosteroids, results in a variety of abnormalities in the developing brain. Of particular relevance to schizophrenia, prenatal stress results in decreased synaptophysin immunoreactivity in the cortex and hippocampus of adult animals (Hayashi et al 1998; Koo et al 2003), as well as alterations in pre- and postsynaptic gene expression in frontal cortex (Kinnunen et al 2003). Prenatal stress inhibits neurogenesis (i.e., the birth of new neurons) in the hippocampus (Coe et al 2003; Lemaire et al 2000). Hippocampal GABA systems are also altered by prenatal stress (Stone et al 2001) and prenatal stress results in long-lasting alterations in the neuroendocrine response to stress in animals, which also could contribute to ongoing central nervous system dysfunction in mammals (Edwards and Burnham 2001; Matthews 2000).

The link between exposure to stress during gestation and subsequent schizophrenia was suggested by a study that prenatal death of father was associated with increased risk of schizophrenia (Kuh & Ben-Sholomo 1997).In a population-based study on increased risk of schizophrenia, it was observed that subjects exposed during the first trimester of pregnancy to the stress of invasion by the Nazi army in the Netherlands had increased rates of schizophrenia (van Os & Selten 1998-”Prenatal exposure to maternal stress and subsequent schizophrenia”. British Journal of Psychiatry, 172, 324-326). An additional population-based study conducted in the Netherlands discovered a (non-significant) increased risk of developing schizophrenia in subjects prenatally exposed to the 1953 Dutch flood disaster (Selten, van der Graaf, et al 1999-”Psychotic illness after prenatal exposure to the 1953 Dutch flood disaster.” Schizophrenia Research, 35, 243-245). Rates of schizophrenia were significantly higher in subjects whose mothers were told of their husbands’ deaths during the war between Finland & Russia while in the 2nd & 3rd trimester as opposed to hearing the news after birth. I wonder if the connection between maternal starvation and later development of schizophrenia made by Susser & Lin (1992-”Schizophrenia after prenatal exposure to Dutch hunger winter of 1944-1945,” Archives of General Psychiatry, 49, 983-988), could also be contributed to by the effects of maternal stress secondary to a lack of food supply .Verdoux and Sutter (2002-”Obstetrical complications, maternal psychopathology, and the risk of psychosis” ) noted: “The association between prenatal exposure to maternal stress and later schizophrenia may be mediated by the direct impact of stress, such as fetal hypoxia induced by vasoconstriction; or more indirectly, by increasing the risk of OC’s [obstetrical complications], such as prematurity, or by increasing the risk of maternal prenatal or postnatal depression” (p.108).

The contribution of individual genes to the etiology of schizophrenia

seems quite small. Odds ratios (ORs) for recently reported susceptibility

genes are less than 2.0. Gilmore and Murray (2006) point out that the OR for the neuregulin (NRG) gene is in the 1.25 to 2.20 range. For the catechol-O-methytransferase (COMT) gene, the OR is at best 1.59. For the dysbindin gene the OR is 1.14 to 1.87. The ORs for several environmental risk factors are similar to those of individual candidate genes in schizophrenia. Environmental risk factors such as urban birth and certain obstetrical complications, e.g., premature rupture of membranes, placental abruption, emergency cesarean delivery and hypoxia-ischemic-related complications, have actually higher ORs than any individual candidate gene.

Gilmore and Murray, in referring to early environmentalrisk factors, are primarily referring to such factors as hypoxia-ischemia, infection and inflammation, malnutrition, etc. However, there is an extensive research base, to which Murray himself has contributed, on psychosocial, sociocultural risk factors in the initiation, course and outcome of schizophrenic disorders. I shall briefly summarize this research.

Wicks et al (2005-”Social adversity in childhood and the risk of developing psychosis: a national cohort study” American Journal of Psychiatry; 162:1652-1657), studied 2.1 million persons born in Sweden from 1963-1983 to investigate the relationship between social adversity in childhood and later risk of developing psychosis. They concluded: “...this national population-based cohort study of two generations showed increased risks for schizophrenia and other psychoses in children from less-advantaged households, thus indicating that social adversity in childhood or fetal life contributes to the risk of developing schizophrenia” (p.1656).

In a recent review of the relevant research, Jane Boydell, Jim van Os and Robin Murray (2004), in their “Is there a role for social factors in a comprehensive developmental model for schizophrenia?” (contained in an excellent new volume “Neurodevelopment and Schizophrenia” edited by Matcheri Keshavan, James Kennedy and Robin Murray in 2004 for Cambridge University Press), noted:

“In the 1950’s and 1960’s, there was much extravagant discussion of the role of social factors in the etiology of schizophrenia. However, there was little scientific basis to this speculation, and it was swept away by the demonstration that people with schizophrenia showed abnormalities of brain structure on computed tomographic scans (Johnstone et al 1976) [it soon became apparent to those of us who were studying both areas of neuroscience research, schizophrenia and the effects of profound fear/stress/anxiety/trauma/social isolation on CNS structure/function, that there was a substantial overlap between the two areas of scientific inquiry]. A decade later, the neurodevelopmental model of schizophrenia was proposed, and it subsequently became the dominant etiological and pathogenetic model (Murray and Fearon, 1999; Murray et al., 1992). As a result of these two developments, researchers have come to regard schizophrenia as a brain disease, and social factors have been largely ignored as putative etiological agents.

It is increasingly clear, however, that the neurodevelopmental model, an essentially neurological concept, does not explain all the available data about schizophrenia. One consequence has been a revival during the 1990’s, particularly in Europe, of research into the role of social factors as causal agents in schizophrenia” (p.224).

Boydell et al (2004) pointed to the neurobiological effects of isolation rearing and social stress in animals. For example, rats raised in isolation demonstrated structural and physiological differences from controls in the hippocampi. Isolation raised rats demonstrate anxiety, learning deficits (analogue of working memory, hypofrontality, etc.?), sensory changes, dopaminergic dysfunction, etc (see the excellent research of Myron Hofer on the psychobiology of developmental loss and separation). In terms of human development, social relationship experiences may alter prefrontal neural systems which mediate emotional self-regulation (Lyons et al 2002). The early social environment impacts on various levels of psychobiological and neurobiological development. The early social environment has been demonstrated to induce synaptic changes that may be indicative of, and perhaps the cause of, alterations in behavioral and cognitive functioning (Ovtscharoff and Braun 2001). There is evidence that the early social environment can mediate the establishment of neural networks that regulate a child’s response to stress and emotional self-control (DiPietro 2000).

Boydell et al (2004) have identified the following broad categories in which social factors have been implicated in the initiation and course of the schizophrenias: family factors (mother-child relationship, unwantedness, family communication deviance, dysfunctional family environment, communal upbringing, early parental loss, expressed emotion, childhood abuse, etc.); an urban effect (city birth, city upbringing, etc.); social isolation (during childhood, moving schools in adolescence, in young adult life, at time of onset, migration and ethnic minority status, discrimination, unemployment, etc.); life events (socioeconomic factors, deprivation, inequality, etc.); interaction between social and other etiological factors (gene-environment interaction, social factors and cognitive processing, social causation versus social selection, etc.).

Brian Koehler PhD
Faculty, Postdoctoral Program
New York University
80 East 11th Street #339
New York NY 10003
212.533.5687
brian_koehler@psychoanalysis.net