Probably the leading theories of the schizophrenias today are the neurodevelopmental ones. These are sometimes combined with neurodegenerative models. Klempan et al (2004) noted:

“A neurodevelopmental etiology of schizophrenia is suggested by neuroimaging and postmortem studies revealing significant and replicated lateral ventricular enlargement, hippocampal and gray matter deficits [we now know that there are white matter deficits as well], and cellular disarray, independent of duration of illness and antipsychotic treatment”(p.3).

Rutter (2004)noted that during the latter part of the last century, “evidence began accumulating from developmentally oriented follow-up studies that abnormalities in interpersonal relationships, neurodevelopmental immaturities, and attentional deficits in childhood all predicted the later onset of schizophrenia” (p.xiii).

The above quotes are taken from “Neurodevelopment and Schizophrenia” edited by M. Keshavan, J. Kennedy & R. Murray in 2004 for Cambridge University Press.

There is a large symptomatic overlap between the above noted ‘precursors’ of later schizophrenia and the research on the effects of significant levels of caregiver anxiety and depression as a type of adverse early environment (the latter research is summarized in a recent article “Maternal depression: An adverse early environment” by A. Breach et al in “Perinatal Stress, Mood and Anxiety Disorders: From Bench to Bedside” edited by A. Riecher-Rössler and M. Steiner in 2005 for Karger). It has been demonstrated that parental anxiety and depression can have negative effects on child development. Within the stress-diathesis model, parental depression/anxiety must be recognized as a child’s earliest adverse life event.

The effects of depression during pregnancy on fetal development can be transmitted in three ways: first, the fetal sequelae of antenatal depression/stress can be directly mediated by neurobiological correlates or substrates of depression/stress such as proinflammatory cytokines and/or glucocorticoids (e.g., cortisol); secondly, indirectly through neuroendocrine processes (e.g., depression-associated hyperactivity of the hypothalamic-pituitary-adrenal axis-HPA-may induce placental hypersecretion of corticotropin-releasing factor-parenthetically, Herbert Rosenfeld, Post-Kleinian psychiatrist, hypothesized years ago, that when the pregnant mother is experiencing a great deal of emotional upset, possibly from lack of support from the partner or culture, which needs to be dissociated, this, at a cellular level, has a very intrusive and persecutory impact on the developing fetus); thirdy, there are the effects of dysphoria on fetal development indirectly through maternal behavior (e.g., effects on maternal self-care, etc.).

Beach et al (2005)noted:

“Children exposed to maternal stress, anxiety, or depression during pregnancy may also suffer adverse neurodevelopmental sequelae that affect various aspects of cognitive and psychosocial function. For example, newborns of depressed mothers perform poorly on neurological examinations, exhibiting poorer motor skills, activity, coordination, and resilience. Additional evidence indicates that the neurodevelopmental effects of antenatal depression persist beyond infancy. Antenatal maternal stress is associated with higher rates of developmental delay and a variety of emotional and behavioral problems in preschool children. Furthermore, children of elementary school age have also demonstrated cognitive delay, behavioral and emotional difficulties, in addition to maladaptive social interactions” (p.73).

Children of mothers who were depressed and anxious during pregnancy, exhibit elevated cortisol response to psychosocial stress. Fetal exposure to prenatal depression/stress is also associated with increased right frontal electroencephalograph (EEG) asymmetry at one month postpartum.

This EEG pattern is consistent with the hypofrontality observed in depressed adults. Toddlers with this pattern of EEG asymmetry more often exhibit negative facial expressions, hostility, aggression, reduced motor activity during observed play situations, and fewer displays of affectionate behavior towards their mother regardless of infant temperament. It is of interest that these phenomena are similar to that which is noted in schizophrenia research of high risk ‘pre-schizophrenic’ children.

Beach et al (2005) concluded their review of the research as follows:

“An impressive array of evidence now demonstrates that early adverse life events contribute significantly to the vulnerability to adulthood psychopathology, medical illnesses, and maladaptive psychosocial functioning. Whereas parental nurture fosters adaptive responses to early life stressors that should protect the child from such vulnerability, studies indicate that parental depression, specifically maternal depression since it has been subjected to greater scrutiny than paternal depression, not only undermines this protection but can itself represent an early adverse life event” (p.76).

Prenatal Stress and Schizophrenia
In rodents, prenatal stress (PS) is associated in the adult offspring with behavioral changes, persistent changes in HPA axis activity, as well as changes in glucocorticoid receptor density (Takahashi et al. 1992; Henry et al. 1994; Lordi et al. 2000; Szuran et al. 2000).In non-human primates, prenatal stress results in attentional difficulties, neuromotor abnormalities, decreased locomotion, and hyperresponsiveness to stress in adult offspring (Schneider et al. 2002). PS in primates results in increased levels of dihydroxyphenlacetic acid (DOPAC), a dopamine metabolite, in offspring suggesting increased dopamine activity.

Maccari and colleagues (1998) demonstrated a major role for maternal glucocorticoids in the developing fetal neuroaxis (dysregulating the hypothalamic-pituitary-adrenal axis, the HPA), as well as maternal behavior which served a neuroprotective role in counteracting the effects of prenatal stress.Schneider and Moore (2000) also provided support for the hypothesis that prenatal stress in humans and animals results in dysregulation of the stress response (the HPA axis), along with alterations particularly in the dopaminergic system of the brain. They concluded that there is supporting evidence for prenatal stress to be considered a behavioral teratogen.They noted:

“The pattern of evidence thus far is supportive of the hypothesis that prenatal stress could be a behavioral teratogen; human correlational results show negative effects of prenatal stress, experiments with both nonhuman primates and other animals show significant behavioral and physiological effects of prenatal stress that can extend into adulthood, and the animal research provides evidence regarding the physiological processes that are likely to be altered by prenatal stress” (p. 236).

Marta Weinstock (1998), in her research on prenatal stress, concluded:
“Exposure to psychological stress during gestation can induce long-lasting behavioral changes in the offspring, characterized by a decreased ability to cope with, or adapt to, stressful situations. This is associated with dysregulation of the HPA axis [limbic-hypothalamic-pituitary-adrenal]... these modifications can affect the developing fetal brain at a critical time during development.” In longitudinal research in humans, schizophrenia has been correlated with exposure to several forms of maternal PS, including death of the father during gestation (Huttunen & Niskanen 1978), unwanted pregnancy (Myhrman et al. 1996), exposure to wars and catastrophes, such as the 1940 invasion of Holland (van Os & Selten 1998), and the nuclear attack on Nagasaki (Koenig et al. 2002). Elevated rates of schizophrenia are also related to maternal depression during pregnancy (Jones et al. 1998). Depression is often associated with hypercortisolemia.

In my paper “The schizophrenias: Neuroscience, Neurophenomenological and Psychoanalytic Perspectives,” I noted the following on the connection between PS and later rates of schizophrenia:

“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).

Perhaps the current neurodevelopmenatal models of the schizophrenias need to take into account parental stress/depression as a significant factor, particularly during gestation and the postnatal period. Hypothetically, these events would impact through epigenetic processes (mediated by methylation of DNA) which could transmit behavioral patterns (particularly reactions to threats to survival) across generations (nature prepares offspring for the same threats encountered by the mother-in today’s world, change is occurring at a much faster rate than natural selection could keep up with, therefore epigenetic processes are a crucial for survival). Epigenetic changes influence the phenotype without altering the genotype. As Benjamin Lewin (2006-”Essential Genes” published by Prentice Hall) noted, these changes in the properties of the cell that are inherited, do not represent a change in genetic information, i.e., no change in the sequence of DNA. We know from various research studies that these changes are potentially reversible, including those involving psychobiological responses to threat.

Brian Koehler PhD
New York University
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brian_koehler@psychoanalysis.net