Adoption studies
A third approach to examining a genetic contribution to schizophrenia is to study the prevalence of the disease in adopted children as compared with their biological and adoptive relatives. Heston (1966) examined 47 children of schizophrenic mothers who were adopted at infancy by parents with whom they had no biological relationship. This group was compared at maturity with a control group of 50 adoptees who were separated from non-schizophrenic mothers. The results supported a genetic aetiology of schizophrenia: whereas five children of schizophrenic mothers developed schizophrenia, none of the children of non-afflicted mothers developed the disorder (Faraone, et al. 1999). In a much larger project, Kety et al., (1988), studied 5,483 Danish children who were adopted between 1923 and 1947. Again, more adoptees who were separated from a schizophrenic biological parent developed schizophrenia or a related disorder than did control adoptees (32% versus 18%, respectively). Furthermore, children born to non-schizophrenic parents but raised by a schizophrenic parent did not show rates of schizophrenia above those predicted for the general population. These findings have been replicated more recently by Kendler et al. (1994) and Kety, et al. (1994).
Brain Structure
Since the early 1980s, with the availability of brain imaging techniques and other developments in neuroscience, it became apparent that the brains of individuals suffering from schizophrenia are measurably different (both structurally and functionally) from those who do not have the disease. Prior to the availability of CT and MRI which allowed to observe the brain structure in living subjects, many neuropathological studies have been consistent in finding abnormalities in the brains of deceased persons with schizophrenia. Evidence from neuroimaging studies has identified two main anatomical differences between the brains of normal people and schizophrenic patients. First, there is a notable enlargement of the and in substantial proportions of persons with schizophrenia (more common in men), and it is only evident at the onset of the illness, and does not progress over the course of it. However, this type of abnormality is also present in other disorders such as Parkinson, bipolar, etc. This suggests that it is more of an indicator, that some form of the abnormality is present, rather than a specific marker for a particular illness (Van Horn & McManus, 1992).
The second major difference is the apparent hypofrontality (reduced blood flow in the frontal regions) in schizophrenic patients. This indicates impaired functioning of that area. The lack of blood flow causes reduction in the size of the brain itself. MRI studies (Soares & Mann, 1997; Lawrie & Abukmeil, 1998) have been consistent in finding loss of temporal lobe volume and loss of temporal lobe gray matter in schizophrenia sufferers. The areas which were found to be most affected are the limbic forebrain, (especially the amygdala and the hippocampus), and the basal ganglia (including the caudate, nucleus accumbens, and olfactory tubercle). Freedman et al., (1995) found that skull volume is reduced in persons with schizophrenia by 3.5%. Since brain growth drives skull growth, these findings suggest that the process causing schizophrenia takes place prior to the completion of brain growth (approximately age 18) (Elkis, et al. 1995). In fact, studies by Fish et al., (1992) and Marcus et al., (1993) demonstrated the presence of mild neurological impairments even in the infants of schizophrenic parents. This strongly suggests that the process leading to schizophrenia is a developmental error occurring prior to birth, rather than a degenerative or destructive process.
The view of developmental neurobiologists supports this claim. They suggest that schizophrenia may be a developmental disorder resulting from neurons being miswired during fetal growth. These errors may lie dormant until puberty, when changes in the brain that occur normally during this critical stage of maturation start interacting adversely with the faulty connections. This research has spurred efforts to identify prenatal factors including infections in utero that may affect development (Murray, et al., 1992). One of the first bits of evidence to support this hypothesis came in 1988 from the study by Mednick et al, of children born to women who had been pregnant during a severe flu epidemic in Helsinki, Finland, in 1957. It was found that the children of mothers who had caught flu in the second trimester of pregnancy, (the time when the neural subplate goes into action), had a greater chance of developing schizophrenia as adults (Figure 2).
Figure 1. Helsinki Study (Mednick et al., 1988).
Biochemical Factors
Many studies have also emphasized the possible role of brain neurotransmitters in the development of schizophrenia. The main focus of research has been directed on the neurotransmitter called dopamine. The dopamine hypothesis of schizophrenia states that there is an overactivity of the dopamine systems in schizophrenia. The hypothesis grew out of the finding that all effective anti-psychotic medications block dopamine brain receptors, and that their potency is correlated to the strength of binding to dopamine type 2 (called D2) receptors in the brain. The support for the hypothesis came from observations that the administration of drugs which increase dopamine activity aggravates psychotic symptoms in some persons with schizophrenia (Jones, & Pilowsky, 2002).
Post mortem neurotransmitter studies have reported increased numbers of D2 receptors in critical portions of the brain, areas such as the basal ganglia and the limbic system. However, not all studies have been consistent with these findings (Harzs, 1982). The main disagreement being the fact that anti-psychotic medications are effective in treating psychosis of any origin, which suggests that elevated dopamine activity may not be specific to schizophrenia. And finally, studying the brains of deceased persons is fraught with problems, simply because of the possible prior treatment with anti-psychotic medication which can in itself increase dopamine receptor levels. The new technology of PET holds much promise for the study of dopamine receptors in the brains of live and unmedicated persons. For example in their latest study using PET Meyer-Lindenberg, et al, (2002) for the first time linked two main brain abnormalities in schizophrenia which were previously unconnected. They have shown that the less patients’ frontal lobes activate during a working memory task, the more the dopamine rises abnormally in the striatum (a relay station deep in the brain). Together with the other evidence, this suggests that the excess dopamine activity may be driven by the defect in the prefrontal cortex. This might have implications for treatment of the disorder which will target prefrontal cortex dysfunction and not just excess dopamine.
There are other proposed biochemical theories such as serotonin association and faulty metabolic brain processes. The evidence for serotonin involvement comes from many patients who have not been helped by "dopamine only" medications but have been helped by combination drugs which are designed to treat symptoms of schizophrenia by blocking both dopamine and serotonin transmissions, such as Clozaril (Rosenzweig, et al. 2002). The faulty metabolic processes have been suggested to be responsible for the production of the hypothetical substances known as psychotogens in the brain. They in turn might resemble the actions of some hallucinogenic substances (several manufactured hallucinogens such as PCP for example, resemble the chemical structures of some neurotransmitters). Metabolic malfunctioning might cause the brain to convert some of the harmless molecules into such substances and produce schizophrenia like behaviors. When PCP was given to animals over a period of some weeks, schizophrenia like symptoms were induced (Jentsch et al., 1997). The condition was reversed by introducing dopamine-blocking antipsychotic drugs which provided further evidence that such metabolic abnormalities might be directly involved in causing schizophrenia (Rosenzweig, et. al 2002).
Environmental / Social Influences
In spite of all the above evidence, the biological perspective for schizophrenia as it stands at the moment appears to be disjointed and rather one sided. It is necessary to take into account environmental and social factors which contribute to the psychological wellbeing of an individual. Factors such as family stress, poor social interactions, infections or viruses, intrauterine starvation or trauma at an early age all might be contributors to the development of schizophrenia later in life. There have been many studies highlighting such a possibility.
For instance, a higher rate of schizophrenia was found among children in the Netherlands born to women who were pregnant during the winter of 1944-45, when the Nazis blockaded Dutch cities, which suggests that malnutrition could also play a role (Gelder, et al. 1989). Also in the latest research by McCreadie (1997; 2002) it has been suggested that the lack of breast milk with its important fatty acids, such as DHA, which are absent in bottle-feeds increases the risk of the neurodevelopmental form of schizophrenia in the individual predisposed to the illness by genetic factors or previous environmental insult. Taking all the reviewed possibilities into account, Mirsky and Duncan (1986) proposed to integrate the psychological and biological findings into a singular model of schizophrenia. According to them schizophrenia is most probably biologically predisposed condition but may not develop into a full blown disorder without environmental influences and stressors.
Conclusion
The evidence reviewed strongly suggests that there are several biological bases for schizophrenia. The genetic studies have provided what is perhaps the most important contribution to the understanding of the disorder. However, the current status of research on genes and schizophrenia has not yet uncovered the specific genes that underlie the disease. And even if that takes place, some researchers such as McGue & Gottesman (1989), admit that analysis of individual genes alone will not give us a full understanding of the causes of schizophrenia. The disease is most definitely a result of interactions of complex systems, therefore a systems approach is needed for understanding its development.
Basic knowledge about brain chemistry and its link to schizophrenia is also expanding rapidly and this area of research looks very promising. It is clear today with the firm findings of reduced frequency, duration, and severity of psychotic episodes in persons treated with anti-psychotic medication that dopamine has a major role to play in schizophrenia like disorders. However, it is not known whether the change in the dopamine activity occurs before or after the onset of the illness. If it occurs after, than overactive dopamine is just another symptom in a long list of symptoms associated with schizophrenia (Jones & Pilowsky, 2002). It may well be that schizophrenia is not a single disorder at all, but rather that it represents a final common syndrome of behaviours and findings about mental status with multiple possible causes. Understanding these causes will be critical for the medical care of patients suffering from schizophrenia, so the doctors can if not cure, then at the least alleviate the suffering this disease brings on the patient and their family and friends.
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