Schizophrenia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2], Irfan Dotani

Overview

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.

The causes of schizophrenia have been the subject of much debate over many decades with various factors proposed and discounted. To date none has been fully elucidated, but evidence suggests that genetic vulnerability and environmental stressors act in combination to result in schizophrenia.

Studies suggest that genetics, early environment, neurobiology and psychological and social processes are important contributory factors. Current psychiatric research into the development of the disorder often focuses on the role of neurobiology, although a reliable and identifiable organic cause has not been found. 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 stressful 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.

It is also thought that processes in early neurodevelopment are important, particularly prenatal processes. In adult life, importance has been placed upon the function (or malfunction) of dopamine in the mesolimbic pathway in the brain. This theory, known as the dopamine hypothesis of schizophrenia largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, reduced psychotic symptoms. However, this theory is now thought to be overly simplistic as a complete explanation. These drugs have now been developed further and antipsychotic medication is commonly used as a first-line treatment. Although effective in many cases, these medications are not well tolerated by some patients due to significant side-effects. The positive symptoms are more responsive to medications; negative symptoms being less so.

Differences in brain structure have been found between people with schizophrenia and those without. However, these tend only to be reliable on the group level and, due to the significant variability between individuals, may not be reliably present in any particular individual. Significant brain atrophy and enlarged ventricles are the most conspicuous of such differences.

Causes

• While the reliability of the schizophrenia diagnosis introduces difficulties in measuring the relative effect of genes and environment (for example, symptoms overlap to some extent with severe bipolar disorder or major depression), evidence suggests that genetic vulnerability and environmental stressors can act in combination to result in diagnosis of schizophrenia.

• The extent to which these factors influence the likelihood of being diagnosed with schizophrenia is debated widely, and currently, controversial.
• 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.
• 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.

• It is thought that causal factors can initially come together in early neurodevelopment, including during pregnancy, to increase the risk of later developing schizophrenia.
• One curious finding is that people diagnosed with schizophrenia are more likely to have been born in winter or spring (at least in the northern hemisphere).
• However, the effect is not large.
  • Some researchers postulate that the correlation is due to viral infections during the third trimester (4–6 months) of pregnancy.
  • There is now significant evidence that prenatal exposure to infections increases the risk for developing schizophrenia later in life, providing additional evidence for a link between in utero developmental pathology and risk of developing the condition.

• Schizophrenia is most commonly first diagnosed during late adolescence or early adulthood suggesting it is often the end process of childhood and adolescent development.
• Studies have indicated that genetic dispositions can interact with early environment to increase the risk of developing schizophrenia, including through:
  • Global neurobehavioral deficits
  • A poorer family environment and disruptive school behavior
  • Poor peer engagement
  • Immaturity or unpopularity
  • Poorer social competence and increasing schizophrenic symptomology emerging during adolescence
• These developmental problems have also been linked to socioeconomic disadvantage or early experiences of traumatic events.

• There is on average a somewhat earlier onset for men than women, with the possible protective influence of the female hormone oestrogen being one hypothesis made and sociocultural influences another.

Causes of schizophrenia

Etiology	Description
Genetic	Substantial evidence suggests that the diagnosis of schizophrenia has a heritable component (some estimates are as high as 80%). Current research suggests that environmental factors play a significant role in the expression of any genetic disposition towards schizophrenia (i.e. if someone has the genes that increase risk, this will not automatically result in a diagnosis of schizophrenia later in life). A recent review of the genetic evidence has suggested a more than 28% chance of one identical twin obtaining the diagnosis if the other already has it (see twin studies), but such studies are not noted for pondering the likelihood of similarities of social class and/or other socio-psychological factors between the twins. The estimates of heritability of schizophrenia from twin studies varies a great deal, with some notable studies showing rates as low as 11.0%–13.8% among monozygotic twins, and 1.8%–4.1% among dizygotic twins. However, 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. The genetic disposition does not always express in twins being the same disorder as cases of one identical twin having schizophrenia and the other having bipolar disorder have been reported. 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 reviews 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. In 2007, British researchers have identified seven different genetic variations that are associated with schizophrenia and which all lie within or very near a gene FXYD6. A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. This gene, which lies on the long arm of chromosome 11, plays an important role in regulating Na/K homeostasis. After-conception causes for increase in schizophrenia-rate in a population Lack of sunshine, in the 3rd trimester of gestation ( in the temperate regions a Spring birth, but also El Nino years in Australia, and a particularly overcast 3-month stretch in, IIRC, Brazil, all followed by birth of increased schizophrenia-rate population ). Medical X-Rays, ( IIRC, also in the 3rd trimester of gestation ). Influenza in the mother, during later pregnancy. Older fathers ( poorer-quality genetic contribution ) Therefore, it is likely a genetic activation, rather-than simple-possession of specific genes, that is the true cause of it ( simply having the genes would be Required, but Not Sufficient: having 'em activated might be the sufficient bit ).
Emotional	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. 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.
Environmental.	Considerable evidence indicates that stressful life events cause or trigger schizophrenia. Childhood experiences of abuse or trauma have also been implicated as risk factors for a diagnosis of schizophrenia later in life. The evidence is also consistent that negative attitudes towards individuals with (or with a risk of developing) schizophrenia can have a significant adverse impact. In particular, critical comments, hostility, authoritarian and intrusive or controlling attitudes (termed 'high expressed emotion' by researchers) from family members have been found to correlate with a higher risk of relapse in schizophrenia across cultures. It is not clear whether such attitudes play a causal role in the onset of schizophrenia, although those diagnosed in this way may claim it to be the primary causal factor. The research has focused on family members but also appears to relate to professional staff in regular contact with clients. While initial work addressed those diagnosed as schizophrenic, these attitudes have also been found to play a significant role in other mental health problems. This approach does not blame 'bad parenting' or staffing, but addresses the attitudes, behaviors and interactions of all parties. Some go as far as to criticise the whole approach of seeking to localise 'mental illness' within one individual — the patient — rather than his/her group and its functionality, citing a scapegoat effect. Factors such as poverty and discrimination also appear to be involved in increasing the risk of schizophrenia or schizophrenia relapse, perhaps due to the high levels of stress they engender, or faults in diagnostic procedure/assumptions. Racism in society, including in diagnostic practices, and/or the stress of living in a different culture, may explain why minority communities have shown higher rates of schizophrenia than members of the same ethnic groups resident in their home country. The "social drift hypothesis" suggests that the functional problems related to schizophrenia, or the stigma and prejudice attached to them, can result in more limited employment and financial opportunities, so that the causal pathway goes from mental health problems to poverty, rather than, or in addition to, the other direction. *Some argue that unemployment and the long-term unemployed and homeless are simply being stigmatised. One particularly stable and replicable finding has been the association between living in an urban environment and schizophrenia diagnosis, even after factors such as drug use, ethnic group and size of social group have been controlled for. A recent study of 4.4 million men and women in Sweden found an alleged 68%–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. 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 a 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. However, the findings regarding cognitive difficulties in schizophrenia are reliable and consistent enough for some researchers to argue that they are diagnostic. 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. Similar cognitive features have been identified in close relatives of people diagnosed with schizophrenia. 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. Some theories suggest positive symptoms of schizophrenia can result from or be worsened by negative emotions, including depressed feelings and low self-esteem and feelings of vulnerability, inferiority or loneliness. Chronic negative feelings and maladaptive coping skills may explain some of the association between psychosocial stressors and symptomology. Critical and controlling behaviour by significant others (high expressed emotion) causes increased emotional arousal and lowered self-esteem 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. 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. Data from a PET study suggests that the less the frontal lobes are activated (red) during a working memory task, the greater the increase in abnormal dopamine activity in the striatum (green), thought to be related to the neurocognitive deficits in schizophrenia.
Infective.	One theory put forward by psychiatrists E. Fuller Torrey and R.H. Yolken is that the parasite Toxoplasma gondii leads to some, if not many, cases of schizophrenia. This is supported by evidence that significantly higher levels of Toxoplasma antibodies in schizophrenia patients compared to the general population.
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.
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.
Hallucinogens	Schizophrenia can sometimes be triggered by heavy use of hallucinogenic or stimulant drugs, 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. Some widely known cases where hallucinogens have been suspected of precipitating schizophrenia are Pink Floyd founder-member Syd Barrett and The Beach Boys producer, arranger and songwriter Brian Wilson. 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. Hallucinogenic drugs were also briefly tested as possible treatments for schizophrenia by psychiatrists such as Humphry Osmond and Abram Hoffer in the 1950s. *It was mainly for this experimental treatment of schizophrenia that LSD administration was legal, briefly before its use as a recreational drug led to its criminalization.
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. 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.
Tobacco	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. 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. An older study found that as much as 88% of outpatients with schizophrenia were smokers. 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 cancer, a side-effect of drugs being taken, or a statistical effect of increased likelihood of dying from causes other than lung cancer. 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. 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. It is of interest that cigarette smoking affects liver function such that the antipsychotic drugs used to treat schizophrenia are broken down in the bloodstream 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. 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. 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.
Others	Calcium channel abnormalities are currently being explored as a factor in schizophrenia. Related to this, three small studies have found some improvements on some measures, in schizophrenia with tardive dyskinesia, with the calcium channel blocking agent nilvadipine added to an existing antipsychotic regimen Currently, there is growing evidence of the crucial role of autoimmunity in the etiology and pathogenesis of schizophrenia. This can be seen as a study of the statistical correlation schizophrenia with other autoimmune diseases and the recent work on the direct detailed study immune status of patients with schizophrenia.