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]

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 behaviour, poor peer engagement, immaturity or unpopularity or 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.

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 the 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 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.

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.

Other

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.