Causes of schizophrenia

Evidence suggests that genetic vulnerability with environmental factors can act in combination resulting in the development of schizophrenia.[8] Although schizophrenia is very strongly heritable, there is also some evidence that all cases are not caused by heredity. Many people who appear to carry "schizophrenia genes" may not become schizophrenic.[9] Recent research suggests that genetic vulnerability to schizophrenia is multifactorial, caused by interactions of several genes.[10]

Individual twin studies and meta-analyses of twin studies have estimated 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), but the heritability estimate varies from 41 to 87%.[11] Concordance rates between monozygotic twins vary in different studies, approximately 50%; whereas dizygotic twins was 17%. Some twin studies[12][13] have found rates as low as 11.0%–13.8% among monozygotic twins, and 1.8%–4.1% among dizygotic twins, however.

Family studies indicate that the closer a person’s genetic relatedness to a person with schizophrenia, the greater the likelihood of developing the disorder. The paternal age is a factor in schizophrenia because of the increased likelihood of mutations in the chromosomes of cells that produce sperms. In contrast, women's oocytes divide twenty-three times before the time of birth and only once after that. The chance of a copying error in DNA replication during cell division increases with the number of cell divisions, and an increase in copying errors may cause an accumulation of mutations that are responsible for an increased incidence of schizophrenia.[9] The average concordance rates are higher for identical twins than for fraternal twins and evidence also suggests that the prenatal and perinatal environments may also affect concordance rates in identical twins.[14]

Although twin studies and family studies have indicated a large degree of heritability for schizophrenia, the exact genetic causes remain unclear. Recently however, quite some large-scale studies have now begun to unravel the genetic underpinnings for the disease. Important segregation should be made between lower risk, common variants (identified by candidate studies or genome-wide association studies(GWAS)) and high risk, rare variants (which could be caused by de novo mutations) and copy-number variations (CNVs).

An older 2003 review of linkage studies also listed seven genes as likely to increase risk for a later diagnosis of the disorder.[8] Two reviews[10][15] suggested that the evidence was strongest for two genes known as dysbindin (DTNBP1) and neuregulin (NRG1), and that a number of other genes (such as COMT, RGS4, PPP3CC, ZDHHC8, DISC1, and AKT1) showed some early promising results. Knockout studies in Drosophila show that reduced expression of dysbindin reduced glutamatergic synaptic transmission, resulting in impaired memory.[16] Variations near the gene FXYD6 have also been associated with schizophrenia in the UK[17][18] but not in Japan.[19] 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.[20] Still another review found evidence that the protein phosphatase 2B (calcineurin) might be involved in susceptibility to schizophrenia.[3]

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, reported in 2008 that there was no evidence of any 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.[21][22]

The perhaps largest analysis of genetic associations in schizophrenia is with the SzGene database at the Schizophrenia Research Forum. One 2008 meta-analysis examined genetic variants in 16 genes and found nominally significant effects.[23]

A 2009 study was able to create mice matching schizophrenic symptoms by the deletion of only one gene set, those of the neuregulin post-synaptic receptor. The result showed that although the mice mostly developed normally, on further brain development, glutamate receptors broke down. This theory supports the glutamate hypothesis of schizophrenia.[24] Another study in 2009 by Simon Fraser University researchers identifies a link between autism and schizophrenia: "The SFU group found that variations in four sets of genes are related to both autism and schizophrenia. People normally have two copies of each gene, but in autistics some genome locations have only single copies and in schizophrenics extra copies are present at the same locations."[25][26]

To increase sample size for a better powered detection of common variants with small effects, GWAS data is continuing to be clustered in large international consortia. The Psychiatric Genetics Consortium (PGC) attempts to aggregate GWAS data on schizophrenia to detect associations of common variants with small effect on disease risk.[27]

In 2011, this collaboration identified by meta-analyse of genome-wide association studies that 129 over 136 single-nucleotide polymorphism (SNP) significantly associated with schizophrenia were located in major histocompatibility complex region of the genome.[28]

In 2013 this dataset was expanded to identify in total 13 candidate loci for the disease, now also implicating calcium signalling as an important factor in the disease.[29]

In 2014 this collaboration expanded to an even larger meta-analysis, the largest to date, on GWAS data (36,989 cases and 113,075 controls) in Nature, indicating 108 schizophrenia-associated genetic loci, of which 83 have not been previously described.[30] Together, these candidate genes pointed to an importance of neurotransmission and immunology as important factors in the disease.

Distinct symptomatic subtypes of schizophrenia groups showed to have a different pattern of SNP variations, reflecting the heterogeneous nature of the disease.[31]

A 2016 study implicated the C4 gene in schizophrenia risk. C4 was found to play a role in synapse pruning, and increased C4 expression leads to reduced dendritic spines and a higher schizophrenia risk.[32]

Other research has suggested that a greater than average number of structural variations such as rare deletions or duplications of tiny DNA sequences within genes (known as copy number variants) are linked to increased risk for schizophrenia, especially in "sporadic" cases not linked to family history of schizophrenia, and that the genetic factors and developmental pathways can thus be different in different individuals.[33][34] A genome wide survey of 3,391 individuals with schizophrenia found CNVs in less than 1% of cases. Within them, deletions in regions related to psychosis were observed, as well as deletions on chromosome 15q13.3 and 1q21.1.[35]

CNVs occur due to non-allelic homologous recombination mediated by low copy repeats (sequentially similar regions). This results in deletions and duplications of dosage sensitive genes. It has been speculated that CNVs underlie a significant proportion of normal human variation, including differences in cognitive, behavioral, and psychological features, and that CNVs in at least three loci can result in increased risk for schizophrenia in a few individuals.[36] Epigenetics may also play a role in schizophrenia, with the expression of Protocadherin 11 X-linked/Protocadherin 11 Y-linked playing a possible role in schizophrenia.[37]

A 2008 investigation of 2,977 schizophrenia patients and 33,746 controls from seven European populations examined CNVs in neurexins, and found that exon-affecting deletions in the NRXN1 gene conferred risk of schizophrenia.[38]

An updated meta-analysis on CNVs for schizophrenia published in 2015 expanded the number of CNVs indicated in the disease, which was also the first genetic evidence for the involvement of GABAergic neurotransmission.[39] This study further supported genetic involvement for excitatory neurotransmission.

Several studies have suggested that genetic overlap exists between schizophrenia and other psychiatric disorders. On 28 February 2013 The Lancet published an article about the possible genetic correlation between autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. They analyzed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestry. This group found four gene areas that all overlapped with the five disorders, two of which regulate calcium balance in the brain.[40]

Lower than average birth weight has been one of the most consistent findings, indicating slowed fetal growth possibly mediated by genetic effects. In the first and only prospective study of the low birthweight, schizophrenia, and enlargement of brain ventricles suggestive of cerebral atrophy, Leigh Silverton and colleagues found that low birthweight (measured prospectively with regard to psychopathology) was associated with enlarged ventricles on CT-Scans in a sample at risk for schizophrenia over 30 years later. These signs suggestive of cerebral atrophy were associated with schizophrenia symptoms.[48] In a follow up study, Silverton et al. noted an interaction between genetic risk for schizophrenia and low birthweight. The risk of enlarged ventricles on brain scan (associated with schizophrenia symptoms and biologically suggestive of Emil Kraepelin's dementia praecox type of schizophrenia ) was greatly increased if the subjects had both a higher genetic load for schizophrenia and lower birthweight. The investigators suggested that in utero insults may specifically stress those with a schizophrenia diathesis suggesting to the authors a diathesis stress etiological model for a certain type of schizophrenia (that Kraepelin identified) with early abnormalities suggesting brain atrophy.[49]

Some investigators have noted, however, that any factor adversely affecting the fetus will affect growth rate, however, some believe that this association may not be particularly informative regarding causation.[43] 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.[50] It should be noted, however, that the majority of studies do not measure the interaction of genetic risk and birthweight as was done in the Silverton et al. studies.

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.[51]

Hypoxia is now being demonstrated as relevant to schizophrenia in animal models, molecular biology and epidemiology studies. One study in Molecular Psychiatry was able to differentiate 90% of schizophrenics from controls based on hypoxia and metabolism.[52] Hypoxia has been recently described as one of the most important of the external factors that influence susceptibility, although studies have been mainly epidemiological. Such studies place a high degree of importance on hypoxic influence, but because of familial pattern of the illness in some families, propose a genetic factor also; stopping short of concluding hypoxia to be the sole cause.[53] 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.[54]

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 or vascular expression" even though only 3.5% of all genes were estimated to be involved in hypoxia/ischemia or the vasculature.[55]

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.[56] 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.[57] 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.[58]

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.[59] 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.[60]

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".[61][62]

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.[63] One paper restated that cerebellum neurological disorders were frequently found in schizophrenics and speculated hypoxia may cause the subsequent cognitive dysmetria[64]

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%). Although objective estimates of hypoxia did not account for all schizophrenic cases; the study revealed increasing odds of schizophrenia according to graded increase in severity of hypoxia.[65]

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 paternal age has been linked to schizophrenia, possibly due to "chromosomal aberrations and mutations of the aging germline."[66] Maternal-fetal rhesus or genotype incompatibility has also been linked, via increasing the risk of an adverse prenatal environment. Also, 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.[43] References for many of these environmental risk factors have been collected in an online database.[67]

There may be an association between celiac disease (gluten intolerance) and schizophrenia in a small proportion of patients, though large randomized controlled trials and epidemiological studies will be needed before such an association can be confirmed. Withdrawal of gluten from the diet is an inexpensive measure which may improve the symptoms in a small (≤3%) number of schizophrenic patients.[68]

In addition, there is some evidence that exposure to toxins such as lead can also increase the risk of later development of schizophrenia spectrum disorders.[69]

A meta-analysis found that high neuroticism increases the risk of psychosis and schizophrenia.[70]

There is some 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 prospective cohort studies has suggested that cannabis statistically doubles the risk of developing schizophrenia on the individual level, and may, if a causal relationship is assumed, be responsible for up to 8% of cases in the population.[3][9][33][43][50][56][57][66][69][78][110][111][112][113][114][115][116][117]

Cannabis misuse by young people is suspected of causing schizophrenia in later life by interfering with and distorting neurodevelopment particularly of the prefrontal cortex region of the brain.[111] An older longitudinal study, published in 1987, suggested a sixfold increase of schizophrenia risks for high consumers of cannabis (use on more than fifty occasions) in Sweden.[33][118]

Cannabis use is also suspected to contribute to the hyperdopaminergic state that is characteristic of schizophrenia.[9][119] Compounds found in cannabis, such as THC, have been shown to increase the activity of dopamine pathways in the brain,[120] suggesting that cannabis may exacerbate symptoms of psychosis in schizophrenics.

Despite increases in cannabis consumption in the 1960s and 1970s in western society, rates of psychotic disorders such as schizophrenia remained relatively stable over time.[121][122][123]

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.[124] Methamphetamine, a potent neurotoxic amphetamine derivative, induces psychosis in a substantial minority of regular users which resembles paranoid schizophrenia. For most people, this psychosis fades away within a month of abstinence but for a minority the psychosis can become chronic. Individuals who develop a long lasting psychosis, despite abstinence from methamphetamine, more commonly have a family history of schizophrenia.[125]

Concerns have been raised that long-term therapy with stimulants for ADHD might cause paranoia, schizophrenia and behavioral sensitization.[126] Family history of mental illness does not predict the incidence of stimulant toxicosis in ADHD children. High rates of childhood stimulant use have been noted in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder. It has been suggested that this small subgroup of children who develop schizophrenia due to stimulant use during childhood have a genetic vulnerability to developing psychosis.[127] In addition, amphetamines are known to cause a stimulant psychosis in otherwise healthy individuals that superficially resembles schizophrenia, and may be misdiagnosed as such by some healthcare professionals.

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, however, are still considered to produce states that are remarkably similar, and are considered to be even better models than stimulants since they produce both positive and negative symptoms.

Approximately three percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. The mechanism of alcohol-related psychosis is due to distortions to neuronal membranes, gene expression, as well as thiamin deficiency. There is evidence that alcohol abuse via a kindling mechanism can occasionally cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia.[128]

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.[129][130] 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.[112] An older study found that as much as 88% of outpatients with schizophrenia were smokers.[113]

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.[131]

A 2003 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.[132] 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 a cohort study of Israeli conscripts found that healthy adolescent smokers were more likely to develop schizophrenia in the future than their nonsmoking peers.[133]

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.[134]

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.[114] 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.[114] However, some researchers have questioned whether self-medication is really the best explanation for the association.[135]

A study from 1989[136] and a 2004 case study[137] show that when haloperidol is administered, nicotine limits the extent to which the antipsychotic increases the sensitivity of the dopamine 2 receptor. Dependent on the dopamine system, symptoms of Tardive Dyskinesia are not found in the nicotine administered patients despite a roughly 70% increase in dopamine receptor activity, but the controls have more than 90% and do develop symptoms. A 1997 study showed that akathisia was significantly reduced upon administration of nicotine when the akathisia was induced by antipsychotics.[138] This gives credence to the idea tobacco could be used to self-medicate by limiting effects of the illness, the medication, or both.

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.[139][140] Stressful life events generally precede the onset of schizophrenia.[141] 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.[115][142] Unemployment and early separation from parents are some important factors which are responsible for the higher rates of schizophrenia among British African Caribbean populations, in comparison to native African Caribbean populations. This is an example which shows that social disadvantage plays an equally major hand in the onset of schizophrenia as genetics.[143]

Childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.[144][145][146][147] Recent large-scale general population studies indicate the relationship is a causal one, with an increasing risk with additional experiences of maltreatment,[148] although a critical review suggests conceptual and methodological issues require further research.[149] There is some evidence that adversities may lead to cognitive biases and altered dopamine neurotransmission, a process that has been termed "sensitization".[150] Childhood trauma, and bereavement or separation in families, have been found to be risk factors for schizophrenia and psychosis.[151]

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.[152]

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.[153] A recent study of 4.4 million men and women in Sweden found a 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.[154]

The effect does not appear to be due to a higher incidence of obstetric complications in urban environments.[155] 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.[156]

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.[157]

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).[158] 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.[116][159] The risk of developing schizophrenia can also be increased by an individual developing a very low sense of self, in which one's boundaries become confused with that of the mother and/ or father. Firm psychological boundaries should be established between one's self and one's identity and one's parents. Pushing the role of parents into the background and developing a healthy sense of self can be a method for recovery.[160] Social support systems are very important for schizophrenics and the people with whom they are in relationships.[161] Recovery from schizophrenia is possible when one develops a healthy self and establishes firm psychological boundaries with each of their parents.[160]