Causes of schizophrenia


Causes of schizophrenia

Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction. A person experiencing schizophrenia is typically characterized as demonstrating disorganized thought and language, and as experiencing delusions or hallucinations, in particular auditory hallucinations.American Psychiatric Association (2000) "Diagnostic and Statistical Manual of Mental Disorders, 4th Edition TR" Washington, DC: American Psychiatric Association.]

The causes of schizophrenia have been the subject of much debate over many decades with various factors proposed and discounted. Studies suggest that genetics, prenatal development, early environment, neurobiology and psychological and social processes are important contributory factors. Current psychiatric research into the development of the disorder is often based on a neurodevelopmental model. In the absence of a confirmed specific pathology underlying the diagnosis, some question the legitimacy of schizophrenia's status as a disease. Furthermore, some propose that the perceptions and feelings involved are meaningful and do not necessarily involve impairment.

Although no common cause of schizophrenia has been identified in all individuals diagnosed with the condition, currently most researchers and clinicians believe it results from a combination of both brain vulnerabilities (either inherited or acquired) and life events. This widely-adopted approach is known as the 'stress-vulnerability' model, and much scientific debate now focuses on how much each of these factors contributes to the development and maintenance of schizophrenia. Schizophrenia is most commonly first diagnosed during late adolescence or early adulthood suggesting it is often the end process of childhood and adolescent development. There is on average a somewhat earlier onset for men than women, with the possible influence of the female hormone oestrogen being one hypothesis and sociocultural influences another.Fact|date=August 2008

Genes

While the reliability of the schizophrenia diagnosis introduces difficulties in measuring the effect of genes (for example, symptoms overlap to some extent with severe bipolar disorder or major depression), evidence suggests that genetic vulnerability and environmental factors can act in combination to result in diagnosis of schizophrenia.cite journal |author=Harrison PJ, Owen MJ |title=Genes for schizophrenia? Recent findings and their pathophysiological implications |journal=Lancet |volume=361 |issue=9355 |pages=417–9 |year=2003 |month=Feb |pmid=12573388 |doi=10.1016/S0140-6736(03)12379-3 |url=] Schizophrenia is likely to be a diagnosis of complex inheritance. Thus, it is likely that several genes interact to generate risk for schizophrenia or for the separate components that can co-occur to lead to a diagnosis.cite journal |author=Owen MJ, Craddock N, O'Donovan MC |title=Schizophrenia: genes at last? |journal=Trends Genet. |volume=21 |issue=9 |pages=518–25 |year=2005 |month=Sep |pmid=16009449 |doi=10.1016/j.tig.2005.06.011 |url=] This, combined with disagreements over which research methods are best, or how data from genetic research should be interpreted, has led to differing estimates over genetic contribution.

Both individual twin studies and meta-analyses of twin studies estimate the heritability of risk for schizophrenia to be approximately 80% (this refers to the proportion of variation between individuals in a population that is influenced by genetic factors, not the degree of genetic determination of individual risk). Adoption studies have also indicated a somewhat increased risk in those with a parent with schizophrenia even when raised apart. Studies suggest that the phenotype is genetically influenced but not genetically determined; that the variants in genes are generally within the range of normal human variation and have low risk associated with them each individually; and that some interact with each other and with environmental risk factors; and that they may not be specific to schizophrenia. Some twin studiescite journal |author=Koskenvuo M, Langinvainio H, Kaprio J, Lönnqvist J, Tienari P |title=Psychiatric hospitalization in twins |journal=Acta Genet Med Gemellol (Roma) |volume=33 |issue=2 |pages=321–32 |year=1984 |pmid=6540965 |doi= |url=] cite journal |author=Hoeffer A, Pollin W |title=Schizophrenia in the NAS-NRC panel of 15,909 veteran twin pairs |journal=Arch. Gen. Psychiatry |volume=23 |issue=5 |pages=469–77 |year=1970 |month=Nov |pmid=5478575 |doi= |url=] have found rates as low as 11.0%–13.8% among monozygotic twins, and 1.8%–4.1% among dizygotic twins, however. In addition, some scientists criticize the methodology of the twin studies, and have argued that the genetic basis of schizophrenia is still largely unknown or open to different interpretations.Fact|date=August 2008

There is currently a great deal of effort being put into molecular genetic studies of schizophrenia, which attempt to identify specific genes which may increase risk. Because of this, the genes that are thought to be most involved can change as new evidence is gathered. A 2003 review of linkage studies listed seven genes as likely to increase risk for a later diagnosis of the disorder. Two more recent reviewscite journal |author=Riley B, Kendler KS |title=Molecular genetic studies of schizophrenia |journal=Eur. J. Hum. Genet. |volume=14 |issue=6 |pages=669–80 |year=2006 |month=Jun |pmid=16721403 |doi=10.1038/sj.ejhg.5201571 |url=] have suggested that the evidence is currently strongest for two genes known as dysbindin ("DTNBP1") and neuregulin (NRG1), with a number of other genes (such as "COMT", "RGS4", "PPP3CC", "ZDHHC8", "DISC1, and "AKT1") showing some early promising results that have not yet been fully replicated.Variations near the gene "FXYD6" have been associated with schizophrenia in the UK [ [http://www.schizophreniaforum.org/new/detail.asp?id=1326 Getting Crowded on Chromosome 11q22—Make Way for Phosphohippolin.] Schizophrenia Research Forum, 14 March 2007. Retrieved on 2007-05-16] [cite journal |author=Choudhury K, McQuillin A, Puri V, "et al" |title=A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia |journal=Am. J. Hum. Genet. |volume=80 |issue=4 |pages=664–72 |year=2007 |month=Apr |pmid=17357072 |pmc=1852702 |doi=10.1086/513475 |url=] but not in Japan. [cite journal |author=Ito Y, Nakamura Y, Takahashi N, "et al" |title=A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population |journal=Neurosci. Lett. |volume=438 |issue=1 |pages=70–5 |year=2008 |month=Jun |pmid=18455306 |doi=10.1016/j.neulet.2008.04.010 |url=] In 2008, rs7341475 SNP of the reelin gene was associated with an increased risk of schizophrenia in women, but not in men.This female-specific association was replicated in several populations.cite journal
author=Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O'Donovan M, O'Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A
title=Genome-Wide Association Identifies a Common Variant in the Reelin Gene That Increases the Risk of Schizophrenia Only in Women
journal = PLoS Genetics
volume=4
issue=2
pages=e28
year=2008
pmid=18282107
doi=10.1371/journal.pgen.0040028
]

Recent research has suggested that a greater than average number of rare deletions or duplications of tiny DNA sequences within genes (known as copy number variants) are linked to increased risk for schizophrenia, especially in those "sporadic" cases not linked to family history of schizophrenia, and that the genetic factors and developmental pathways can thus be different in different individuals.cite journal
author=Walsh T |coauthors=McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J |title=Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia |journal=Science |volume=320 |issue=5875 |pages=539–43 |year=2008 |month=Apr |pmid=18369103 |doi=10.1126/science.1155174
url=http://www.sciencemag.org/cgi/content/abstract/320/5875/539
] [cite journal |author=Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M |title=Strong association of de novo copy number mutations with sporadic schizophrenia |journal=Nat. Genet. |volume=40 |issue=7 |pages=880–5 |year=2008 |month=Jul |pmid=18511947 |doi=10.1038/ng.162 |url=]

The largest most comprehensive genetic study of its kind, involving tests of several hundred single nucleotide polymorphisms (SNPs) in nearly 1,900 individuals with schizophrenia or schizoaffective disorder and 2,000 comparison subjects, has reported no significant association between the disorders and any of 14 previously identified candidate genes ("RGS4", "DISC1", "DTNBP1", "STX7", "TAAR6","PPP3CC", "NRG1", "DRD2", "HTR2A", "DAOA", "AKT1", "CHRNA7", "COMT", and "ARVCF").The statistical distributions suggested nothing more than chance variation. The authors concluded that the findings make it unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects could not be ruled out. [Cite journal
author = Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C et al.
url = http://ajp.psychiatryonline.org/cgi/content/abstract/165/4/497
title = No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics.
journal = American Journal of Psychiatry
year = 2008
month = Apr
volume = 165
issue = 4
pages = 497–506
doi = 10.1176/appi.ajp.2007.07101573
pmid = 18198266
Comment:
* Cite journal
author = S. P. Hamilton
url = http://ajp.psychiatryonline.org/cgi/content/full/165/4/420
title = Schizophrenia candidate genes: are we really coming up blank?
journal = American Journal of Psychiatry
year = 2008
month = Apr
volume = 165
issue = 4
pages = 420–3
doi = 10.1176/appi.ajp.2008.08020218
pmid = 18381911
]

Obstetric events

It is well established that obstetric complications or events are associated with an increased chance of the child later developing schizophrenia, although overall they constitute a non-specific risk factor with a relatively small effect. Obstetric complications occur in approximately 25 to 30% of the general population and the vast majority do not develop schizophrenia, and likewise the majority of individuals with schizophrenia have not had a detectable obstetric event. Nevertheless, the increased average risk is well-replicated, and such events may moderate the effects of genetic or other environmental risk factors. The specific complications or events most linked to schizophrenia, and the mechanisms of their effects, are still under examination.cite journal |author=Clarke MC, Harley M, Cannon M |title=The role of obstetric events in schizophrenia |journal=Schizophr Bull |volume=32 |issue=1 |pages=3–8 |year=2006 |month=Jan |pmid=16306181 |doi=10.1093/schbul/sbj028 |url=http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/32/1/3]

One epidemiological finding is that people diagnosed with schizophrenia are more likely to have been born in winter or springcite journal |author=Davies G, Welham J, Chant D, Torrey EF, McGrath J |title=A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia |journal=Schizophr Bull |volume=29 |issue=3 |pages=587–93 |year=2003 |pmid=14609251 |doi= |url=http://schizophreniabulletin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14609251] (at least in the northern hemisphere). However, the effect is not large. Explanations have included a greater prevalence of viral infections at that time, or a greater likelihood of vitamin D deficiency. A similar effect (increased likelihood of being born in winter and spring) has also been found with other, healthy populations, such as chess players. [cite journal |author=Gobet F, Chassy P |title=Season of birth and chess expertise |journal=J Biosoc Sci |volume=40 |issue=2 |pages=313–6 |year=2008 |month=Mar |pmid=18335581 |doi= 10.1017/S0021932007002222|url=http://bura.brunel.ac.uk/bitstream/2438/736/1/Seasonality+and+chess.pdfPDF (65.8 KiB)] Women who were pregnant during the Dutch famine of 1944, where many people were close to starvation (experiencing malnutrition) had a higher chance of having a child who would later develop schizophrenia.cite journal |author=Susser E, Neugebauer R, Hoek HW, "et al" |title=Schizophrenia after prenatal famine. Further evidence |journal=Arch. Gen. Psychiatry |volume=53 |issue=1 |pages=25–31 |year=1996 |month=Jan |pmid=8540774 |doi= |url=] Studies of Finnish mothers who were pregnant when they found out that their husbands had been killed during the Winter War of 1939–1940 have shown that their children were significantly more likely to develop schizophrenia when compared with mothers who found out about their husbands' death after pregnancy, suggesting that maternal stress may have an effect.cite journal |author=Huttunen MO, Niskanen P |title=Prenatal loss of father and psychiatric disorders |journal=Arch. Gen. Psychiatry |volume=35 |issue=4 |pages=429–31 |year=1978 |month=Apr |pmid=727894 |doi= |url=]

Fetal growth

Lower than average birth weight has been one of the most consistent findings, indicating slowed fetal growth possibly mediated by genetic effects. Almost any factor adversely affecting the fetus will affect growth rate, however, so the association has been described as not particularly informative regarding causation. In addition, the majority of birth cohort studies have failed to find a link between schizophrenia and low birth weight or other signs of growth retardation.

Animal models have suggested links between intrauterine growth restriction and specific neurological abnormalities similar to those that may be involved in the development of schizophrenia, including ventricular enlargement and reduced hippocampal volume in guinea pigs. [cite journal |author=Mallard EC, Rehn A, Rees S, Tolcos M, Copolov D |title=Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia |journal=Schizophr. Res. |volume=40 |issue=1 |pages=11–21 |year=1999 |month=Nov |pmid=10541002 |doi= 10.1016/S0920-9964(99)00041-9|url=http://linkinghub.elsevier.com/retrieve/pii/S0920-9964(99)00041-9]

Hypoxia

It has been hypothesized since the 1970s that brain hypoxia (low oxygen levels) before, at or immediately after birth may be a risk factor for the development of schizophrenia. [cite journal |author=Handford HA |title=Brain hypoxia, minimal brain dysfunction, and schizophrenia |journal=Am J Psychiatry |volume=132 |issue=2 |pages=192–4 |year=1975 |month=Feb |pmid=1111324 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=1111324] [The above reference is cited in a 2006 work, in giving a history of minimal brain dysfunction saying: "It was also noted that individuals who experienced perinatal brain hypoxia constituted a population at risk for minimal brain dysfunction, and that children attending psychiatric clinics often presented with illnesses or perinatal complications of a sort known to be associated with neurological brain damage (Handford 1975)."Disorganized Children : A Guide for Parents and Professionals Jessica Kingsley Publishers Ltd. Stein, Samuel M.p135] This has been recently described as one of the most important of the external factors that influence susceptability, although studies have been mainly epidemiological. Fetal hypoxia, in the presence of certain unidentified genes, has been correlated with reduced volume of the hippocampus, which is in turn correlated with schizophrenia.cite journal |author=Van Erp TG, Saleh PA, Rosso IM, "et al" |title=Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers |journal=The American journal of psychiatry |volume=159 |issue=9 |pages=1514–20 |year=2002 |month=Sep |pmid=12202271 |doi= |url=http://ajp.psychiatryonline.org/cgi/content/full/159/9/1514] Although most studies have interpreted hypoxia as causing some form of neuronal dysfunction or even subtle damage, it has been suggested that the physiological hypoxia that prevails in normal embryonic and fetal development, or pathological hypoxia or ischemia, may exert an effect by regulating or dysregulating genes involved in neurodevelopment. A literature review judged that over 50% of the candidate genes for susceptibility to schizophrenia met criteria for "ischemia–hypoxia regulation and/or vascular expression".cite journal |author=Schmidt-Kastner R, van Os J, W M Steinbusch H, Schmitz C |title=Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia |journal=Schizophrenia research |volume=84 |issue=2-3 |pages=253–71 |year=2006 |month=Jun |pmid=16632332 |doi=10.1016/j.schres.2006.02.022 |url=http://linkinghub.elsevier.com/retrieve/pii/S0920996406001113]

A longitudinal study found that obstetric complications involving hypoxia were one factor associated with neurodevelopmental impairments in childhood and with the later development of schizophreniform disorders. Fetal hypoxia has been found to predict unusual movements at age 4 (but not age 7) among children who go on to develop schizophrenia, suggesting that its effects are specific to the stage of neurodevelopment.cite journal |author=Rosso IM, Bearden CE, Hollister JM, "et al" |title=Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study |journal=Schizophr Bull |volume=26 |issue=2 |pages=367–78 |year=2000 |pmid=10885637 |doi= |url=http://schizophreniabulletin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10885637] A Japanese case study of monozygotic twins discordant for schizophrenia (one has the diagnosis while the other does not) draws attention to their different weights at birth and concludes hypoxia may be the differentiating factor. [cite journal |author=Kunugi H, Urushibara T, Murray RM, Nanko S, Hirose T |title=Prenatal underdevelopment and schizophrenia: a case report of monozygotic twins |journal=Psychiatry Clin. Neurosci. |volume=57 |issue=3 |pages=271–4 |year=2003 |month=Jun |pmid=12753566 |doi= 10.1046/j.1440-1819.2003.01116.x|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1323-1316&date=2003&volume=57&issue=3&spage=271] The unusual functional laterality in speech production (e.g. right hemisphere auditory processing) found in some individuals with schizophrenia could be due to aberrant neural networks established as a compensation for left temporal lobe damage induced by pre- or perinatal hypoxia. [cite journal |author=Murray RM, Fearon P |title=The developmental 'risk factor' model of schizophrenia |journal=J Psychiatr Res |volume=33 |issue=6 |pages=497–9 |year=1999 |pmid=10628525 |doi= 10.1016/S0022-3956(99)00032-1|url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3956(99)00032-1] Prenatal and perinatal hypoxia appears to be important as one factor in the neurodevelopmental model, with the important implication that some forms of schizophrenia may thus be preventable. [cite journal |author=Cannon M, Murray RM |title=Neonatal origins of schizophrenia |journal=Arch. Dis. Child. |volume=78 |issue=1 |pages=1–3 |year=1998 |month=Jan |pmid=9534666 |pmc=1717442 |doi= |url=http://adc.bmj.com/cgi/pmidlookup?view=long&pmid=9534666]

Research on rodents seeking to understand the possible role of prenatal hypoxia in disorders such as schizophrenia has indicated that it can lead to a range of sensorimotor and learning/memory abnormalities. Impairments in motor function and coordination, evident on challenging tasks when the hypoxia was severe enough to cause brain damage, were long-lasting and described as a "hallmark of prenatal hypoxia". [cite journal |author=Golan H, Huleihel M |title=The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent models |journal=Developmental science |volume=9 |issue=4 |pages=338–49 |year=2006 |month=Jul |pmid=16764607 |doi=10.1111/j.1467-7687.2006.00498.x |url=http://www3.interscience.wiley.com/journal/118633736/abstract?CRETRY=1&SRETRY=0] [cite journal |author=Golan H, Kashtutsky I, Hallak M, Sorokin Y, Huleihel M |title=Maternal hypoxia during pregnancy delays the development of motor reflexes in newborn mice |journal=Developmental neuroscience |volume=26 |issue=1 |pages=24–9 |year=2004 |pmid=15509895 |doi=10.1159/000080708 |url=] Several animal studies have indicated that fetal hypoxia can affect many of the same neural substrates implicated in schizophrenia, depending on the severity and duration of the hypoxic event as well as the period of gestation, and in humans moderate or severe (but not mild) fetal hypoxia has been linked to a series of motor, language and cognitive deficits in children, regardless of genetic liability to schizophrenia. [Ellman, LM and Cannon TD, "Chapter 7. [http://books.google.com.au/books?id=jAx9HFFaLGIC&pg=PA69&dq=fetal+hypoxia+schizophrenia+motor&ei=r0KzSK_xNpHcsgOgsdXqBA&sig=ACfU3U3nca_RhDA2VgUNfP4lOULUIm7R_w Environmental pre- and preinatal influences in etiology"] in Clinical Handbook of Schizophrenia by Kim T. Mueser, Dilip V. Jeste New York : Guilford Press, ©2008 p69]

Whereas most studies find only a modest effect of hypoxia in schizophrenia, a longitudinal study using a combination of indicators to detect possible fetal hypoxia, such as early equivalents of Neurological Soft Signs or obstetric complications, reported that the risk of schizophrenia and other nonaffective psychoses was "strikingly elevated" (5.75% versus 0.39%). [cite journal |author=Zornberg GL, Buka SL, Tsuang MT |title=Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: a 19-year longitudinal study |journal=The American journal of psychiatry |volume=157 |issue=2 |pages=196–202 |year=2000 |month=Feb |pmid=10671387 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=10671387]

Other factors

There is an emerging literature on a wide range of prenatal risk factors, such as prenatal stress, intrauterine (in the womb) malnutrition, and prenatal infection. Increased parental age has been linked, possibly due to prenatal complications increasing the risk of genetic mutations. Maternal-fetal rhesus or genotype incompatibility has also been linked, via increasing the risk of an adverse prenatal environment. And, in mothers with schizophrenia, an increased risk has been identified via a complex interaction between maternal genotype, maternal behavior, prenatal environment and possibly medication and socioeconomic factors.

Infections

Numerous viral infections, in utero or in childhood, have been associated with an increased risk of later developing schizophrenia. [cite journal |author=Brown AS |title=The risk for schizophrenia from childhood and adult infections |journal=The American journal of psychiatry |volume=165 |issue=1 |pages=7–10 |year=2008 |month=Jan |pmid=18178749 |doi=10.1176/appi.ajp.2007.07101637 |url=http://ajp.psychiatryonline.org/cgi/content/full/ajp;165/1/7] Schizophrenia is somewhat more common in those born in winter to early spring, when infections are more common. [cite journal |author=Torrey EF, Miller J, Rawlings R, Yolken RH |title=Seasonality of births in schizophrenia and bipolar disorder: a review of the literature |journal=Schizophrenia research |volume=28 |issue=1 |pages=1–38 |year=1997 |month=Nov |pmid=9428062 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0920-9964(97)00092-3]

Influenza has long been studied as a possible factor. A 1988 study found that individuals who were exposed to the Asian flu as second trimester fetuses were at increased risk of eventually developing schizophrenia. [cite journal |author=Mednick SA, Machon RA, Huttunen MO, Bonett D |title=Adult schizophrenia following prenatal exposure to an influenza epidemic |journal=Archives of general psychiatry |volume=45 |issue=2 |pages=189–92 |year=1988 |month=Feb |pmid=3337616 |doi= |url=] This result was corroborated by a later British study of the same pandemic, [cite journal |author=Cooper SJ |title=Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic |journal=The British journal of psychiatry|volume=161 |issue= |pages=394–6 |year=1992 |month=Sep |pmid=1393310 |doi= |url=] , but not by a 1994 study of the pandemic in Croatia. [cite journal |author=Erlenmeyer-Kimling L, Folnegović Z, Hrabak-Zerjavić V, Borcić B, Folnegović-Smalc V, Susser E |title=Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia |journal=The American journal of psychiatry |volume=151 |issue=10 |pages=1496–8 |year=1994 |month=Oct |pmid=8092342 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=8092342] A Japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic. [cite journal |author=Mino Y, Oshima I, Tsuda T, Okagami K |title=No relationship between schizophrenic birth and influenza epidemics in Japan |journal=J Psychiatr Res |volume=34 |issue=2 |pages=133–8 |year=2000 |pmid=10758255 |doi= 10.1016/S0022-3956(00)00003-0|url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3956(00)00003-0]

Polio, measles, varicella-zoster, rubella, herpes simplex virus type 2, maternal genital infections, and more recently "Toxoplasma gondii", have been correlated with the later development of schizophrenia.cite journal |author=Mortensen PB, Nørgaard-Pedersen B, Waltoft BL, Sørensen TL, Hougaard D, Yolken RH |title=Early infections of Toxoplasma gondii and the later development of schizophrenia |journal=Schizophr Bull |volume=33 |issue=3 |pages=741–4 |year=2007 |month=May |pmid=17329231 |doi=10.1093/schbul/sbm009 |url=http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/3/741] However, studies of postmortem brain tissue have reported equivocal or negative results, including no evidence of herpesvirus or T. Gondii DNA in schizophrenia in a recent study. [cite journal |author=Conejero-Goldberg C, Torrey EF, Yolken RH |title=Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients |journal=Schizophr. Res. |volume=60 |issue=1 |pages=65–9 |year=2003 |month=Mar |pmid=12505139 |doi= 10.1016/S0920-9964(02)00160-3|url=http://linkinghub.elsevier.com/retrieve/pii/S0920996402001603]

Psychiatrists E. Fuller Torrey and R.H. Yolken have hypothesized that the common parasite "Toxoplasma gondii" contributes to some if not many cases of schizophrenia.cite journal |author=Torrey EF, Yolken RH |title=Toxoplasma gondii and schizophrenia |journal=Emerging Infect. Dis. |volume=9 |issue=11 |pages=1375–80 |year=2003 |month=Nov |pmid=14725265 |doi= |url=http://www.cdc.gov/ncidod/EID/vol9no11/03-0143.htm ] Studies have tended to find moderately higher levels of Toxoplasma antibodies in those with schizophrenia [cite journal |author=Torrey EF, Bartko JJ, Lun ZR, Yolken RH |title=Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis |journal=Schizophr Bull |volume=33 |issue=3 |pages=729–36 |year=2007 |month=May |pmid=17085743 |doi=10.1093/schbul/sbl050 |url=] [cite journal |author=Wang HL, Wang GH, Li QY, Shu C, Jiang MS, Guo Y |title=Prevalence of Toxoplasma infection in first-episode schizophrenia and comparison between Toxoplasma-seropositive and Toxoplasma-seronegative schizophrenia |journal=Acta Psychiatr Scand |volume=114 |issue=1 |pages=40–8 |year=2006 |month=Jul |pmid=16774660 |doi=10.1111/j.1600-0447.2006.00780.x |url=] and possibly higher rates of prenatal or early postnatal exposure to "Toxoplasma gondii", but not to acute infection. Causal mechanisms remain speculative.

There is some evidence for the role of autoimmunity in the development of some cases of schizophrenia. A statistical correlation has been reported with various autoimmune diseasescite journal |author=Eaton WW, Byrne M, Ewald H, "et al" |title=Association of schizophrenia and autoimmune diseases: linkage of Danish national registers |journal=Am J Psychiatry |volume=163 |issue=3 |pages=521–8 |year=2006 |month=Mar |pmid=16513876 |doi=10.1176/appi.ajp.163.3.521 |url=] and direct studies have linked dysfunctional immune status to some of the clinical features of schizophrenia.cite journal |author=Jones AL, Mowry BJ, Pender MP, Greer JM |title=Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? |journal=Immunol. Cell Biol. |volume=83 |issue=1 |pages=9–17 |year=2005 |month=Feb |pmid=15661036 |doi=10.1111/j.1440-1711.2005.01305.x |url=] cite journal |author=Strous RD, Shoenfeld Y |title=Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited |journal=J. Autoimmun. |volume=27 |issue=2 |pages=71–80 |year=2006 |month=Sep |pmid=16997531 |doi=10.1016/j.jaut.2006.07.006 |url=]

Childhood antecedents

In general, the antecedents of schizophrenia are subtle and those who will go on to develop schizophrenia do not form a readily identifiable subgroup. Average group differences from the norm may be in the direction of superior as well as inferior performance. Overall, birth cohort studies have indicated subtle nonspecific behavioral features, some evidence for psychotic-like experiences (particularly hallucinations), and various cognitive antecedents. There have been some inconsistencies in the particular domains of functioning identified and whether they continue through childhood and whether they are specific to schizophrenia.cite journal |author=Welham J, Isohanni M, Jones P, McGrath J |title=The Antecedents of Schizophrenia: A Review of Birth Cohort Studies |journal=Schizophr Bull |volume= |issue= |pages= |year=2008 |month=Jul |pmid=18658128 |doi=10.1093/schbul/sbn084 |url=]

A prospective study found average diffferences across a range of developmental domains, including reaching milestones of motor development at a later age, having more speech problems, lower educational test results, solitary play preferences at ages four and six, and being more socially anxious at age 13. Lower ratings of the mother's skills and understanding of the child at age 4 were also related. [cite journal |author=Jones P, Rodgers B, Murray R, Marmot M |title=Child development risk factors for adult schizophrenia in the British 1946 birth cohort |journal=Lancet |volume=344 |issue=8934 |pages=1398–402 |year=1994 |month=Nov |pmid=7968076 |doi= 10.1016/S0140-6736(94)90569-X|url=]

Some of the early developmental differences were identified in the first year of life in a study in Finland, although generally related to psychotic disorders rather than schizophrenia in particular. [cite journal |author=Isohanni M, Jones PB, Moilanen K, "et al" |title=Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort |journal=Schizophr. Res. |volume=52 |issue=1-2 |pages=1–19 |year=2001 |month=Oct |pmid=11595387 |doi= 10.1016/S0920-9964(00)00179-1|url=http://linkinghub.elsevier.com/retrieve/pii/S0920996400001791] The early subtle motor signs persisted to some extent, showing a small link to later school performance in adolescence. [cite journal |author=Isohanni M, Murray GK, Jokelainen J, Croudace T, Jones PB |title=The persistence of developmental markers in childhood and adolescence and risk for schizophrenic psychoses in adult life. A 34-year follow-up of the Northern Finland 1966 birth cohort |journal=Schizophr. Res. |volume=71 |issue=2-3 |pages=213–25 |year=2004 |month=Dec |pmid=15474893 |doi=10.1016/j.schres.2004.03.008 |url=http://linkinghub.elsevier.com/retrieve/pii/S0920996404001045] An earlier Finnish study found that childhood performance of 400 individuals diagnosed with schizophrenia was significantly worse than controls on subjects involving motor co-ordination (sports and handcrafts) between ages 7 and 9, but there were no differences on academic subjects (contrary to some other IQ findings). [cite journal |author=Cannon M, Jones P, Huttunen MO, Tanskanen A, Murray R |title=Motor Co-ordination Deficits as Predictors of Schizophrenia Among Finnish School Children |journal=Hum. Psychopharmacol. Clin. Exp. |volume=14 |issue=7 |pages=491–7 |year=1999 |doi= 10.1002/(SICI)1099-1077(199910)14:7<491::AID-HUP134>3.0.CO;2-V|url=http://www3.interscience.wiley.com/journal/66002277/abstract] However, reanalysis of the data from the later Finnish study, on older children (14 to 16) in a changed school system, using narrower diagnostic criteria and with less cases but more controls, did not support a significant difference on sports and handicraft performance. [Isohanni, M., Isohanni, I., Nieminen, P., Jokelainen, J. and Järvelin, M.-R., 2000. [http://archpsyc.ama-assn.org/cgi/content/full/57/8/813 School predictors of schizophrenia. Letter to the editor.] Arch. Gen. Psychiatry 57, p. 813.] However, another study found that unusual motor coordination scores at 7 years of age were associated in adulthood with both those with schizophrenia and their unaffected siblings, while unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sibling status.

A birth cohort study in New Zealand found that children who went on to develop schizophreniform disorder had, as well as emotional problems and interpersonal difficulties linked to all adult psychiatric outcomes measured, significant impairments in neuromotor, receptive language, and cognitive development.cite journal |author=Cannon M, Caspi A, Moffitt TE, "et al" |title=Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort |journal=Arch. Gen. Psychiatry |volume=59 |issue=5 |pages=449–56 |year=2002 |month=May |pmid=11982449 |doi= 10.1001/archpsyc.59.5.449|url=http://archpsyc.ama-assn.org/cgi/content/full/59/5/449] A retrospective study found that adults with schizophrenia had performed better than average in artistic subjects at ages 12 and 15, and in linguistic and religious subjects at age 12, but worse than average in gymnastics at age 15. [I. Helling, A. Öhman, C. M. Hultman [http://www3.interscience.wiley.com/journal/118826976/abstract School achievements and schizophrenia: a case–control study] Acta Psychiatrica Scandinavica Volume 108 Issue 5, Pages 381 - 386]

Some small studies on offspring of individuals with schizophrenia have identified various neurobehavioral deficits, [cite journal |author=Hans SL, Marcus J, Nuechterlein KH, Asarnow RF, Styr B, Auerbach JG |title=Neurobehavioral deficits at adolescence in children at risk for schizophrenia: The Jerusalem Infant Development Study |journal=Arch. Gen. Psychiatry |volume=56 |issue=8 |pages=741–8 |year=1999 |month=Aug |pmid=10435609 |doi= 10.1001/archpsyc.56.8.741|url=http://archpsyc.ama-assn.org/cgi/pmidlookup?view=long&pmid=10435609] a poorer family environment and disruptive school behaviour, [cite journal |author=Carter JW, Schulsinger F, Parnas J, Cannon T, Mednick SA |title=A multivariate prediction model of schizophrenia |journal=Schizophr Bull |volume=28 |issue=4 |pages=649–82 |year=2002 |pmid=12795497 |doi= |url=http://schizophreniabulletin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12795497] poor peer engagement, immaturity or unpopularity [cite journal |author=Hans SL, Auerbach JG, Asarnow JR, Styr B, Marcus J |title=Social adjustment of adolescents at risk for schizophrenia: the Jerusalem Infant Development Study |journal=J Am Acad Child Adolesc Psychiatry |volume=39 |issue=11 |pages=1406–14 |year=2000 |month=Nov |pmid=11068896 |doi= 10.1097/00004583-200011000-00015|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0890-8567&volume=39&issue=11&spage=1406] or poorer social competence and increasing schizophrenic symptomology emerging during adolescence. [cite journal |author=Dworkin RH, Bernstein G, Kaplansky LM, "et al" |title=Social competence and positive and negative symptoms: a longitudinal study of children and adolescents at risk for schizophrenia and affective disorder |journal=Am J Psychiatry |volume=148 |issue=9 |pages=1182–8 |year=1991 |month=Sep |pmid=1882996 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=1882996]

A minority "deficit syndrome" subtype of schizophrenia is proposed to be more marked by early poor adjustment and behavioral problems, as compared to non-deficit subtypes. [Galderisi S, Maj M, Mucci A, Cassano GB, Invernizzi G, Rossi A, Vita A, Dell'Osso L, Daneluzzo E, Pini S. (2002) [http://ajp.psychiatryonline.org/cgi/content/full/159/6/983 Historical, psychopathological, neurological, and neuropsychological aspects of deficit schizophrenia: a multicenter study] Am J Psychiatry. 2002 Jun;159(6):983-90.]

Substance use

The relationship between schizophrenia and drug use is complex, meaning that a clear causal connection between drug use and schizophrenia has been difficult to tease apart. There is strong evidence that using certain drugs can trigger either the onset or relapse of schizophrenia in some people. It may also be the case, however, that people with schizophrenia use drugs to overcome negative feelings associated with both the commonly prescribed antipsychotic medication and the condition itself, where negative emotion, paranoia and anhedonia are all considered to be core features.

The rate of substance use is known to be particularly high in this group. In a recent study, 60% of people with schizophrenia were found to use substances and 37% would be diagnosable with a substance use disorder.cite journal |author=Swartz MS, Wagner HR, Swanson JW, "et al" |title=Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study |journal=J. Nerv. Ment. Dis. |volume=194 |issue=3 |pages=164–72 |year=2006 |month=Mar |pmid=16534433 |doi=10.1097/01.nmd.0000202575.79453.6e |url=]

Amphetamines

As amphetamines trigger the release of dopamine and excessive dopamine function is believed to be responsible for many symptoms of schizophrenia (known as the dopamine hypothesis of schizophrenia), amphetamines may worsen schizophrenia symptoms.Fact|date=September 2008

Hallucinogens

Schizophrenia can sometimes be triggered by heavy use of hallucinogenic or stimulant drugs, [cite journal |author=Mueser KT, Yarnold PR, Levinson DF, "et al" |title=Prevalence of substance abuse in schizophrenia: demographic and clinical correlates |journal=Schizophr Bull |volume=16 |issue=1 |pages=31–56 |year=1990 |pmid=2333480 |doi= |url=http://schizophreniabulletin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2333480] although some claim that a predisposition towards developing schizophrenia is needed for this to occur. There is also some evidence suggesting that people suffering schizophrenia but responding to treatment can have relapse because of subsequent drug use.

Drugs such as ketamine, PCP, and LSD have been used to mimic schizophrenia for research purposes. Using LSD and other psychedelics as a model has now fallen out of favor with the scientific research community, as the differences between the drug induced states and the typical presentation of schizophrenia have become clear. The dissociatives ketamine and PCP are still considered to produce states that are remarkably similar however.

Cannabis

There is evidence that cannabis use can contribute to schizophrenia. Some studies suggest that cannabis is neither a sufficient nor necessary factor in developing schizophrenia, but that cannabis may significantly increase the risk of developing schizophrenia and may be, among other things, a significant causal factor. Nevertheless, some previous research in this area has been criticised as it has often not been clear whether cannabis use is a cause or effect of schizophrenia. To address this issue, a recent review of studies from which a causal contribution to schizophrenia can be assessed has suggested that cannabis statistically doubles the risk of developing schizophrenia on the individual level, and may, assuming a causal relationship, be responsible for up to 8% of cases in the population.cite journal |author=Arseneault L, Cannon M, Witton J, Murray RM |title=Causal association between cannabis and psychosis: examination of the evidence |journal=Br J Psychiatry |volume=184 |issue= |pages=110–7 |year=2004 |month=Feb |pmid=14754822 |doi= 10.1192/bjp.184.2.110|url=http://bjp.rcpsych.org/cgi/content/full/184/2/110]

An older longitudinal study, published in 1987, suggested six-fold increase of schizophrenia risks for high consumers of cannabis (use on more than fifty occasions) in Sweden. [cite journal |author=Andréasson S, Allebeck P, Engström A, Rydberg U |title=Cannabis and schizophrenia. A longitudinal study of Swedish conscripts |journal=Lancet |volume=2 |issue=8574 |pages=1483–6 |year=1987 |month=Dec |pmid=2892048 |doi= 10.1016/S0140-6736(87)92620-1|url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(87)92620-1]

Clues from tobacco use

People with schizophrenia tend to smoke significantly more tobacco than the general population. The rates are exceptionally high amongst institutionalized patients and homeless people. In a UK census from 1993, 74% of people with schizophrenia living in institutions were found to be smokers.cite paper | author = McNeill, Ann | title = Smoking and mental health — a review of the literature | publisher = SmokeFree London Programme | date = 2001 | url = http://www.ash.org.uk/html/policy/menlitrev.pdf | format = PDF | accessdate = 2006-12-14 ] cite paper | author = Meltzer H, Gill B, Petticrew M, Hinds K. | title = OPCS Surveys of Psychiatric Morbidity Report 3: Economic Activity and Social Functioning of Adults With Psychiatric Disorders. | publisher = London, Her Majesty’s Stationery Office | date = 1995 [http://www.statistics.gov.uk/STATBASE/Product.asp?vlnk=7993&More=Y Available for fee.] ] A 1999 study that covered all people with schizophrenia in Nithsdale, Scotland found a 58% prevalence rate of cigarette smoking, to compare with 28% in the general population. cite journal | last = Kelly | first = C | coauthors = McCreadie RG | title = Smoking Habits, Current Symptoms, and Premorbid Characteristics of Schizophrenic Patients in Nithsdale, Scotland | journal = The American Journal of Psychiatry | volume = 156 | pages = 1751–1757 | publisher = American Psychiatric Association | date = 1999 | url = http://ajp.psychiatryonline.org/cgi/content/abstract/156/11/1751 | accessdate = 2006-12-14 | pmid = 10553739 ] An older study found that as much as 88% of outpatients with schizophrenia were smokers.cite journal | last = Hughes | first = JR | coauthors = Hatsukami DK, Mitchell JE, Dahlgren LA | title = Prevalence of smoking among psychiatric outpatients | journal = The American Journal of Psychiatry | volume = 143 | pages = 993–997 | publisher = American Psychiatric Association | date = 1986 | url = http://ajp.psychiatryonline.org/cgi/content/abstract/143/8/993 | accessdate = 2006-12-14 |pmid = 3487983]

Despite the higher prevalence of tobacco smoking, people diagnosed with schizophrenia have a much lower than average chance of developing and dying from lung cancer. While the reason for this is unknown, it may be because of a genetic resistance to the cancer, a side-effect of drugs being taken, or a statistical effect of increased likelihood of dying from causes other than lung cancer."Conditions in Occupational Therapy: effect on occupational performance." ed. Ruth A. Hansen and Ben Atchison (Baltimore: Lippincott Williams & Williams, 2000), 54&ndash;74. ISBN 0-683-30417-8]

A recent study of over 50,000 Swedish conscripts found that there was a small but significant protective effect of smoking cigarettes on the risk of developing schizophrenia later in life.cite journal |author=Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingsson T, Lewis G |title=Investigating the association between cigarette smoking and schizophrenia in a cohort study |journal=Am J Psychiatry |volume=160 |issue=12 |pages=2216–21 |year=2003 |month=Dec |pmid=14638593 |doi= 10.1176/appi.ajp.160.12.2216|url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=14638593] While the authors of the study stressed that the risks of smoking far outweigh these minor benefits, this study provides further evidence for the 'self-medication' theory of smoking in schizophrenia and may give clues as to how schizophrenia might develop at the molecular level. Furthermore, many people with schizophrenia have smoked tobacco products long before they are diagnosed with the illness, and some groups advocate that the chemicals in tobacco have actually contributed to the onset of the illness and have no benefit of any kind.Fact|date=September 2008

It is of interest that cigarette smoking affects liver function such that the antipsychotic drugs used to treat schizophrenia are broken down in the blood stream more quickly. This means that smokers with schizophrenia need slightly higher doses of antipsychotic drugs in order for them to be effective than do their non-smoking counterparts.Fact|date=September 2008

The increased rate of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. One possible reason is that smoking produces a short term effect to improve alertness and cognitive functioning in persons who suffer this illness.cite web | last = Compton | first = Michael T. | title = Cigarette Smoking in Individuals with Schizophrenia | publisher = Medscape Psychiatry & Mental Health | date = 2005-11-16 | url = http://www.medscape.com/viewarticle/516304_print | accessdate = 2007-05-17 ] It has been postulated that the mechanism of this effect is that people with schizophrenia have a disturbance of nicotinic receptor functioning which is temporarily abated by tobacco use.

Life experiences

ocial adversity

The chance of developing schizophrenia has been found to increase with the number of adverse social factors (e.g. indicators of socioeconomic disadvantage or social exclusion) present in childhood. [cite journal |author=Wicks S, Hjern A, Gunnell D, Lewis G, Dalman C |title=Social adversity in childhood and the risk of developing psychosis: a national cohort study |journal=The American journal of psychiatry |volume=162 |issue=9 |pages=1652–7 |year=2005 |month=Sep |pmid=16135624 |doi=10.1176/appi.ajp.162.9.1652 |url=http://ajp.psychiatryonline.org/cgi/content/full/162/9/1652] [cite journal |author=Mueser KT, McGurk SR |year=2004 |title=Schizophrenia |journal=The Lancet |volume=363 |issue=9426 |pages=2063–72 |pmid=15207959 |doi=10.1016/S0140-6736(04)16458-1] Stressful life events generally precede the onset of schizophrenia.cite journal |author=Day R, Nielsen JA, Korten A, "et al" |title=Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization |journal=Cult Med Psychiatry |volume=11 |issue=2 |pages=123–205 |year=1987 |month=June |pmid=3595169 |doi= 10.1007/BF00122563|url=] A personal or recent family history of migration is a considerable risk factor for schizophrenia, which has been linked to psychosocial adversity, social defeat from being an outsider, racial discrimination, family dysfunction, unemployment and poor housing conditions.cite journal |author=Selten JP, Cantor-Graae E, Kahn RS |year=2007 |month=Mar |title=Migration and schizophrenia |journal=Current Opinion in Psychiatry |volume=20 |issue=2 |pages=111–115 |pmid=17278906 |url=http://www.co-psychiatry.com/pt/re/copsych/abstract.00001504-200703000-00003.htm |accessdate=2008-07-06 |doi=10.1097/YCO.0b013e328017f68e] [cite journal |author=Cantor-Graae E, Selten JP |title=Schizophrenia and migration: a meta-analysis and review |journal=Am J Psychiatry |volume=162 |issue=1 |pages=12–24 |year=2005 |month=Jan |pmid=15625195 |doi=10.1176/appi.ajp.162.1.12 |url=http://ajp.psychiatryonline.org/cgi/content/full/162/1/12] Childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life. [cite journal |author=MacMillan HL, Fleming JE, Streiner DL, "et al" |title=Childhood abuse and lifetime psychopathology in a community sample |journal=Am J Psychiatry |volume=158 |issue=11 |pages=1878–83 |year=2001 |month=November |pmid=11691695 |doi= 10.1176/appi.ajp.158.11.1878|url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=11691695] [cite journal |author=Schenkel LS, Spaulding WD, DiLillo D, Silverstein SM |title=Histories of childhood maltreatment in schizophrenia: relationships with premorbid functioning, symptomatology, and cognitive deficits |journal=Schizophr. Res. |volume=76 |issue=2-3 |pages=273–86 |year=2005 |month=Jul |pmid=15949659 |doi=10.1016/j.schres.2005.03.003 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TC2-4FWT420-3&_user=10&_coverDate=04%2F08%2F2005&_rdoc=1&_fmt=summary&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a75a0204ebb590104747e8115cddd64a] [cite journal |author=Janssen I, Krabbendam L, Bak M, "et al" |title=Childhood abuse as a risk factor for psychotic experiences |journal=Acta Psychiatr Scand |volume=109 |issue=1 |pages=38–45 |year=2004 |month=Jan |pmid=14674957 |doi= 10.1046/j.0001-690X.2003.00217.x|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0001-690X&date=2004&volume=109&issue=1&spage=38] [cite journal |author=Read J, Perry BD, Moskowitz A, Connolly J |title=The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model |journal=Psychiatry |volume=64 |issue=4 |pages=319–45 |year=2001 |pmid=11822210 |doi= |url=http://www.childtrauma.org/CTAMATERIALS/Psychiatry_02.pdf] Recent large-scale general population studies indicate the relationship is a causal one, with an increasing risk with additional experiences of maltreatment, [cite journal |author=Read J, van Os J, Morrison AP, Ross CA |title=Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications |journal=Acta psychiatrica Scandinavica |volume=112 |issue=5 |pages=330–50 |year=2005 |month=Nov |pmid=16223421 |doi=10.1111/j.1600-0447.2005.00634.x |url=http://www3.interscience.wiley.com/journal/118641029/abstract] although a critical review suggests conceptual and methodological issues require further research. [cite journal |author=Morgan C, Fisher H |title=Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma--a critical review |journal=Schizophrenia bulletin |volume=33 |issue=1 |pages=3–10 |year=2007 |month=Jan |pmid=17105965 |doi=10.1093/schbul/sbl053 |url=http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/1/3] There is some evidence that adversities may lead to cognitive biases and/or altered dopamine neurotransmission, a process that has been termed "sensitization". [cite journal |author=Collip D, Myin-Germeys I, Van Os J |title=Does the concept of "sensitization" provide a plausible mechanism for the putative link between the environment and schizophrenia? |journal=Schizophr Bull |volume=34 |issue=2 |pages=220–5 |year=2008 |month=Mar |pmid=18203757 |doi=10.1093/schbul/sbm163 |url=] Specific social experiences have been linked to specific psychological mechanisms and psychotic experiences in schizophrenia. In addition, structural neuroimaging studies of victims of sexual abuse and other traumas have sometimes reported findings similar to those sometimes found in psychotic patients, such as thinning of the corpus callosum, loss of volume in the anterior cingulate cortex, and reduced hippocampal volume. [cite journal |author=Bentall RP, Fernyhough C |title=Social Predictors of Psychotic Experiences: Specificity and Psychological Mechanisms |journal=Schizophr Bull |volume= |issue= |pages= |year=2008 |month=Aug |pmid=18703667 |doi=10.1093/schbul/sbn103 |url=http://schizophreniabulletin.oxfordjournals.org/cgi/content/abstract/sbn103v1]

Urbanicity

A particularly stable and replicable finding has been the association between living in an urban environment and the development of schizophrenia, even after factors such as drug use, ethnic group and size of social group have been controlled for.cite journal |author=van Os J |title=Does the urban environment cause psychosis? |journal=Br J Psychiatry |volume=184 |issue= |pages=287–8 |year=2004 |month=Apr |pmid=15056569 |doi= 10.1192/bjp.184.4.287|url=http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=15056569] A recent study of 4.4 million men and women in Sweden found an 68%&ndash;77% increased risk of diagnosed psychosis for people living in the most urbanized environments, a significant proportion of which is likely to be described as schizophrenia.cite journal |author=Sundquist K, Frank G, Sundquist J |title=Urbanisation and incidence of psychosis and depression: follow-up study of 4.4 million women and men in Sweden |journal=Br J Psychiatry |volume=184 |issue= |pages=293–8 |year=2004 |month=Apr |pmid=15056572 |doi= 10.1192/bjp.184.4.293|url=http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=15056572] The effect does not appear to be due to a higher incidence of obstetric complications in urban environments. [cite journal |author=Eaton WW, Mortensen PB, Frydenberg M |title=Obstetric factors, urbanization and psychosis |journal=Schizophr. Res. |volume=43 |issue=2-3 |pages=117–23 |year=2000 |month=June |pmid=10858630 |doi= 10.1016/S0920-9964(99)00152-8|url=http://linkinghub.elsevier.com/retrieve/pii/S0920-9964(99)00152-8] The risk increases with the number of years and degree of urban living in childhood and adolescence, suggesting that constant, cumulative, or repeated exposures during upbringing occurring more frequently in urbanized areas are responsible for the association. [cite journal |author=Pedersen CB, Mortensen PB |title=Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk |journal=Arch. Gen. Psychiatry |volume=58 |issue=11 |pages=1039–46 |year=2001 |month=Nov |pmid=11695950 |doi= 10.1001/archpsyc.58.11.1039|url=http://archpsyc.ama-assn.org/cgi/pmidlookup?view=long&pmid=11695950] Various possible explanations for the effect have been judged unlikely based on the nature of the findings, including infectious causes or a generic stress effect. It is thought to interact with genetic dispositions and, since there appears to be nonrandom variation even across different neighborhoods, and an independent association with social isolation, it has been proposed that the degree of "social capital" (e.g. degree of mutual trust, bonding and safety in neighborhoods) can exert a developmental impact on children growing up in these environments. [cite journal |author=Krabbendam L, van Os J |title=Schizophrenia and urbanicity: a major environmental influence—conditional on genetic risk |journal=Schizophr Bull |volume=31 |issue=4 |pages=795–9 |year=2005 |month=October |pmid=16150958 |doi=10.1093/schbul/sbi060 |url=http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/31/4/795#BIB37]

Close relationships

Evidence is consistent that negative attitudes from others increase the risk of schizophrenia relapse, in particular critical comments, hostility, authoritarian, and intrusive or controlling attitudes (termed 'high expressed emotion' by researchers).cite journal |author=Bebbington P, Kuipers L |title=The predictive utility of expressed emotion in schizophrenia: an aggregate analysis |journal=Psychol Med |volume=24 |issue=3 |pages=707–18 |year=1994 |month=August |pmid=7991753 |doi= |url=] Although family members and significant others are not held responsible for schizophrenia - the attitudes, behaviors and interactions of all parties are addressed - unsupportive dysfunctional relationships may also contribute to an increased risk of developing schizophrenia.cite journal |author=Bentall RP |coauthors=Fernyhough C, Morrison AP, Lewis S, Corcoran R |year=2007 |title=Prospects for a cognitive-developmental account of psychotic experiences |journal=Br J Clin Psychol |volume=46 | issue=Pt 2 |pages=155–73 |pmid=17524210 | doi = 10.1348/014466506X123011] [cite journal |author=Subotnik, KL |coauthors=Goldstein, MJ, Nuechterlein, KH, Woo, SM and Mintz, J |year=2002 |title=Are Communication Deviance and Expressed Emotion Related to Family History of Psychiatric Disorders in Schizophrenia? |journal=Schizophrenia Bulletin |volume=28 |issue=4 |pages=719–29 |pmid=12795501]

Neural processes

tructural

Studies have tended to show various subtle average differences in the volume of certain areas of brain structure between people with and without diagnoses of schizophrenia, although it has become increasingly clear that there is no single pathological neuropsychological or structural neuroanatomic profile, due partly to heterogeneity within the disorder.cite journal |author=Flashman LA, Green MF |title=Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment |journal=Psychiatr. Clin. North Am. |volume=27 |issue=1 |pages=1–18, vii |year=2004 |month=Mar |pmid=15062627 |doi=10.1016/S0193-953X(03)00105-9 |url=] The most consistent volumetric findings are (first-onset patient vs control group averages), slightly less grey matter volume and slightly increased ventricular volume in certain areas of the brain. The two findings are thought to be linked. Although the differences are found in first-episode cases, grey matter volumes are partly a result of life experiences, drugs and malnutrition etc, so the exact role in the disorder is unclear. In addition, ventricle volumes are amongst the mostly highly variable and environmentally-influenced aspects of brain structure, and the percentage difference in group averages in schizophrenia studies has been described as "not a very profound difference in the context of normal variation." [cite journal |author=Allen JS, Damasio H, Grabowski TJ |title=Normal neuroanatomical variation in the human brain: an MRI-volumetric study |journal=American journal of physical anthropology |volume=118 |issue=4 |pages=341–58 |year=2002 |month=August |pmid=12124914 |doi=10.1002/ajpa.10092 |url=] A slightly smaller than average whole-brain volume has also been also been found, and slightly smaller hippocampal volume in terms of group averages. These differences may be present from birth or develop later, and there is substantial variation between individuals.cite journal |author=Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA |title=Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies |journal=Br J Psychiatry |volume=188 |issue= |pages=510–8 |year=2006 |month=June |pmid=16738340 |doi=10.1192/bjp.188.6.510 |url=]

Most schizophrenia studies have found average reduced volume of the left medial temporal lobe and left superior temporal gyrus, and half of studies have revealed deficits in certain areas of the frontal gyrus, parahippocampal gyrus and temporal gyrus. [cite journal |author=Honea R, Crow TJ, Passingham D, Mackay CE |title=Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies |journal=American Journal of Psychiatry |volume=162 |issue=12 |pages=2233–45 |year=2005 |month=Dec |pmid=16330585 |doi=10.1176/appi.ajp.162.12.2233 |url=http://ajp.psychiatryonline.org/cgi/content/full/162/12/2233] However, at variance with some findings in individuals with chronic schizophrenia (where use of antipsychotics and other factors may have a confounding effect), significant group differences of temporal lobe and amygdala volumes are not shown in first-episode patients on average. [cite journal |author=Vita A, De Peri L, Silenzi C, Dieci M |title=Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies |journal=Schizophrenia Research |volume=82 |issue=1 |pages=75–88 |year=2006 |month=February |pmid=16377156 |doi=10.1016/j.schres.2005.11.004 |url=] The neurobiological abnormalities are so varied that no single abnormality is observed across the entire group of people with DSM-IV–defined schizophrenia. In addition, it remains unclear whether the structural differences are unique to schizophrenia or cut across the traditional diagnostic boundaries between schizophrenia and affective disorders - though perhaps being unique to conditions with psychotic features.cite journal |author=Prasad KM, Keshavan MS |title=Structural cerebral variations as useful endophenotypes in schizophrenia: do they help construct "extended endophenotypes"? |journal=Schizophrenia Bulletin |volume=34 |issue=4 |pages=774–90 |year=2008 |month=July |pmid=18408230 |doi=10.1093/schbul/sbn017]

Studies of the rare childhood-onset schizophrenia (before age 13) indicate a greater-than-normal loss of grey matter over several years, progressing from the back of the brain to the front, levelling out in early adulthood. Such a pattern of "pruning" occurs as part of normal brain development but appears to be exaggerated in childhood-onset psychotic disorders, particularly in schizophrenia. Abnormalities in the volume of the ventricles or frontal lobes have also been found in some studies, but not in others. Volume changes are most likely glial and vascular rather than purely neuronal, and reduction in grey matter may primarily reflect a reduction of neuropil rather than a deficit in the total number of neurons. Other studies, especially some computational studies, have shown that a reduction in the number of neurons can cause psychotic symptoms [cite journal |author=Hoffman R, McGlashan T |title=Neural network models of schizophrenia. |journal=Neuroscientist |volume=7 |issue=5 |pages=441–54 |year=2001 |month=Oct |pmid=11597103 |url=] . Studies to date have been based on small numbers of the most severe and treatment-resistant patients taking antipsychotics. [cite journal |author=Arango C, Moreno C, Martínez S, "et al" |title=Longitudinal brain changes in early-onset psychosis |journal=Schizophrenia Bulletin |volume=34 |issue=2 |pages=341–53 |year=2008 |month=Mar |pmid=18234701 |doi=10.1093/schbul/sbm157]

Functional

Some studies using neuropsychological tests and brain imaging technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes.cite book |author=Green, Michael |title=Schizophrenia revealed: from neurons to social interactions |publisher=Norton |location=New York |year=2001 |pages= |isbn=0-393-70334-7 |oclc= |doi= |accessdate=] Abnormalities of the kind shown are linked to the same neurocognitive deficits often associated with schizophrenia, particularly in areas of memory, [cite journal |author=Park S, Holzman PS |title=Schizophrenics show spatial working memory deficits |journal=Arch. Gen. Psychiatry |volume=49 |issue=12 |pages=975–82 |year=1992 |month=Dec |pmid=1449384 |doi= |url=] attention, problem solving, executive function, and social cognition.Fact|date=January 2008 Observations of the frontal lobe in patients with schizophrenia are inconsistent: While many studies have found abnormalities, others have found no [cite journal |author=Wible CG, Shenton ME, Hokama H, "et al" |title=Prefrontal cortex and schizophrenia. A quantitative magnetic resonance imaging study |journal=Arch. Gen. Psychiatry |volume=52 |issue=4 |pages=279–88 |year=1995 |month=April |pmid=7702444 |doi= |url=] or only a statistically insignificant [cite journal |author=Selemon LD, Rajkowska G, Goldman-Rakic PS |title=Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method |journal=J. Comp. Neurol. |volume=392 |issue=3 |pages=402–12 |year=1998 |month=Mar |pmid=9511926|doi=10.1002/(SICI)1096-9861(19980316)392:3<402::AID-CNE9>3.0.CO;2-5] difference. Data from a PET studycite journal |author=Meyer-Lindenberg A, Miletich RS, Kohn PD, "et al" |title=Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia |journal=Nat. Neurosci. |volume=5 |issue=3 |pages=267–71 |year=2002 |month=March |pmid=11865311 |doi=10.1038/nn804 |url=] suggests that the less the frontal lobes are activated during a working memory task, the greater the increase in abnormal dopamine activity in the striatum, thought to be related to the neurocognitive deficits in schizophrenia.

Electroencephalograph (EEG) recordings of persons with schizophrenia performing perception oriented tasks showed an absence of gamma band activity in the brain, indicating weak integration of critical neural networks in the brain.cite journal |author=Spencer KM, Nestor PG, Perlmutter R, "et al" |title=Neural synchrony indexes disordered perception and cognition in schizophrenia |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=49 |pages=17288–93 |year=2004 |month=Dec |pmid=15546988 |pmc=535363 |doi=10.1073/pnas.0406074101 |url=] Those who experienced intense hallucinations, delusions and disorganized thinking showed the lowest frequency synchronization. None of the drugs taken by the persons scanned had moved neural synchrony back into the gamma frequency range. Gamma band and working memory alterations may be related to alterations in interneurons that produce the neurotransmitter GABA.

Dopamine

Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. An influential theory, known as the "dopamine hypothesis of schizophrenia", proposed that a malfunction involving dopamine pathways was therefore the cause of (the positive symptoms of) schizophrenia. Evidence for this theory includes [Stefan, Martin (2002). "An Atlas of Schizophrenia", p. 54] findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors; [cite journal |author=Creese I, Burt DR, Snyder SH |title=Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs |journal=Science (journal) |volume=192 |issue=4238 |pages=481–3 |year=1976 |month=April |pmid=3854 |doi= |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=3854] and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia; [Angrist B, van Kammen DP (1984). "CNS stimulants as a tool in the study of schizophrenia," "Trends in Neurosciences", 7:388–90] [cite journal |author=Lieberman JA, Kane JM, Alvir J |title=Provocative tests with psychostimulant drugs in schizophrenia |journal=Psychopharmacology (Berl.) |volume=91 |issue=4 |pages=415–33 |year=1987 |pmid=2884687 |doi= 10.1007/BF00216006|url=] and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum.

However, there was controversy and conflicting findings over whether post-mortem findings resulted from chronic antipsychotic treatment. Studies using SPET and PET methods in drug naive patients have generally failed to find any difference in dopamine D2 receptor density compared to controls. Recent findings from meta-analyses suggest that there may be a small elevationin dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful. [cite journal |author=Laruelle M |title=Imaging dopamine transmission in schizophrenia. A review and meta-analysis |journal=Q J Nucl Med |volume=42 |issue=3 |pages=211–21 |year=1998 |month=September |pmid=9796369 |doi= |url=] citation | author = Stone, James M.; Morrison, Paul D.; Pilowsky, Lyn S. | year = 2006 | title = Review: Glutamate and dopamine dysregulation in schizophrenia a synthesis and selective review | journal = Journal of Psychopharmacology | volume = 21 | issue = 4 | pages = 440 | doi = 10.1177/0269881106073126 | pmid = 17259207] In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity.

It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them. [cite journal |author=Abi-Dargham A, Moore H |title=Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia |journal=Neuroscientist |volume=9 |issue=5 |pages=404–16 |year=2003 |month=October |pmid=14580124 |doi= 10.1177/1073858403252674|url=http://nro.sagepub.com/cgi/pmidlookup?view=long&pmid=14580124] Increased dopamine sensitivity may be a common final pathway.cite journal |author=Seeman P, Schwarz J, Chen JF, "et al" |title=Psychosis pathways converge via D2high dopamine receptors |journal=Synapse |volume=60 |issue=4 |pages=319–46 |year=2006 |month=Sep |pmid=16786561 |doi=10.1002/syn.20303 |url=]

Another reliable finding is that there is an excess of binding sites insensitive to a certain testing agent (raclopride) [Albert Hung Choy Wonga, Hubert H.M. Van Tol (2003) "Schizophrenia: from phenomenology to neurobiology" Neuroscience and Biobehavioral Reviews 27, p276]

Another one of Philip Seeman's findings was that the dopamine D2 receptor protein looked abnormal in schizophrenia. Proteins change states by flexing.The activating of the protein by folding could be permanent or fluctuating, [Cite journal
author = Philip Seeman & H. B. Niznik
year = 1990
title = Dopamine receptors and transporters in Parkinson's disease and schizophrenia
journal = FASEB Journal
volume = 4
pages = 2737–2744
] just like the courses of patients' illnesses waxes and wanes. Increased folding of a protein leads to increased risk of 'additional fragments' forming [cite journal |author=Rote KV, Rechsteiner M |title=Degradation of proteins microinjected into HeLa cells. The role of substrate flexibility |journal=J. Biol. Chem. |volume=261 |issue=33 |pages=15430–6 |year=1986 |month=Nov |pmid=2430958 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2430958] The schizophrenic d2 receptor has a unique additional fragment when digested by papain in the test-tube in the FASEB experiment above, but none of the controls exhibited the same fragment.The D2 receptor in schizophrenia are thus in a highly active state as found by Philip Seeman et al.

Glutamate

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophreniacite journal |author=Konradi C, Heckers S |title=Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment |journal=Pharmacol. Ther. |volume=97 |issue=2 |pages=153–79 |year=2003 |month=Feb |pmid=12559388 |doi= 10.1016/S0163-7258(02)00328-5|url=http://linkinghub.elsevier.com/retrieve/pii/S0163725802003285] and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.cite journal |author=Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA |title=Effects of ketamine in normal and schizophrenic volunteers |journal=Neuropsychopharmacology |volume=25 |issue=4 |pages=455–67 |year=2001 |month=Oct |pmid=11557159 |doi=10.1016/S0893-133X(01)00243-3 |url=] The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.cite journal |author=Coyle JT, Tsai G, Goff D |title=Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia |journal=Ann. N. Y. Acad. Sci. |volume=1003 |issue= |pages=318–27 |year=2003 |month=November |pmid=14684455 |doi= 10.1196/annals.1300.020|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2003&volume=1003&spage=318] Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia.cite journal |author=Tuominen HJ, Tiihonen J, Wahlbeck K |title=Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis |journal=Schizophr. Res. |volume=72 |issue=2-3 |pages=225–34 |year=2005 |month=Jan |pmid=15560967 |doi=10.1016/j.schres.2004.05.005 |url=]

Other

Dyregulation of neural calcium homeostasis has been hypothesized to be a link between the glutamate and dopaminergic abnormalities [cite journal |author=Yarlagadda A |title=Role of calcium regulation in pathophysiology model of schizophrenia and possible interventions |journal=Med. Hypotheses |volume=58 |issue=2 |pages=182–6 |year=2002 |month=Feb |pmid=11812200 |doi=10.1054/mehy.2001.1511 |url=] and some small studies have indicated that calcium channel blocking agents can lead to improvements on some measures in schizophrenia with tardive dyskinesia. [cite journal |author=Yamada K, Ashikari I, Onishi K, Kanba S, Yagi G, Asai M |title=Effectiveness of nilvadipine in two cases of chronic schizophrenia |journal=Psychiatry Clin. Neurosci. |volume=49 |issue=4 |pages=237–8 |year=1995 |month=Aug |pmid=9179944 |doi= 10.1111/j.1440-1819.1995.tb01891.x|url=]

There is evidence of irregular cellular metabolism and oxidative stress in the prefrontal cortex in schizophrenia, involving increased glucose demand and/or cellular hypoxia. [cite journal |author=Prabakaran S, Swatton JE, Ryan MM, "et al" |title=Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress |journal=Mol. Psychiatry |volume=9 |issue=7 |pages=684–97, 643 |year=2004 |month=Jul |pmid=15098003 |doi=10.1038/sj.mp.4001511 |url=http://www.nature.com/mp/journal/v9/n7/abs/4001511a.html]

Development of specific delusions

Andrew Sims has said that the top two 'Factors mainly concerned in the germination of delusions' are:1. Disorder of brain functioning and 2. background influences of temperament and personality [cite book |author=Sims, Andrew |title=Symptoms in the mind: an introduction to descriptive psychopathology |publisher=W. B. Saunders |location=Philadelphia |year=2002 |pages=127 |isbn=0-7020-2627-1 |oclc= |doi= |accessdate=] .

Higher levels of dopamine qualify as a symptom of 'disorders of brain function'. They are needed to sustain certain delusions is confirmed by a study on delusional disorder (another psychotic syndrome). "...pHVA [homovanillic acid] was employed as a "state marker" of the [delusional] disorder...": Delusions of persecution and delusions of jealousy were able to be differentiated by the amount of acid that was released when the dopamine was digested."... From these findings, it seems that pHVA varies depending upon the subtype and course of schizophrenia, and it is also strongly influenced by neuroleptic treatment." [cite journal |author=Morimoto K, Miyatake R, Nakamura M, Watanabe T, Hirao T, Suwaki H |title=Delusional disorder: molecular genetic evidence for dopamine psychosis |journal=Neuropsychopharmacology |volume=26 |issue=6 |pages=794–801 |year=2002 |month=Jun |pmid=12007750 |doi=10.1016/S0893-133X(01)00421-3 |url=http://www.nature.com/npp/journal/v26/n6/full/1395864a.html] This is confirmed in that very high recreational use of amphetamine produces Gender Identity Disorder delusions (which the DSM says are rare) [cite journal |author=Lothstein LM |title=Amphetamine abuse and transsexualism |journal=J. Nerv. Ment. Dis. |volume=170 |issue=9 |pages=568–71 |year=1982 |month=Sep |pmid=7108506 |doi= |url=] , while medical doses of amphetamine can produce morbid jealousy [cite journal |author=Pillai K, Kraya N |title=Psychostimulants, adult attention deficit hyperactivity disorder and morbid jealousy |journal=Aust N Z J Psychiatry |volume=34 |issue=1 |pages=160–3 |year=2000 |month=Feb |pmid=11185930 |doi= 10.1046/j.1440-1614.2000.00694.x|url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0004-8674&date=2000&volume=34&issue=1&spage=160] The subject of the large recreational amphetamine dose had an unconfirmed zero sperm count. One journal says amphetamine affects overall fertility in mice only at very high doses [cite journal |author=Yamamoto Y, Yamamoto K, Hayase T |title=Effect of methamphetamine on male mice fertility |journal=J. Obstet. Gynaecol. Res. |volume=25 |issue=5 |pages=353–8 |year=1999 |month=Oct |pmid=10533332 |doi= |url= (It was important to include this as true transsexuals are known for low sperm count and this information may counter depression in someone who has this)] - showing how the state of dopamine must be at a rare high.

Sims briefly examines delusional content, but in a separate section, and not elaborating on personalities that are commonly associated with each delusion; but says "Jaspers considered there is a subtle change in personality due to the illness itself; and this creates the condition for the development of the delusional atmosphere in which the delusional intuition arises" [cite book |author=Sims, Andrew |title=Symptoms in the mind: an introduction to descriptive psychopathology |publisher=W. B. Saunders |location=Philadelphia |year=2002 |pages=128 |isbn=0-7020-2627-1 |oclc= |doi= |accessdate=]

Cultural factors have "a decisive factor in shaping delusions". [cite journal |author=Draguns JG, Tanaka-Matsumi J |title=Assessment of psychopathology across and within cultures: issues and findings |journal=Behav Res Ther |volume=41 |issue=7 |pages=755–76 |year=2003 |month=Jul |pmid=12781244 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0005796702001900] For example, delusions of guilt and punishment are frequesnt in a Western, Christian country like Austria, but not in Pakistan - where it is more likely persecution. It says cultural factors have a decisive influence in shaping delusions. [cite journal |author=Stompe T, Friedman A, Ortwein G, "et al" |title=Comparison of delusions among schizophrenics in Austria and in Pakistan |journal=Psychopathology |volume=32 |issue=5 |pages=225–34 |year=1999 |pmid=10494061 |doi= 10.1159/000029094|url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=psp32225] . Frequent delusions of guilt and punishment are shown in Austria as well and this is with Parkinson's patients treated with l-dopa. [cite journal |author=Birkmayer W, Danielczyk W, Neumayer E, Riederer P |title=The balance of biogenic amines as condition for normal behaviour |journal=J. Neural Transm. |volume=33 |issue=2 |pages=163–78 |year=1972 |pmid=4643007 |doi= 10.1007/BF01260902|url=http://www.springerlink.com/index/N11474QQ25R5U236.pdf]

Cognition and emotion

A number of cognitive biases or deficits have been found in people diagnosed with schizophrenia. These include jumping to conclusions when faced with limited or contradictory information; specific biases in reasoning about social situations, for example assuming other people cause things that go wrong (external attribution); difficulty distinguishing inner speech from speech from an external source (source monitoring); difficulty in adjusting speech to the needs of the hearer, related to theory of mind difficulties; difficulties in the very earliest stages of processing visual information (including reduced latent inhibition); difficulty with attention e.g. being more easily distracted, attentional bias towards threat. Some of these tendencies have been shown to worsen or appear when under emotional stress or in confusing situations. As with the related neurological findings, they are not shown by all individuals with a diagnosis of schizophrenia and it is not clear how specific they are to schizophrenia or to particular symptoms. [cite journal |author=Broome MR, Woolley JB, Tabraham P, "et al" |title=What causes the onset of psychosis? |journal=Schizophr. Res. |volume=79 |issue=1 |pages=23–34 |year=2005 |month=Nov |pmid=16198238 |doi=10.1016/j.schres.2005.02.007 |url=] However, the findings regarding cognitive difficulties in schizophrenia are reliable and consistent enough for some researchers to argue that they are diagnostic. [cite journal |author=Lewis R |title=Should cognitive deficit be a diagnostic criterion for schizophrenia? |journal=J Psychiatry Neurosci |volume=29 |issue=2 |pages=102–13 |year=2004 |month=Mar |pmid=15069464 |pmc=383342 |doi= |url=http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-29/issue-2/pdf/pg102.pdf] Impaired capacity to appreciate one's own and others' mental states has been reported to be the single-best predictor of poor social competence in schizophrenia. [cite journal |author=Brüne M, Abdel-Hamid M, Lehmkämper C, Sonntag C |title=Mental state attribution, neurocognitive functioning, and psychopathology: what predicts poor social competence in schizophrenia best? |journal=Schizophr. Res. |volume=92 |issue=1-3 |pages=151–9 |year=2007 |month=May |pmid=17346931 |doi=10.1016/j.schres.2007.01.006 |url=] Similar cognitive features have been identified in close relatives of people diagnosed with schizophrenia. [cite journal |author=Sitskoorn MM, Aleman A, Ebisch SJ, Appels MC, Kahn RS |title=Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis |journal=Schizophr. Res. |volume=71 |issue=2-3 |pages=285–95 |year=2004 |month=Dec |pmid=15474899 |doi=10.1016/j.schres.2004.03.007 |url=]

A number of emotional factors have been implicated in schizophrenia, with some models putting them at the core of the disorder. It was thought that the appearance of blunted affect meant that sufferers did not experience strong emotions, but more recent studies indicate there is often a normal or even heightened level of emotionality, particularly in response to negative events or stressful social situations. [cite journal |author=Cohen AS, Docherty NM |title=Affective reactivity of speech and emotional experience in patients with schizophrenia |journal=Schizophr. Res. |volume=69 |issue=1 |pages=7–14 |year=2004 |month=July |pmid=15145465 |doi=10.1016/S0920-9964(03)00069-0 |url=] Some theories suggest positive symptoms of schizophrenia can result from or be worsened by negative emotions, including depressed feelings and low self-esteem [cite journal |author=Smith B, Fowler DG, Freeman D, "et al" |title=Emotion and psychosis: links between depression, self-esteem, negative schematic beliefs and delusions and hallucinations |journal=Schizophr. Res. |volume=86 |issue=1-3 |pages=181–8 |year=2006 |month=September |pmid=16857346 |doi=10.1016/j.schres.2006.06.018 |url=] and feelings of vulnerability, inferiority or loneliness. [Beck, AT (2004). [http://www.atypon-link.com/SPC/doi/abs/10.1891/jcop.18.3.281.65649?cookieSet=1&journalCode=jcop A Cognitive Model of Schizophrenia,] "Journal of Cognitive Psychotherapy", 18 (3), 281–288. Retrieved on 2007-05-16. ] Chronic negative feelings and maladaptive coping skills may explain some of the association between psychosocial stressors and symptomology. [cite journal |author=Horan WP, Blanchard JJ |title=Emotional responses to psychosocial stress in schizophrenia: the role of individual differences in affective traits and coping |journal=Schizophr. Res. |volume=60 |issue=2-3 |pages=271–83 |year=2003 |month=Apr |pmid=12591589 |doi= 10.1016/S0920-9964(02)00227-X|url=http://linkinghub.elsevier.com/retrieve/pii/S092099640200227X] Critical and controlling behaviour by significant others (high expressed emotion) causes increased emotional arousal [cite journal |author=Tarrier N, Turpin G |title=Psychosocial factors, arousal and schizophrenic relapse. The psychophysiological data |journal=Br J Psychiatry |volume=161 |issue= |pages=3–11 |year=1992 |month=Jul |pmid=1638327 |doi= |url=] and lowered self-esteem [cite journal |author=Barrowclough C, Tarrier N, Humphreys L, Ward J, Gregg L, Andrews B |title=Self-esteem in schizophrenia: relationships between self-evaluation, family attitudes, and symptomatology |journal=J Abnorm Psychol |volume=112 |issue=1 |pages=92–9 |year=2003 |month=Feb |pmid=12653417 |doi= 10.1037/0021-843X.112.1.92|url=http://content.apa.org/journals/abn/112/1/92] and a subsequent increase in positive symptoms such as unusual thoughts. Countries or cultures where schizotypal personalities or schizophrenia symptoms are more accepted or valued appear to be associated with reduced onset of, or increased recovery from, schizophrenia.

Related studies suggest that the content of delusional and psychotic beliefs in schizophrenia can be meaningful and play a causal or mediating role in reflecting the life history or social circumstances of the individual. [cite journal |author=Birchwood M, Meaden A, Trower P, Gilbert P, Plaistow J |title=The power and omnipotence of voices: subordination and entrapment by voices and significant others |journal=Psychol Med |volume=30 |issue=2 |pages=337–44 |year=2000 |month=March |pmid=10824654 |doi= 10.1017/S0033291799001828|url=] Holding minority or poorly understood sociocultural beliefs, for example due to ethnic background, has been linked to increased diagnosis of schizophrenia. The way an individual personally understands and attributes their delusions or hallucinations (e.g. as threatening or as potentially positive) has also been found to influence functioning and recovery. [cite journal |author=Honig A, Romme MA, Ensink BJ, Escher SD, Pennings MH, deVries MW |title=Auditory hallucinations: a comparison between patients and nonpatients |journal=J. Nerv. Ment. Dis. |volume=186 |issue=10 |pages=646–51 |year=1998 |month=Oct |pmid=9788642 |doi= 10.1097/00005053-199810000-00009|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0022-3018&volume=186&issue=10&spage=646]

Information processing disorders - backed up by Andrzej Jakubik "Personality disorders" (ISBN 83-200-2087-5). pages 218 and following, suggests that in paranoid schizophrenia short term memory organization levels and data processing structures relatedare impaired, especially selection, structuralisation and recall related functional circuits.His references are :cite journal |author=Hamlin RM, Folsom AT |title=Impairment in abstract responses of schizophrenics, neurotics, and brain-damaged patients |journal=J Abnorm Psychol |volume=86 |issue=5 |pages=483–91 |year=1977 |month=Oct |pmid=915109 |doi= 10.1037/0021-843X.86.5.483|url=] cite journal |author=Grzywa A |title= [The thinking of patients with schizophrenia as an expression of disorders of information processing] |language=Polish |journal=Psychiatr. Pol. |volume=20 |issue=3 |pages=215–24 |year=1986 |pmid=3541017 |doi= |url=] Grzywa A.: Psychologiczne mechanizmy ksztaltowania sie przekonan urojeniowych. Postepy Psychiatrii Neurologicznej, 1992, 1,34-41. (Psychological mechanisms of delusional beliefs creation) ] cite journal |author=Grzywa A, Chlewiński Z |title= [Relationship between information processing and short- and long-term memory in patients with paranoid schizophrenia] |language=Polish |journal=Psychiatr. Pol. |volume=18 |issue=3 |pages=219–24 |year=1984 |pmid=6536004 |doi= |url=] cite journal |author=Grzywa A, Chlewiński Z |title= [Analysis of errors in the transformation of abstract concepts by patients with paranoid schizophrenia] |language=Polish |journal=Psychiatr. Pol. |volume=18 |issue=4 |pages=333–8 |year=1984 |pmid=6536018 |doi= |url=] cite journal |author=Grzywa A, Chlewiński Z |title= [Delusional thinking—its definition and classification] |language=Polish |journal=Psychiatr. Pol. |volume=20 |issue=5 |pages=369–76 |year=1986 |pmid=3295923 |doi= |url=] cite journal |author=Harvey PD, Earle-Boyer EA, Weilgus MS, Levinson JC |title=Encoding, memory, and thought disorder in schizophrenia and mania |journal=Schizophr Bull |volume=12 |issue=2 |pages=252–61 |year=1986 |pmid=3715419 |doi= |url=http://schizophreniabulletin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3715419] cite journal |author=Koh SD, Kayton L, Peterson RA |title=Affective encoding and consequent remembering in schizophrenic young adults |journal=J Abnorm Psychol |volume=85 |issue=2 |pages=156–66 |year=1976 |month=Apr |pmid=1254776 |doi= 10.1037/0021-843X.85.2.156|url=] cite journal |author=Koh SD, Marusarz TZ, Rosen AJ |title=Remembering of sentences by schizophrenic young adults |journal=J Abnorm Psychol |volume=89 |issue=2 |pages=291–4 |year=1980 |month=Apr |pmid=7365141 |doi= 10.1037/0021-843X.89.2.291|url=] cite journal |author=Oltmanns TF |title=Selective attention in schizophrenic and manic psychoses: the effect of distraction on information processing |journal=J Abnorm Psychol |volume=87 |issue=2 |pages=212–25 |year=1978 |month=April |pmid=649860 |doi= 10.1037/0021-843X.87.2.212|url=] cite journal |author=Pogue-Geile MF, Oltmanns TF |title=Sentence perception and distractibility in schizophrenic, manic, and depressed patients |journal=J Abnorm Psychol |volume=89 |issue=2 |pages=115–24 |year=1980 |month=April |pmid=7365124 |doi= 10.1037/0021-843X.89.2.115|url=] cite journal |author=Pishkin V, Williams WV |title=Cognitive deficit in schizophrenia. Subvocal mediation, rigidity, and complexity parameters |journal=J. Nerv. Ment. Dis. |volume=171 |issue=1 |pages=24–9 |year=1983 |month=Jan |pmid=6848644 |doi= |url=] Puszczewicz B.:Organizacja pamieci u chorych na schizofrenie paranoidalna. WSPS, Warszawa 1987 (praca magisterska) (Memory organisation in schizophrenia sufferers) ] cite journal |author=Weiss KM, Vrtunski PB, Simpson DM |title=Information overload disrupts digit recall performance in schizophrenics |journal=Schizophr. Res. |volume=1 |issue=4 |pages=299–303 |year=1988 |pmid=3154517 |doi= 10.1016/0920-9964(88)90007-2|url=] cite journal |author=Forgus RH, DeWolfe AS |title=Coding of cognitive input in delusional patients |journal=J Abnorm Psychol |volume=83 |issue=3 |pages=278–84 |year=1974 |month=June |pmid=4844915 |doi= 10.1037/h0036694|url=]

Notes

External links

*dmoz|Health/Mental_Health/Disorders/Schizophrenia/
*dmoz|Health/Mental_Health/Disorders/Schizophrenia/Support_Groups/ — Support Groups
*dmoz|Health/Mental_Health/Disorders/Schizophrenia/Articles_and_Research/ - Articles and research
* [http://orthomolecular.org/library/jom/1999/articles/1999-v14n01-p049.shtml Adrenochrome hypothesis]
* [http://www.polygenicpathways.co.uk/schizportal.htm PolygenicPathways] Annotated lists of genes and risk factors implicated in schizophrenia


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