pathophysiology of schizophrenia

Rather than being seen as one single disease entity, schizophrenia is better visualised as a heterogenous group of disorders. The pathophysiologic processes that underlay these conditions remain much of a mystery, and it is sometimes very difficult to clearly differentiate between aetiological and pathophysiologic factors. However, research has shown that several observations and theories regarding the aetiology and pathophysiology of these disorders can be made.

The first of these involves genetic susceptibility and neurodevelopmental factors that appear to contribute to the pathogenesis of schizophrenia. Increasingly, evidence shows that these factors have a major role to play (Murray, Callaghan, Castle & Lewis, 1992). It has been shown, for example, that monozygotic twins have an increased risk of both developing schizophrenia (around 50%) compared to the lower risk rate in dizygotic twins of only 12% (Kendler & Diehl, 1993). This figure is significant, as it also demonstrates that schizophrenia is not entirely genetic in origin (if it were a genetic disorder with Mendelian properties, it could be expected to decline in frequency over many generations, but this is not the case). The same research showed that the strength of these genetic factors varies from family to family, but, on average 10% of first-degree relatives (which includes parents, siblings and children) of a person with schizophrenia will also develop the disorder. If both parents have the diagnosis, then half their children will also develop the disorder. Chromosomes 1, 3, 5, 6, 8, 11, 13, 18, 22 (the last involving a near-doubled risk of schizophrenia; schizophrenia.com (n.d.)) and the X chromosome appear to be involved (Kendler & Diehl, 1993; schizophrenia.com (n.d)). Mutations in some genes on these chromosomes have been found to increase the chance of a person developing schizophrenia. However, each of these genes is thought to increase a person’s vulnerability to schizophrenia by only a small proportion. In 2004, Dr. Daniel Weinberger, Director of the American Genes, Cognition and Psychosis Program, at the National Institute of Mental Health, stated that he estimated the current number of gene variations linked to schizophrenia to be approximately 10 (schizophrenia.com, (n.d.)). According to the same website, those who have a third degree relative with schizophrenia are twice as likely to develop schizophrenia as those in the general population, those with a second degree relative have a several-fold higher incidence, and first degree relatives have an incidence of schizophrenia ten times higher than the general populace. The site also supplies the following diagrams, showing the differing rates of risk for various relatives of people diagnosed with schizophrenia. The differences in the two diagrams are explained because they included different data sets, leading to different distributions.

There also appears to be a relationship between paternal age and the development of schizophrenia in his offspring. A study in Israel found that the older the father, the higher the rate of mutations in sperm cells, leading to an increased risk of schizophrenia. For example, a child born to a father aged over 50 is three times more likely to develop the disorder, compared to children of younger fathers. The researchers who performed this study have postulated that this effect could explain the persistence of schizophrenia despite the fact that many schizophrenics (60-70%) do not marry and have children (Thackery & Harris, 2002).

Another factor is maternal infection during pregnancy. This stems from the fact that the birthrate of patients with schizophrenia during the winter and spring months is 5% to 8% higher worldwide than the birthrate of the general population during the same seasons. Although not proven, it is postulated that early viral infections may play a causative role in the development of schizophrenia. For example, the 1957 influenza A2 epidemic in Helsinki resulted in a 50% increase in schizophrenia in the offspring of women who developed the infection during their second trimester (Mednick, Machon, Huttunen & Bonett, 1988). Brown, Cohen, Greenwald & Susser (2000)  and Susser, Brown & Gorman (1999) showed that other infections, particularly rubella, may predispose to schizophrenia development. According to Noll (2007), the rise in rates of schizophrenia since the 18^th century directly mirrors that of the incidence of keeping cats as pets. This observation lead researchers to ask whether cats cause schizophrenia, and several studies have shown that people with schizophrenia had higher rates of exposure to cats in childhood compared to normal controls. Other studies have shown that infection with Toxoplasmosis, a viral disease caused by exposure to cat faeces or undercooked meat, may in fact predispose to schizophrenia. Antibodies to this disease have been found in people with schizophrenia and well as their mothers (Noll 2007).

A further factor that stems from around the time of birth is found when hypoxia in the infant arises during a difficult delivery. Cannon, van Erp, Rosso, Huttunen, Lönnqvist, Pirkola, Salonen, Valanne, Poutanen & Standertskjöld-Nordenstam (2002) found that this phenomenon resulted in an increased number of  structural brain abnormalities in schizophrenic patients and their siblings (without schizophrenia) compared with those control subjects who were at low genetic risk of schizophrenia. The odds of developing schizophrenia appear to increase linearly with an increasing number of hypoxia-associated obstetric complications (Higgins & George, 2007). Other research has shown that perinatal complications in later diagnosed schizophrenics may cause ventricular enlargement and decreased hippocampus volume (Kendell, Juszczak & Cole, 1996). Furthermore, Harrison, Gunnell, Glazebrook, Page & Kwiecinski (2001) found that there were links between the development of schizophrenia and low socioeconomic status at birth. According to Higgins & George (2007) there is even a link between schizophrenia development and where the individual was born or raised. A study conducted in Denmark found that those patients who were resident in urban settings at the time of their 15^th birthday had roughly a two and a half times chance of developing schizophrenia than those who were resident in rural settings at the same milestone. Prenatal nutritional deficits also appear to have a bearing on the development of schizophrenia (Brown, Susser, Butler, Richardson Andrews, Kaufmann & Gorman, 1996). For example, a study carried out in the Netherlands found an increased incidence of schizophrenia twenty years after a famine affected the population of that country when it was occupied by the Nazis in 1944-5. While this study appears to show that maternal starvation during the first trimester of pregnancy predisposed o the development of schizophrenia, it may in fact be due to maternal stress rather than any other cause. Indeed extreme stress, as experienced during wartime, after the loss of  a spouse, during natural disasters, as a result of an unwanted pregnancy, or even due to depression experienced by the mother during pregnancy, all appear to increase the risk of schizophrenia development in offspring (Lobato, Belmonte-de-Abreu, Knijnik, Teruchkin, Ghisolfi & Henriques, 2001). Other pregnancy and birth complications that appear to have some impact on the development of schizophrenia include preeclampsia, bleeding during pregnancy, umbilical cord complications, premature rupture of amniotic membrane, prematurity, prolonged labour, the use of resuscitation, incubators, forceps or suction during delivery, an abnormal foetal presentation at delivery, low birth weight, small head circumference, and low Apgar scores (McNeil, Cantor-Graae & Ismail, 2000; Lobato et al, 2001). According to Panksepp (2004), all of these various perinatal abnormalities have been reported in 21-40% of patients diagnosed with schizophrenia. So, there are a number of factors that surround pregnancy and delivery that appear to have a contributing factor to the later development of schizophrenia in offspring. The question is, how exactly do the factors lead to the development of the disorder?

Perhaps these factors lead to anatomical abnormalities within the brain, which in turn give rise to schizophrenia. This theory has come more to the fore since the advent of modern imaging technology, such as CT scans and MRI. The first published CT scans of schizophrenic brains arrived in the scene in 1976, and showed enlarged lateral ventricles (Higgins & George, 2007). Later, MRI scans also showed this abnormality, as well as subtle decreases in total brain volume and total grey matter volume (with the temporal lobe losing disproportionately more volume than other areas of the brain (Noll, 2007)).. These latter changes may well explain the apparent change in size of brain ventricles: the ventricles expand to fill the gap left by grey matter loss. This loss may become particularly apparent in adolescence, when there is a great deal of remodeling of the brain, the purpose of which is to create a more efficient organ. Thus, theoretically at least, schizophrenia may be due to overenthusiastic remodeling of the brain during adolescence (cortical pruning) – a theory that may be further borne out by the fact that by far and away the majority of cases of schizophrenia first come to light within the same chronological period (mean age of onset is 20 years for males and 25 years for females (Faterni & Clayton, 2008) as this adolescent brain remodeling (Higgins & George, 2007). Selemon & Goldman-Rakic (1999) compared neuronal density in three areas of the brain, and found that neuronal density was greater in the brains of schizophrenic patients compared to normal controls. This gave rise to the reduced neuropil hypothesis: that schizophrenic patients have the same number of neurons as healthy controls, but they are packed together in less space, resulting from reduced cell size, less branching, and decreased spine formation. This study also showed that it was not just one area of the brain that was involved with schizophrenia, but that the whole cortex appears to be involved. Weinberger, Berman & Zec (1986) studied regional blood flow measurements within the brain while subjects were performing the Wisconsin card sort task, and found that normal controls exhibited increased blood flow to the frontal lobes, while schizophrenics did not, implying that somehow the frontal lobes of schizophrenic patients were in some way impaired. Hansen & Gottesman (2005) suggested that a chronic inflammation of cerebral blood vessels may be the cause behind many of the brain abnormalities found in schizophrenia. Hof, Haroutunian, & Friedrich (2003) found that patients with schizophrenia have fewer oligodendrocytes in the white matter of their brains than did normal controls. Studies by Dierks, Linden, Jandl, Formisano, Goebel, Lanfermann & Singer (1999) and Hubl, Koenig, Strik, Federspiel, Kreis, Boesch, Maier, Schroth, Lovblad  & Dierks (2004) found that the auditory hallucinations so often found in schizophrenia appear to be caused by abnormalities in the area of the brain that registers external sounds. Furthermore, these studies reinforced the fact that both grey and white matter appear to be affected in schizophrenia.

References:

Brown, A.S., Cohen, P., Greenwald, S., & Susser, E. (2000). Nonaffective psychosis after prenatal exposure to rubella. American Journal of Psychiatry: 157(3) 438-443.

Brown, A.S., Susser, E.S., Butler, P.D., Richardson Andrews, R., Kaufmann, C.A., & Gorman, J.M. (1996). Neurobiological plausibility of prenatal nutritional deprivation as a risk factor for schizophrenia. Journal of Nervous and Mental Disorders 184: 71-85.

Cannon, T.D., van Erp, T.G., Rosso, I.M., Huttunen, M., Lönnqvist, J., Pirkola, T., Salonen, O., Valanne, L., Poutanen, V.P., & Standertskjöld-Nordenstam, C.G. (2002). Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Archives of General Psychiatry, 59:35-41.

Dierks, T., Linden, D.E., Jandl, M., Formisano, E., Goebel, R., Lanfermann, H,, & Singer, W. (1999) Activation of Heschl’s gyrus during auditory hallucinations. Neuron 22[3]:615-621.

Faterni, S.H., & Clayton, P.J. (eds.) (2008). The medical basis of psychiatry. Totown, NJ: Humana Press.

Hansen,  D.R., & Gottesman, L.L. (2005). Schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Medical Genetics, 6:7

Harrison, G., Gunnell, D., Glazebrook, C., Page, K., & Kwiecinski, R. (2001). Association between schizophrenia and social inequality at birth: Case- control study. British Journal of Psychiatry 179:346-350.

Higgins, E.S., & George, M.S. (2007). The neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness. Philadelphia, PA: Lippincott, Williams & Wilkins.

Hof, P.R., Haroutunian, V., & Friedrich, V.L. (2003). Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biological Psychiatry 53[12]:1075-1085.

Hubl, D., Koenig, T., Strik, W., Federspiel, A., Kreis, R., Boesch, C., Maier, S.E., Schroth, G., Lovblad, K., & Dierks, T. (2004). Pathways that make voices: white matter changes in auditory hallucinations. Archives of General Psychiatry 61[7]: 658-668.

Kendell, R.E., Juszczak, E., & Cole, S.K. (1996). Obstetric complications and schizophrenia: A case control study based on standardised obstetric records. British Journal of Psychiatry 168:556-561.

Kendler, K.S., & Diehl, S.R. (1993). The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophrenia Bulletin 19:261-285.

Lobato, M.I., Belmonte-de-Abreu, P., Knijnik, D., Teruchkin, B., Ghisolfi, E., & Henriques, A. (2001). Neurodevelopmental risk factors in schizophrenia. Brazilian Journal of Medical and Biological Research 34: 155-163.

McNeil, T.F., Cantor-Graae, E., & Ismail, B. (2000). Obstetric complications and congenital malformation in schizophrenia. Brain Research Review 31: 166-178.

Mednick, S.A., Machon, R.A., Huttunen, M.O., & Bonett, D (1988). Adult schizophrenia following prenatal exposure to an influenza epidemic. Archives of General Psychiatry 45:189-192.

Murray, R.M., O'Callaghan, E., Castle, D.J., & Lewis, S.W. (1992). A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 18:319-332.

Noll, R. (2007). Encyclopedia of schizophrenia and other psychotic disorders. 3^rd edition. New York, NY: Facts on File Inc.

Panksepp, J. (2004). Textbook of biological psychiatry. Hoboken, NJ: Wiley-Liss Inc.

schizophrenia.com (n.d.). Heredity and the genetics of schizophrenia. Retrieved  from http://www.schizophrenia.com/research/hereditygen.htm

Selemon, L.D., & Goldman-Rakic, P.S. (1999).The reduced neuropil hypothesis: A circuit based model of schizophrenia. Biological Psychiatry 45[1]:17-25.

Susser, E.S., Brown, A.S., & Gorman, J.M. (1999). Prenatal exposures in schizophrenia. Washington DC: American Psychiatric Press.

Thackery, E. & Harris, M. (eds.) (2002). Encyclopedia of mental disorders. Farmington Mills, MI; Gale Group.

Weinberger, D.R., Berman, K.F., & Zec, R.F. (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Archives of General Psychiatry 43[2]:114-124.