Environmental and genetic affects and schizophrenia
Environmental and genetic affects and schizophreniathe relative importance of genetic and environmental factors in the
aetiology of schizophrenia.
Graeme Gordon
...poor Ophelia, divided from herself and her fair judgement without the which we arepictures or mere beasts...
Shakespeare, Hamlet
The term 'schizophrenia' (a splitting of psychic function, Strange, 1992) was first introduced in 1911 by Eugen Bleuler to denote the breakdown of integration between emotions, thought and actions. The symptoms of this disease are heterogeneous and there is still disagreement about diagnosis.
The annual incidence of schizophrenia is between 0.1 and 0.5 per 1000 depending on the diagnostic criteria used - representing a lifetime risk of 1 per cent (Strange, 1992). Onset of the disease is most commonly in late adolescence or early adulthood. In the U.S.A., schizophrenia fills more beds than almost any other illness and the financial cost of schizophrenia due to direct
medical costs, lost productivity and Social Security pensions is between $30 billion and $48 billion according to Federal figures (American Pychological Association (APA), 1996).
There are many theories about the aetiology of schizophrenia, but research has failed to pinpoint the origins. There is evidence that environmental pathogens (for example, viruses) are involved in the causation of schizophrenia. There is also evidence for a role of hereditary influences and obstetric complications on the incidence of schizophrenia. Furthermore, psychological influences have also been suggested as important in precipitating episodes of schizophrenia (for example, significant life events and interactions within the family). The symptoms and syndromes of schizophrenia are complex and very heterogeneous. Thus, the resulting theories reflect this complexity. This heterogeneity causes disagreement about diagnosis, illustrating the huge importance to explain the basis of schizophrenia and to establish the root causes - if they due indeed exist. The term schizophrenia may infact be an umbrella term covering a number of different diseases. Even if this was to be the case, the importance
still lies in establishing the root causes as this is the route to successful treatment.
In past years, psychiatric researchers theorised that schizophrenia arose from bad parenting. It was believed that a mother could cause the symptoms of schizophrenia through inadequate care. Such a mother was characterised by being "cold, distant and unfeeling" and due to this was called "schizophrenigenic" (APA, 1996). This has since been discredited as a theory. However, it wasn't until more sophisticated techniques for examining brain structure in vivo were
introduced in the late 1970s that schizophrenia was thought to be due to 'organic' brain changes. Previously it was a "general feeling that...it was considered a purely 'functional' disease" (Strange, 1992). The initial finding of the brain scans in the late 70s was that the brain changes in many, but not all, schizophrenics were manifested as ventricular enlargement. From such an observation, a number of theories arose about the causes of schizophrenia related to ventricular enlargement (for example, Crow, cited in Strange, 1992). However, more recent brainimaging has found there to be no correlation. Even so, it is an example of how observations in schizophrenics can aid the development of theories of aetiology.
Further observations that have led to the development of theories of the aetiology of schizophrenia include the observations that schizophrenics "have a lower head circumference at birth, show behavioural peculiarities as children, have an increased rate of minor physical abnormalities, delayedrodevelopmental milestones, low IQ and behavioural abnormalities in
childhood, and have an increased size of cerebral ventricles" (Weinberger, 1995). These observations have become warning signals that a child has a predisposition to schizophrenia, as well as leading to the neurodevelopmental hypothesis of schizophrenia. The point that a child may have a predisposition, suggesting a hereditary factor, will be discussed.
A similar study looked back at the childhood of schizophrenics and found there to be "two roads to schizophrenia" (Neumann et al., 1995). Six female and 23 male schizophrenics (average age of 35) were compared with a psychiatrically normal brother or sister. Their mothers were asked to recall the children's behaviour during the four four-year periods from birth to age sixteen. The
symptoms included in a checklist included social withdrawal, anxiety, depression, attention deficits, delinquency, and aggression. They reported that: "as a group, the pre-schizophrenic children had more behavioural problems than their siblings. In the first four years they showed attention deficits. At ages five to eight, they suffered from anxiety, depression, and thought disturbances. As they grew older there were signs of aggression and social withdrawal".
However, it was found that these problems were concentrated in a smaller group consisting of only 27 per cent of the pre-schizophrenic children. The other three-quarters of pre-schizophrenic children differed only slightly from their brothers and sisters up to the age of sixteen. Although the study does appear to have limitations - for example, the subjects were almost all male and their families were all of high socio-economic class - it does have implications on the aetiology of schizophrenia. For example, pointing toward a eurodevelopmental cause of the disorder.
Another example of such observations is from a study on eye tracking and visual attention (Archives of General Psychiatry, cited in Ward, 1997). "Doctors have known that there was something different about the eyes of many people with schizophrenia - and the eyes of their family members too" (Ward, 1997). The study Ward reports on investigates eye tracking (the ability to follow a moving target with the eyes) in first degree relatives of schizophrenics. They
found that in comparison to the eight per cent of the general population who are unable to do this task, 50 to 85 per cent of schizophrenics and 45 per cent of their parents or siblings are unable to perform this relatively simple task. The implication of this finding is that it points to a clear genetic factor in schizophrenia. Offering further support to the overwhelming evidence of
clear hereditary influences in schizophrenia.
Studies within families have shown that there is a ten per cent chance of developing schizophrenia in first degree relatives of schizophrenics (compared with one per cent in the general population). Sibling's have a nine percent chance of developing the disease. The lifetime risk of developing schizophrenia is correlated with genetic relatedness to a schizophrenic. First degree relatives do have a higher risk than second or third degree relatives.
This is illustrated in Figure 1. Such an illustration shows a clear hereditary influence on schizophrenia.
However, no hereditary gene has been identified as yet, although studies have identified a number of regions of chromosomes that may be involved.
Barondes et al. (cited in Freeman, 1997) identified regions of chromosomes that may be linkedto a genetic predisposition to schizophrenia. Those chromosomes are 3, 6, 8, 9, 20 and 22 (the23 pairs of human chromosomes, including the sex chromosomes, are numbered 1 through 23). Further studies have identified genetic markers for schizophrenia on chromosomes 6, 8, 9, 13 and 22 (Gottesman, cited in DeAngelis, 1997). These genetic markers refer to parts of a gene that are suspected to be linked to specific problems or features; they are less specific than locating the gene itself. DeAngelis (1997) reports that some of these findings have been replicated - in particular on chromosomes 6 and 22. As with the diagnosis of schizophrenia, there is disagreement about which chromosomes are involved in the transmission of schizophrenia. This is exemplified above - the fact that the Barondes study found there to be one more chromosome linked to schizophrenia than that cited by DeAngelis. Such a failure to find wholly consistent results is further exemplified in a study by Maziade et al. (1997). Their investigation into regions where 'schizophrenic genes' are likely to be found resulted in the identification of four specific areas - chromosomes 11q, 3q, 18q, 6p. Again, an inconsistency to that of the other findings cited in above. Even so, what such studies do show is that there is clear evidence for an hereditary influence in schizophrenia.
It is important to note that schizophrenia is not inherited in the same way as the colour of one's eyes or hair. Like many other genetically related illnesses, schizophrenia appears when the body is undergoing the hormonal and physical changes of adolescence. It has thus been suggested that schizophrenia lies "dormant" during childhood (APA, 1996). However, it is clear from the observations mentioned above that the effects are noticeable during childhood.
Furthermore, it is important to understand how the onset of such a "severe form of psychopathy" (Gottesman, cited in DeAngelis, 1997) comes about and whether it may lie "dormant" for longer periods and even indefinitely - missing out a generation.
It is from such questions that the idea that environmental stressors trigger the onset of the illness has arisen. From this idea theories have been developed and an example of such a theory, that is a culmination of findings from a number of studies, is that of the "phospholipid hypothesis" (Peet et al., 1995). This hypothesis predicts that schizophrenics have a genetic predisposition towards a disorder, modulated by environmental factors, that causes schizophrenia.
The "phospholipid hypothesis" was provided by studies showing that polyunsaturated fatty acids (PUFA) of the omega-3 and omega-6 series are depleted in cell membranes of neuroleptic treated schizophrenics (Peet et al., 1995). Peet compared the PUFA composition of red blood cell (RBC) membranes from schizophrenics and control subjects. The results are shown in Glen et al. (cited in Peet et al., 1995) found that the lowest RBC membrane levels of PUFA were
in the 'worst-state' schizophrenics. Furthermore, Peet and colleagues found "reduced levels of omega-6 PUFA correlated with plasma levels of thiobarbituric acid reactive substances (TBARS), suggesting that there was increased oxidative breakdown of these PUFA in our patients" (Peet et al., 1995). Peet et al. (1997) also found this to be the case in untreated schizophrenics from India and Malaysia. Thus, it appears that PUFA breakdown is increased in schizophrenics. Peet et al. (1995) cite further evidence of this. For example, a study using
magnetic resonance spectroscopy (Pettegrew et al.) found "decreased levels of
phosphomonoesters and increased levels of phosphodiesters in the frontal cortex of drug free schizophrenics, consistent with increased breakdown and/or decreased synthesis of membrane phospholipids". In another study cited, this index of increased phospholipid breakdown correlates with the severity of schizophrenic symptoms expressed. Furthermore, they also found there to be increased pentane levels in air expired from schizophrenics compared to that of
control subjects. This is consistent with increased oxidative breakdown of PUFA. Peet et al. (1995) suggest a mechanism that would promote the increased breakdown of membrane PUFA is that of increased phospholipase activity (this is the enzyme that reaks down fat). They based this hypothesis on the finding that significant elevations of phospholipase A2 (cPLA2) were reported in the platelets of schizophrenics (Gattaz, cited in Peet et al., 1995). Also, they cite two reports of abnormalities in the cPLA2 gene of schizophrenics. A more recent study by Peet (unpublished) has found a significant genetic abnormality that is over-represented in schizophrenics relative to ethnically matched controls. It is because of this that it is hypothesised that schizophrenics have a genetic predisposition to depleted membrane levels of PUFA. Peet et al. (1995) suggest that this could be modulated by dietary intake in infancy and later life which could underlie the reported neurodevelopmental abnormalities in schizophrenia. The efficacy of dietary intake on the modulation of PUFA levels has yet to be established.
The suggestion that environmental factors are involved with the incidence of schizophrenia in the "phospholipid hypothesis" is concurrent with the present direction of thought as to the aetiology of schizophrenia.
It is a current belief that schizophrenics do have a genetic predisposition to the disease and that certain factors of the environment act either as triggers or in some cases direct causal influences. Further examples of such theories that have evolved from this belief shall follow.
From observations of the biochemistry of schizophrenics it has become clear that they have an neurochemical imbalance. Thus, much research has been focused on neurotransmitters - the substances that allow communication between nerve cells. It is from such research that three different neurotransmitter systems have been targeted as areas of action of antipsychotic treatment. The three neurotransmitters are dopamine, serotonin, and norepinephrine (British
Columbia Schizophrenia Society, 1997). The primary focus of action of most antipsychotic drugs is on the dopamine system. This has been identified as the most involved system in the abnormalities of the brain found in schizophrenics. It is hypothesised that deficiencies in this
system affect mood and other mental processes. The actual dopamine receptors that these antipsychotic drugs act on are D2 receptors - relieving some of the symptoms, but are no way curative. However, Japanese researchers, led by Yoshiro Okubo of the Tokyo Medical and Dental University of Medicine, using positron emission tomography (PET) have found significant deficiencies of similar receptors to D2, known as D1, in the brains of schizophrenics (cited in
Schizophrenia.com, 1997a). This reduction was reported to be correlated to the severity of symptoms. In an analysis of the research, E. Nestler of the Yale School of Medicine said that research will now have to be focused on determining whether schizophrenia involves either the loss of cells transmitting nerve impulses, neurons, in the outer part of the brain or sustained impairment in the activity of existing neurons (cited in Schizophrenia.com, 1997a). Such
knowledge would not only be beneficial in establishing a clear aetiology but also pinpoint the most effective areas of treatment of the disease.
A similar area of research to that of the receptor hypothesis, is that surrounding the hypothesis that altered or faulty neural circuitry may be a primary cause of schizophrenia.
In recent years it has become clear that schizophrenia is associated with a structural defect in the brain, "probably in the neural circuitry of the cerebral cortex and limbic system" (Benes, 1996). The idea that schizophrenia might be a degenerative disorder was first considered at the turn of the century, by Emil Kraepelin (Benes, 1996). It was his influence that led researchers to the examine the brains of schizophrenics post mortem. In the early 1920s some degenerative changes were found, but these were not exclusive to schizophrenia. Because of this, the study of schizophrenia was a rare occurrence and was called "the graveyard of neuropathologists" (Benes, 1996). However, today, post mortem studies of the brain have gained new respectability due to the contributions made to the understanding of Alzheimer's and Huntingdon's diseases. Also, with more sophisticated tools of examining the brain, in vivo, the need for post mortem examinations has declined. It is due to brain imaging techniques that a greater understanding of the degenerative processes involved in schizophrenia have been gained. The first brain imaging study of schizophrenia was actually published in 1927 by neuroradiologists using pneumoencephalography: "X-rays taken after the injection of air beneath the membrane that covers the brain" (Benes, 1996). The pneumoencephalograms showed enlarged ventricles (interior cavities), even after they were improved due to great criticism. Even so, neurologists ignored these findings as well as those of post mortem brains of schizophrenics. Not until the 1970s were brain imaging techniques reintroduced as reliable sources of information into the aetiology of schizophrenia. This was the time when antipsychotic drugs came into use and it became clear that their effects were related to the activity of the neurotransmitter dopamine. Eve Johnstone et al. (cited in Benes, 1996) reported the first computed tomography (CT) scans of chronic schizophrenics showing enlarged ventricles. A few years before Johnstone's work appeared, Jan Stevens (1973) published his "landmark paper" (Benes, 1996). Stevens was the first to associate schizophrenia with an abnormality in the neural circuitry of the cerebral cortex and lymbic system. It was from his work in comparing
schizophrenia to temporal lobe epilepsy that he suggested that schizophrenia might involve a defect in the connections between the temporal lobe of the cerebral cortex and dopaminergic (dopamine-producing) neurons near the base of the brain.
In the last 10 to 15 years, it has become more evident that schizophrenia is a degenerative disorder. For example, in 1985 "there were a number of studies using computer-assisted microscopic techniques that have found less tissue and fewer neurons than average in several cortical and limbic regions of the schizophrenic brain" (Benes, 1996). Despite this apparent degeneration, there has been no finding of an increase in the number of glial cells (cells that clean up the debris of the dying neurons). This process of neuronal loss is known as apoptosis and is believed to be the cause at least in part of schizophrenia.
There is a growing body of evidence that people who develop schizophrenia in adulthood had a brain abnormality from their earliest months of life (Bongfiglioli, 1997). She states that "problems with early brain evelopment...in the womb, are emerging as the most convincing root cause of
schizophrenia" (Bongfiglioli, 1997, p.1). In her report she cites the work of Weinberger who found that there was a link between schizophrenia and birth complications as well as flu during pregnancy. This association of the incidence of schizophrenia to problems experienced during pregnancy is supported by evidence from a study cited by Garver (1997) in which it was found that in some cases the illness results from a failure of development in the middle three months of pregnancy, leaving the brain vulnerable in early adulthood, when the programmed elimination of redundant neuronal connections (called apoptosis) exposes this maldevelopment. As mentioned, a possible cause of the maldevelopment during pregnancy may be exposure to flu viruses.
In a paper published in Scientific American (Beardsley, 1997) it was reported that "an unrecognised infection by a virus or other agent might trigger at least some cases of schizophrenia" (Beardsley, 1997, p.1). Support for this has long been noted by physicians - that antipsychotic drugs have an antimicrobial effect on recognised viral infections. Furthermmore, researchers at the Johns Hopkins Children's Center have discovered that some metabolites (breakdown products) of the anitpsychotic drug clozapine stop the replication of HIV in human cell cultures (Volkers, 1997). Previous studies of antipsychotics have indicated that many of them posses anti-viral activity, according to Volkers: "thorazine has been shown to slow the progression of AIDs in HIV-infected patients, and lithium can inhibit the replication of herpes simplex viruses" (Volkers, 1997, p.1). Such findings support the theory that viral infections may play a role in schizophrenia.
More specific evidence of viruses influencing the incidence of schizophrenia is the correlation between exposure to influenza during and the risk of developing schizophrenia in later life. It has been reported that (Machon et al., 1997) in uetero exposure to influenza during the second trimester of pregnancy may increase the risk of adult major affective disorder, especially in families who have shown a predisposition towards mental illness such as schizophrenia. In
their study, Machon et al. (1997) looked at the incidence of schizophrenia in relation to the 1957 flu epidemic in Helsinki, Finland. Their findings are illustrated in Figure 2 below. They concluded that exposure to flu caused a neurodevelopmental disturbance that triggered their predisposition to develop schizophrenia.
So the question arises as to how exposure to influenza may cause schizophrenia. Although the first symptoms of schizophrenia arguably appear in late adolescence or early adulthood , "neuroscientists now believe that the seeds of the disorder are often sown during fetal [foetal] development" (Schizophrenia.com, 1996). "Arguably" because as mentioned above, symptoms are observable in preschizophrenics during childhood. During foetal development the brain is
'wired up'. This involves nerve cells growing, dividing, and building connections with each other. It is reported (Schizophrenia.com, 1996) that the flaw in brains of many schizophrenics is that certain cells migrate to the wrong areas, leaving regions of the brain permanently out of place or 'miswired'. It is speculated that such misconnections may develop when the catches a virus
during pregnancy. Weinberger
(1995) states that: "based on the weight of evidence, half or more of schizophrenia seems to be due to abnormalities in fetal brain development". A study cited in Schizophrenia.com (1996), based on tissue from autopsies, found "neurons out-of-place in the prefrontal areas of 7 of 20 brains from patients with schizophrenia and in none of the 20 brains from people without the
disorder. The study is the fourth of its kind to report wayward cells in various parts of the cortex in people with schizophrenia" (Schizophrenia.com, 1996, p.2). It is reported that these out-of-place cells are "unexpected large residues of the neural subplate". The subplate is a structure that guides other neurons to their proper sites in the brain, forming in the fourth month
of pregnancy - the second trimester. It then gradually disappears almost entirely within the first month of life, having completed the task of aiming neurons toward their location in the cortex. Potkin et al. (cited in Schizophrenia.com, 1996) report that this migration of cells through the
subplate occurs "almost entirely in the second trimester of fetal development". Thus, disrupting this process will result in the neurons being placed wrongly or being misconnected - what is found in schizophrenics. A possible cause of this failure of the neural subplate to perform its task may be a viral infection caught by the mother that penetrates the placenta - "interfering with the
operation of the neural subplate during the critical months of fetal brain development" (Potkin et al., cited in Schizophrenia.com, 1996).
Further evidence supporting the theory that a viral infection may cause schizophrenia can be found in several studies showing that there tends to be a higher rate of schizophrenia among children born roughly in the months of December through March (Schizophrenia.com, 1996) - a time of year when the mother is most likely to catch the flu or other viral infections.
A theory that is similar to the viral infection hypothesis is that of oxygen deprivation. In the same way that it has been theorised that a viral infection could cause schizophrenia, it has been suggested that foetal oxygen deprivation, or hypoxia, might play a role in the development of the disorder (DeAngelis, 1997). Prenatal hypoxia can occur due to many different factors, including
"the umbilical cord wrapping itself around the neck of the foetus; the mother's placenta being cut or compressed; delayed foetal lung development; and untreated aspiration of meconium, or foetal matter, at birth" (Cannon, cited in DeAngelis, 1997). Such complications are referred to in general as obstetric complications. Cannon examined hypoxia rates and later development of schizophrenia in about 1,100 adults extrapolated from another study. The original sample from which Cannon's subjects were from included 194 schizophrenics, 135 of their non-schizophrenic siblings, 895 controls with other psychiatric problems, and 7,886 controls without psychiatric problems. Cannon found that the higher the number of hypoxia-related obstetric complications, the greater the chance an individual would be schizophrenic, and the lower the chance he or she would be an unaffected sibling of a schizophrenic (cited in DeAngelis, 1997). In contrast to this finding, Cannon also found that adults who had developed psychiatric disorders other than schizophrenia did not show greater rates of prenatal hypoxia. This evidence certainly points to at least an environmental factor influencing the incidence of schizophrenia. Whether it is a causal factor is yet to be fully established.
Another suggestion of how maldevelopment of the brain in the prenatal stages of life can influence the incidence of schizophrenia is that of malnutrition. The idea that nutritional deficiency may some way be involved in the triggering, at least, of schizophrenia is supported by a study Susser et al. (1996). In an investigation into the high incidence of schizophrenia in those born in the Netherlands at a particular point during World War Two, Susser et al. (1996) found that exposure to famine was correlated to risk of schizophrenia. At the end of World War Two a Nazi blockade caused a famine in the Netherlands. Susser et al. (1996) found that the risk of developing schizophrenia increased for people born between 10/15/45 and 12/31/45.