Compare and contrast two or more theories of Schizophrenia.

Schizophrenia, a Greek word meaning “split brain”, was coined by Eugen Bleuler in 1908 to describe a type of dementia praecox which emphasizes a break from reality and disintegration between emotions, thought and actions. In contemporary term, schizophrenia is a mental disorder with impairments in the perception, psychomotor behaviour and affect; manifested as a syndrome characterized by two categories of symptoms, positive (hallucinations, delusions and disorganization) and negative (social withdrawal, apathy, poverty of speech), expressed variably in the sufferers (Crow, 1980; Andreasen, 1995). Although the underlying mechanism of schizophrenia remains somewhat elusive, theories of the causation of schizophrenia based on evidence at different levels, ranging from biochemical, neurodevelopmental, cognitive to social, have been proposed. In this essay, I will focus on two of the most prominent theories, Dopamine hypothesis and neurodevelopmental theory. I will first outline the main body and the evidence in support of the theories, and then compare the theories on the basis of its explanation of the development and associated symptoms of schizophrenia, and corresponding limitations. Here, I would like to argue that despite the differences between the two theories, they are not mutually exclusive; contrarily, they can complement each other to give a better picture of the causation of Schizophrenia.

Dopamine hypothesis has been suggested to be one of the few theories with strong empirical ground and has attracted a lot of attention in the research and drug treatment for the last 50 years. Carlsson and Lindqvist (1963) first proposed the “dopamine hypothesis”, stating that schizophrenia is caused by over-reactivity of dopaminergic system (especially in the mesolimbic dopamine projection). This hypothesis was initially based on the earlier findings of Delay and Deniker (1952), who discovered that chlorpromazine, a dopamine antagonist used to prevent surgical shock, had dramatic ameliorating effects on the positive symptoms of schizophrenia. This was in line with the circumstantial evidence that; a. all anti-psychotic drugs which are effective treatments for disorder were dopamine antagonists (Creese et al., 1976); and b. application of L-DOPA (a dopamine agonist) or amphetamine can induce schizophrenia-like symptoms in many normal controls, and worsen positive symptoms already present in some schizophrenic patients (Davidson et al. 1987).

On the other hand, with the technology of brain scanning, many studies have found evidence of loss of brain tissue in schizophrenic patients (Carlson, 2003). Weinberger and Wyatt (1982) reported the relative ventricle size of the schizophrenics was more than twice as large as that of normal control subjects, and a more recent meta-analysis by Daniel et al (1991) also suggested there was ventricular enlargement in schizophrenics. Together with evidence from genetic and epidemiological studies, the neurodevelopmental theory of schizophrenia was proposed (Weinberger, 1995). A consensus view of the neurodevelopmental theory of schizophrenia is that schizophrenia is predominantly a genetic disorder, with early environmental events playing a subsidiary role. These factors interact and produce aberrant cerebral development in the prenatal or perinatal period. The aberrant defects are static and the behavioural consequences remain relatively latent until long after the primary pathogenetic process has run it course.

In terms of the development of the disorder, the neurodevelopmental theory, despite the criticism of idea of the static aberrant defects, offers a very strong account of the initial development of the disorder, which is utterly missing in the dopamine hypothesis. In the neurodevelopmental theory, the interaction between genetic and environmental factors in an early period of life leaves the person with a susceptibility for developing schizophrenia. Indeed, although it is clear that schizophrenia is not a single gene disorder, the evidence for the involvement of genetic factors is well established. Kety (1968) did a famous study showing that the incidence of schizophrenia in the biological relatives of schizophrenics is unusually high (17% for siblings and 48% for identical twins) while the incidence in adopted families of schizophrenics is the same as in the normal population (1%). Also, Gottesman & Shields (1982)’s twin studies showed that the concordance for schizophrenia in monozygotic twins is more than four times higher than the concordance in dizygotic twins. These findings implicated a high heritability of schizophrenia. Recently, association studies using quantitative trait loci (QTL) replicated linkages studies (Shaw et al., 1998) and showed that there are several genes located on different chromosomes, e.g. Neuregulin 1, are responsible for schizophrenia (Owen et al., 2005). These findings suggested that genes may determine a susceptibility to acquire schizophrenia. Such a susceptibility hypothesis implies that some individuals are carriers of the genetics factors for schizophrenia without every expressing the disorder and this is supported by experiments showing the offspring of twins who are discordant for schizophrenia have the same probability of developing the disorder (Gottesman and Berelsen, 1989). The involvement of genetic factors suggested in neruodevelopmental theory might explain the homogeneous distribution of schizophrenia around the world. There is also support for a role for early environmental factors in the development of disorder, for example, the high incidence rate of history of birth difficulties in schizophrenics (Verdoux et al, 1997) and high rates of schizophrenia among people whose mothers were exposed to the influenza virus, especially those giving birth in late winter and early springs (seasonality effect) (Kendell and Adams, 1991).

While the neurodevelopmental theory has made a good attempt to explain the initial development of schizophrenia, the dopamine hypothesis gains more credit in term of explaining what is actually going wrong in the brain and associated symptoms during a schizophrenic episode. The over-reactivity of dopaminergic system in mesolimbic system in schizophrenia is ingeniously demonstrated by recent studies by Laruelle et al. (1996, 1999). In their studies, a brain imaging technique, SPECT, and amphetamine challenge were employed together to investigate the activity of the dopaminergic system in the striatum. In brief, amphetamine is a drug which stimulates the release of endogenous dopamine by causing the dopa-tranpsorters present in the terminal buttons to run backward, pumping the dopamine out and preventing the re-uptake of dopamine. The induced endogenous release of dopamine is measured by the competition between dopamine and specific radiotracers for D2 receptor sites in striatum. The more active the dopaminergic system is, the more release of dopamine is induced, which increases the competition between dopamine and radiotracers and thus causes a decrease in binding potential of radiotracers. It is found that compared to normal controls, drug-free schizophrenics (eliminating the potential complications caused by previous drug treatments) have a significantly higher radiotracer displacement and the amphetamine challenge worsened the positive symptoms in patients. These findings suggested there is over-reactivity of the dopaminergic system in striatum in schizophrenics and it is responsible for the positive symptoms. Also, they showed that the exaggerated response of the dopamine system to the amphetamine challenge is only detected in patients who were in the acute phase. The transient hyperdoapminergic state suggested there is a role of dopamine during the schizophrenic episode. These findings provide a good support of the dopamine hypothesis which delineates the underlying biological mechanisms during schizophrenic episodes. In contrast, the neurodevelopment theory only attributes the disorder to early cerebral abnormalities.

One of the criticisms against dopamine hypothesis is that it only appears to apply to positive symptoms while the cerebral abnormalities in the neurodevelopmental theory has a wider scope in potentially explaining both positive and negative symptoms, though it does not explicitly account for how they arise. However, it has been suggested that dopamine does play a role in negative symptoms. Recent fMRI studies showed that there is a decrease in the activity of prefrontal cortex in schizophrenic patients (Taulor 1996), while Okubo et al (1997) found decreased numbers of D1 dopamine receptors in the prefrontal cortex of schizophrenics. These suggested a relationship between the decreased dopamine activity and the hypofrontality in schizophrenics. More importantly, in the same study, Okubo et al. found that the decrease in D1 receptors correlated with the extent of negative symptoms. It fits well with what Weinberger et al. suggested in 1986; that the negative symptoms are caused by hypofrontality (decrease activity of the prefrontal cortex). More links were found between the dopaminergic systems in prefrontal cortex and mesolimbic system in recent research. Carr and Sesack (2000) showed that neurons of prefrontal cortex send axons to the ventral tegmental area where they form synapses with GABA-secreting neurons that progress to nucleus accumbens and Jacksone et al. (2001) found that electrical stimulation of prefrontal cortex inhibited the release of dopamine in nucleus accumbens. Thus it appears that the original theory can be extended to account for negative symptoms.

Alternatively, the negative symptoms may arise as a consequence of an interaction between a dysfunction in the dopamine system and a second dysfunction. Krystal et al. (1994) demonstrated that normal volunteer receiving steady low does infusions of ketamine, a NMDA antagonist, exhibited negative symptoms and cognitive impairments similar to those presented in schizophrenia. Further evidence that the negative symptoms of schizophrenia arise as a consequence of NMDA receptor dysfunction comes from a combination of brain imaging studies, genetic studies, pharmacological interventions (cf. Coyle, 2006). There has been evidence proposing an interaction between the dopamine and glutamate system in critical brain regions such as hippocampus (Lisman & Otmakhova, 2001). Consistent with the notion of the interaction between two systems, it was shown that infusion of PCP (an indirect NMDA antagonist which induces both the positive and negative symptoms) into prefrontal cortex led to an increase of dopamine utilization in nucleus accumbens, and PCP induced worsening of symptoms was positively correlated with decrease in dopamine activity in prefrontal cortex (Jentsch et al, 1998). Taken alongside the evidence for hypofrontality, these two extensions of the dopamine hypothesis provide a good account of the negative symptoms.

In conclusion, the dopamine hypothesis and the neurodevelopmental theory can each explain certain aspects of the causation of schizophrenia. While the neurodevelopmental theory depicts the initial development of the disorder which involved aberrant cerebral structure caused by the interaction of genetic and environmental factors, the dopamine theory combines with recent research findings to explain the biochemical deficits in schizophrenia. In spite of the different focus of these two theory, I think it is clear that they are not mutually exclusive but instead can be put together to give a fair decent account of the development and underlying mechanism of schizophrenia at biological level. However, neither of them offers an explanation to the maintenance of the disorder (e.g. relapses) or of particular symptoms, and in this regard cognitive theories, such as that of Frith & Done (1989) and Morrison (1998) are more useful. Future research should attempt to integrate the dopamine hypothesis, neurodevelopmental theory, and cognitive accounts of particular symptoms in order to provide a full account of schizophrenia.