Schizophrenia

Schizophrenia: A critical review of biological causal theory past and present.

Assumed knowledge: . DSM IV classification of schizophrenia. . Basic brain architecture/function. . Basic neuropharmacology . Evolutionary theory.

Schizophrenia is generally a well known mental Illness that skillfully evades an all encompassing descri ption. In simple terms, schizophrenia is an acute or chronic psychotic disorder; it is on a multi-spectral scale from mild to severe and there are prescribed combinations of co-occurring symptoms. These symptoms generally present as episodes of disordered and/or heightened/reduced perceptions of reality. These episodes can be interspersed with periods of 'relative stability' or present as a gradual reduction in sociability promulgating a downwards permanency of change. Schizophrenia is equally prevalent in all societies, regardless of biological sex, endogenous culture (Horrobin, 1998) but not necessarily 'diaspora' culture (Wessley et al, 1991): for example, there appears to be an over representation of 'Afro-Caribbeans' within the U.S. and U.K. Another important issue is 'Urbanicity'; the positive relationship between population density and prevalence of schizophrenia (Krabbendam & Van Os, 2005). Schizophrenia's demographic status is not precise, but generally falls somewhere between 1% and 1.3% of any given population (Kendler et al, 1996).

Horrobin (1998) discusses schizophrenia in terms of a 'universal' with its roots in evolution. Passionately describing schizophrenia as: ".the illness that made us human". In simple terms when mankind 'diverged' by developing a larger brain and intelligence. This change was sparked in part by neurochemical developments. The chemicals (lipids, proteins and their relationship with glutamate) necessary for developing creativity, sociability and leadership are the same ones possibly implicated with the onset of schizophrenia. Therefore it could be suggested that mankind could not have progressed without the potential for this and other 'mental disorders' (Horrobin, 1998).

However, schizophrenia is not that simple. The symptoms can be described in terms of 'behavioural positivity' and 'behavioural negativity' (McCarthy, 2004). That is, expressed behaviour which adds to the person (including hallucinations and delusions of persecution/grandeur) and/or observable changes which reduce behaviour within the person (including reduced: motor activity, speech, gesticulation, sociability and a general interest in life). This is sometimes referred to as Positive (Type-1) and Negative (Type-2) schizophrenia. It is also suggested that because their aetiologies (cause, progression and by implication treatment) are so different, they should warrant classification as quite separate disorders (McCarthy, 2004). Unfortunately there is little evidence to suggest 'single causation' for either Type-1 or Type-2, as each individual case of schizophrenia is unique and each case presents a varied 'baseline' occupancy of symptoms, including the possibility of positive and negative symptoms within the same person (Boyle, 1990). However using the common cold and flu as an analogy (different causes but similar symptoms); technically it is possible to catch a cold while you are suffering with flu!

Historically, a schizophrenia type disorder was first identified by Kraeplin in 1898 (he referred to it as 'Dementia Praecox' or early onset senility of youth) and a short while later (1908), the actual term 'schizophrenia was coined by Bleuler (Noll, 2007). Since then, there has been a steady progression of acquired knowledge. This has lead to a consensus, that the primary cause of schizophrenia is a biological (genetic) inheritable disorder of the brain usually triggered by an 'environmental' event, trigger or insult (Kerwin, 1992).

Prior to these neurophysiological explanations it was thought that schizophrenia was the product of external events and more specifically the causal factor was claimed to be abnormal childhood experiences (especially within the family unit) rather than abnormal brain function (Kasinin et al, 1934).

Schizophrenia was not described in terms of brain disease or disorder until the middle 1960`s (L`Abate et al, 1962). This line of research looked for brain abnormalities in diagnosed schizophrenics in comparison to 'low/no risk' control groups (based on familial medical history). However this line of research proved fruitless at the time because on many of the tasks, schizophrenics out-performed the control groups. This was not fully understood in terms of increased brain activity (possibly the effect of heightened dopmaninergic activity on memory and learning). Therefore, as a means of linking brain abnormality/dysfunction to the cause of schizophrenia, it probably did more harm than good in the search for a biological explanation.

French research of the 1950`s (Laborit et al, 1952) discovered that administering antipsychotic drugs was a much better way of controlling some schizophrenics in comparison to other physical methods (e.g. E.C.T. and psychosurgery) or other drug based methods (e.g. insulin induced coma). Later research (Hirsch, 1982), has shown that antipsychotic drugs in general affect neurotransmitters (in the case of schizophrenia by 'down regulating' the dopamine activity) and that drugs from the group known as `Butyrophenone` (which includes Halopridol) and `Fluphenazine` (Alpha-flupenthixol) were discovered to be particularly effective forms of treatment.

It was thereby assumed that an increase in or an above normal count of active dopamine vesicles was a causal precondition for the onset of positive (or Type-1) schizophrenia (remembering that Type-1 presents itself as an increase in activity in an inappropriate way). As observed antipsychotic drugs dampen down the dopamenergic activity and in doing so reduce the severity of the schizophrenic symptoms. It is also known that drugs like amphetamine can mimic certain characteristics of schizophrenia (amphetamine psychosis: panic attacks and delusions etc). This mimicking of schizophrenia is achieved by substance abuse up-regulation of dopaminergic activity (Strange, 1992). Therefore the initial biological explanation of schizophrenia was that super-inflated (excitorary) dopaminergic activity in the brain was a major causal trigger of the disorder and that treatment was to dampen down this activity (Randrup and Munkvad, 1972).

However later studies (cf. Mackay at al, 1982; & Crow et al, 1984) state that post-mortem neurochemical evidence does not support the hypothesis. That is, deceased schizophrenic patients do not appear to have abnormally high levels of dopamine. More so this research suggests that they probably had a naturally developed supersensitivity to dopamine caused by an over-exposure to a decreased number of D2 receptors specific to dopamine. It is this supersensitivity to 'normal' levels of dopamine which possibly plays a major role in the expression of schizophrenia in an individual.

Until recently explanations of Type-1 (positive) schizophrenia have focused almost exclusively on dopaminergic activity. However much recent research (Moghaddam, 2003 and Egan et al, 2004) has highlighted the role of glutamate. Glutamate is a neuromodulator whereas dopamine is a neurotransmitter, the difference is like: "an on/off switch compared to a dimmer switch" (Moghaddam, 2003). Research into this deeper level of synaptic activity has revealed a link between glutamate under-activity in dopamine receptors, psychoses and dysfunction of working memory. Drug treatment to up-regulate glutamate has shown a reduction in these schizotypal symptoms (Stefani & Moghaddam, 2005). Thus supporting that the 'Dopamine Hypothesis' could be amended to: 'It is receptor sensitivity to dopamine (modulated by glutamate) and not the actual level of dopamine that determines the severity of a Type-1 Schizophrenic episode'. (McCarthy, 2004. p48).

However all is not that simple, research (Moghaddam, 2003) suggests that the low activity of glutamate on the D2 receptor reduces its efficiency. Therefore there is more dopamine than the receptors can cope with and this is the cause of the cognitive dysfunction (memory, perception etc) associated with positive schizophrenia. Therefore it would be easy to suggest that Type-1 positive schizophrenia has a chemical cause and is therefore controlled with a chemical (drug) treatment; case closed. Unfortunately further tests (Stefani & Moghaddam, 2005) have also identified that low glutamate activity can also produce some negative symptoms (avolition, apathy, and blunted affect) of the sort normally associated with Type-2 schizophrenia. As we shall see, this type of schizophrenia has to date presented itself as having a neuro-architectural cause and not a neurotransmitter cause; questioning the claim that Type-1 and Type-2 schizophrenia are quite separate disorders.

This leads to Type-2 schizophrenia; the cause of which appears to be changes in the brain's structure in the form of neurodegeneration (loss of brain grey matter) and/or neurodevelopment (changes as the brain matures, especially ventricle enlargement) and would be commensurate with the lessened potential associated with this kind of schizophrenia (McCarthy, 2004).

Research using 'Functional Magnetic Resonance Imagery` (fMRI) techniques, has identified that diagnosed schizophrenics have enlarged ventricles cavities in comparison to low/no risk control groups (Andreason et al, 1982 & 1990). Therefore it is reasonable to suggest increased ventricle size is a likely precursor to the onset of one particular form of schizophrenia (Type 2: because of late onset, its slow imperceptible development and its resistance to drug treatment). Another phenomenon identified is that grey matter tissue is reduced in areas including the hippocampi and frontal/ temporal regions; this would possibly have an affect on memory, movement and higher order understanding (Zipursky et al, 1992 & 1998).

This raises the question of neurodegeneration (does the brain start to develop normally and then as a precursor to onset start to change) or neurodevelopmental (brain starts off abnormal and the developing abnormality does not become apparent until puberty). Teenage 'First Episode' (FE) patients scanned at the onset of schizophrenia showed evidence of enlarged ventricles and a deficit in temporal lobe grey matter in comparison to no/low risk control groups. However in comparison to long-term schizophrenic patients it becomes clear that whereas ventricle size is constant throughout the disease, grey matter deficit was markedly less in FE schizophrenics than in long-term chronic sufferers. Therefore there is evidence to suggest that the reduction in grey matter is progressive and becomes more profound with chronicity (Lim et al, 1996). Research by Rapport et al (1997) further supported this evidence with longitudinal studies of 'at risk' children (a parent with schizophrenia) compared to a low/no risk group, with a follow up after two years and four years. They discovered evidence to suggest that there is a progressive enlargement of the ventricles only up to a certain point in the early stages of brain development and it is fixed by about the age of 2 years old.

If schizophrenia is degenerative (caused by loss of brain tissue), then it would be expected that evidence of `gliosis` would be present (scar tissue formed when brain cells die). Some support is evidenced; Roberts and Bruton, (1990) discovered that gliosis is detectable and that this loss is linked to reduction in the cortex rather than the size of the ventricles (abnormal enlargement) Therefore it is safe at this time to assume that ventricle enlargement is developmental in the first two years of life and that grey matter loss is a progressive neurodegeneration starting at a later stage (probably puberty).

Reduction in gray matter at a later stage in the development of schizophrenia is further supported by recent research. Gogtay et al (2007) evidenced in a longitudinal study (with control groups), that in childhood onset schizophrenia (COS) gray matter loss is not seen until puberty and slowly develops into a critical loss by early adulthood. Salisbury et al (2007) further progressed evidence by demonstrating not only a gray matter reduction post-onset but also a negative association between rate of tissue loss and reduced modality potential tested in areas such as auditory function/capability. A final point of evidence for the link between abnormal brain growth and schizophrenia is supplied by Gurling (2006); who evidenced a genetic marker responsible (PCM1: pericentriolar material) for abnormal development, post-puberty in gray matter from the orbitolfrontal cortex (disruption to cell division). A reduction in gray matter here could result in inappropriate social behaviours, symptoms often associated with Type 2 schizophrenia.

To sum up, increased knowledge of the role of glutamate offers a causal explanation of the controllable Type-1 positive schizophrenia; that is chemical; causation and drug stabilization treatment. The link between abnormal brain growth and grey matter loss/ventricle enlargement offers a strong explanation of the more permanent, less treatable Type-2 schizophrenia. That is ventricle enlargement is the precursor for Type-2 schizophrenia and that gray matter loss exacerbates the negative symptoms post-puberty to early adulthood. But perhaps of greatest interest are the negative symptoms also associated with reduced glutamate activity. This offers an explanation of why both positive and negative symptoms can co-occur in the same patient and offers support for the creation of either a distinct sub-category of Type-1 or a new Type-3 category of schizophrenia.(where both positive and negative symptoms are present in the same patient).