Risk factors of schizophrenia

Although twin studies and family studies have indicated a large degree of heritability for schizophrenia, the exact genetic causes remain unclear. However, some large-scale studies have 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.[13] Two reviews[14][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 single nucleotide polymorphism (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] Studies have found evidence that the protein phosphatase 3 known as calcineurin might be involved in susceptibility to schizophrenia.[21]

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.[22][23]

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.[24]

A 2009 study was able to create mice matching symptoms of schizophrenia 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.[25] 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 those people with autism some genome locations have only single copies, and in those with schizophrenia extra copies are present at the same locations."[26][27]

To increase sample size for a better powered detection of common variants with small effects, data from genome-wide association studies (GWAS) is continuing to be clustered in large international consortia. The Psychiatric Genomics Consortium (PGC) attempts to aggregate GWAS data on schizophrenia to detect associations of common variants with small effect on disease risk.[28]

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.[29]

In 2013 this dataset was expanded to identify in total 13 candidate loci for the disease, and also implicated calcium signalling as an important factor in the disease.[30]

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.[31] 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.[32]

A 2016 study implicated the C4A gene in schizophrenia risk. C4A was found to play a role in synapse pruning, and increased C4A expression leads to reduced dendritic spines and a higher schizophrenia risk.[33]

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 variations) 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.[34][35] 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.[36]

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.[37] 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.[38]

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.[39]

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.[40] This study further supported genetic involvement for excitatory neurotransmission.

Several studies have suggested a genetic overlap and possible genetic correlation between schizophrenia and other psychiatric disorders including autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, and major depressive disorder. One genome-wide association study analyzed single-nucleotide polymorphism (SNP) data for the five disorders; four gene areas overlapped with the five disorders, two of which regulate calcium balance in the brain.[41]

It is well established that pregnancy complications are associated with an increased risk 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.[42]

There is some evidence that exposure to toxins such as lead can also increase the risk of later development of schizophrenia spectrum disorders.[43]

One epidemiological finding is that people diagnosed with schizophrenia are more likely to have been born in winter or spring[44] (at least in the northern hemisphere). This has been termed the seasonality effect, 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.[45] A similar effect (increased likelihood of being born in winter and spring) has also been found with other, healthy populations, such as chess players.[46]

Many women who were pregnant during the Dutch famine of 1944, suffered from malnutrition, and many of their children later developed schizophrenia.[47] 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 childbirth, suggesting that prenatal stress may have an effect.[48]

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.[49] 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.[50]

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.[42] 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.[51] 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.[52]

Hypoxia is demonstrated as relevant to schizophrenia in animal models, molecular biology and epidemiology studies. One study was able to differentiate 90% of cases of schizophrenia from controls based on hypoxia and metabolism.[53] Hypoxia has been 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.[54] 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.[55]

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.[56]

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.[57] 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.[58] 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.[59]

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.[60] 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.[61]

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".[62][63]

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.[64] One paper restated that cerebellum neurological disorders were frequently found in those with schizophrenia and speculated hypoxia may cause the subsequent cognitive dysmetria[65]

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 neurologic 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 cases of schizophrenia; the study revealed increasing odds of schizophrenia according to graded increase in severity of hypoxia.[66]

A number of viral infections exposed to during prenatal development, have been associated with an increased risk of later developing schizophrenia. Schizophrenia is somewhat more common in those born in winter to early spring, when infections are more common.[67]

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.[68] This result was corroborated by a later British study of the same pandemic,[69] but not by a 1994 study of the pandemic in Croatia.[70] A Japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic.[71]

Polio, measles, varicella-zoster, rubella, herpes simplex virus type 2, maternal genital infections, Borna disease virus, and Toxoplasma gondii[72] have been correlated with the later development of schizophrenia.[73] Psychiatrists E. Fuller Torrey and R.H. Yolken have hypothesized that the latter, a common parasite in humans, contributes to some, if not many, cases of schizophrenia.[74]

In a meta-analysis of several studies, they found moderately higher levels of Toxoplasma antibodies in those with schizophrenia[75][76] and possibly higher rates of prenatal or early postnatal exposure to Toxoplasma gondii, but not acute infection. However, in another study of postmortem brain tissue, the authors have reported equivocal or negative results, including no evidence of herpes virus or T. gondii involvement in schizophrenia.[77]

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 diseases[78] and direct studies have linked dysfunctional immune status to some of the clinical features of schizophrenia.[79][80]

This is known as the pathogenic theory of schizophrenia or germ theory of schizophrenia. It is a pathogenic theory of disease in which it is thought that a proximal cause of certain cases of schizophrenia is the interaction of the developing fetus with pathogens such as viruses, or with antibodies from the mother created in response to these pathogens (in particular, Interleukin 8).[81] Substantial research suggests that exposure to certain illnesses (e.g., influenza) in the mother of the neonate (especially at the end of the second trimester) causes defects in neural development which may emerge as a predisposition to schizophrenia around the time of puberty, as the brain grows and develops.[82]

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."[83] 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.[42] References for many of these environmental risk factors have been collected in an online database.[84]

There may be an association between non-celiac gluten sensitivity and schizophrenia in a small proportion of people,[85] 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 people with schizophrenia.[86]

A meta-analysis found that high neuroticism increases the risk of psychosis and schizophrenia.[87]

Several long-term studies found that individuals born with congenital visual impairment do not develop schizophrenia.[88][89]

The effects of estrogen in schizophrenia have been studied in view of the association between the onset of menopause in women who develop schizophrenia at this time. Add-on estrogen therapies have been studied and evaluated for their effect on the symptoms experienced. Raloxifene studies have shown positive results.[90][91]

Findings have supported the hypothesis that schizophrenia is associated with alterations of the tryptophane-kynurenine metabolic pathway due to activation of specific sections of the immune system.[92][93]

The relevance of some auto-antibodies that act against the NMDAR and VGKC is being studied.[94][95] Current estimates suggest that between 1.5 [96] - 6.5[95]% of patients have these antibodies in their blood. Preliminary results have shown that these patients can be treated with immunotherapy such as IVIG or Plasma exchange and steroids, on top of anti-psychotic medication, which can lead to a reduction in symptoms.[97]

In general, the antecedents of schizophrenia are subtle and those who will go on to develop schizophrenia do not form a readily identifiable subgroup - which would lead to identification of a specific cause. 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.[51]

A prospective study found average differences 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.[98]

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.[99] The early subtle motor signs persisted to some extent, showing a small link to later school performance in adolescence.[100] 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).[101] (Patients in this age group with these symptoms were significantly less likely to progress to high school, despite academic ability.[102])

Symptoms of schizophrenia often appear soon after puberty, when the brain is undergoing significant maturational changes. Some investigators believe that the disease process of schizophrenia begins prenatally, lies dormant until puberty, and then causes a period of neural degeneration that causes the symptoms to emerge.[10] 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.[103] 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.[58]

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.[57] 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.[104]

Some small studies on offspring of individuals with schizophrenia have identified various neurobehavioral deficits,[105] a poorer family environment and disruptive school behaviour,[106] poor peer engagement, immaturity, or unpopularity[107] or poorer social competence and increasing schizophrenic symptomology emerging during adolescence.[108]

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.[109]

There is evidence that childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.[110] Some researchers reported that hallucinations and other symptoms considered characteristic of schizophrenia and psychosis were at least as strongly related to neglect and childhood abuse as many other mental health problems.[111] The researchers concluded that there is a need for staff training in asking patients about abuse, and a need to offer appropriate psychosocial treatments to those who have been neglected and abused as children.[111]

The relationship between schizophrenia and substance abuse is complex, making a clear causal connection difficult. Most substances of abuse can induce psychosis. A diagnosis of substance-induced psychosis is made if symptoms persist after drug use or intoxication has ended.[112] A number of substance-induced psychoses have the potential to transition to schiziohrenia, most notably linked to cannabis.

A 2019 review found that the pooled proportion of transition from substance-induced psychosis to schizophrenia was 25% (95% CI 18%–35%), compared with 36% (95% CI 30%–43%) for "brief, atypical and not otherwise specified" psychoses.[113] The type of substance was the primary predictor of transition to schizophrenia, with highest rates associated with cannabis (6 studies, 34%, CI 25%–46%), hallucinogens (3 studies, 26%, CI 14%–43%) and amphetamines (5 studies, 22%, CI 14%–34%). Lower rates were reported for opioid (12%), alcohol (10%) and sedative (9%) induced psychoses. Transition rates were slightly lower in older cohorts but were not affected by sex, country of the study, hospital or community location, urban or rural setting, diagnostic methods, or duration of follow-up.[113]

The rate of substance use is known to be particularly high in this group. One study found that 60% of people with schizophrenia were found to use substances and 37% would be diagnosable with a substance use disorder.[114]

There is growing evidence that cannabis use can contribute to schizophrenia.[113][115] 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 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.[10][34][42][43][51][57][58][73][83][116][117][118][119][120][121][122][123]

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.[117] 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.[34][124]

Cannabis use is also suspected to contribute to the hyperdopaminergic state that is characteristic of schizophrenia.[10][125] Compounds found in cannabis, such as THC, have been shown to increase the activity of dopamine pathways in the brain,[126] suggesting that cannabis may exacerbate symptoms of psychosis in schizophrenia.

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.[127][128][129]

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.[130] 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.[131]

Concerns have been raised that long-term therapy with stimulants for ADHD might cause paranoia, schizophrenia and behavioral sensitization.[132] 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.[133] 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 (angel dust), and LSD (acid), have been used to mimic schizophrenia for research purposes. Using LSD and other psychedelics as a research model has fallen out of favor, 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 thiamine deficiency. There is evidence that alcohol abuse via a kindling mechanism can occasionally cause the development of chronic substance-induced psychosis[134] that may transition to schizophrenia.[113]

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.[135][136] 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.[118] An older study found that as much as 88% of outpatients with schizophrenia were smokers.[119]

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.[137]

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.[138]

The increased rate of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[139] One possible reason is that smoking produces a short term effect to improve alertness and cognitive functioning in persons who suffer this illness.[120] 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.[120] However, some researchers have questioned whether self-medication is really the best explanation for the association.[140]

A study from 1989[141] and a 2004 case study[142] 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.[143] 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.[144][145] Stressful life events generally precede the onset of schizophrenia.[146] 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.[121][147] 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.[148]

Childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.[149][150][151][152] Large-scale general population studies have indicated that the relationship is a causal one, with an increasing risk with additional experiences of maltreatment,[153] although a critical review suggests conceptual and methodological issues require further research.[154] There is some evidence that adversities may lead to cognitive biases and altered dopamine neurotransmission, a process that has been termed "sensitization".[155] Childhood trauma, and bereavement or separation in families, have been found to be risk factors for schizophrenia and psychosis.[156]

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.[157]

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.[158] A 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.[159]

The effect does not appear to be due to a higher incidence of obstetric complications in urban environments.[160] 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.[161] The cumulative effects of pollution associated with the urban environment have been suggested as the link between urbanicity and the higher risk of developing schizophrenia.[162]

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.[163]

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).[164] 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.[122][165] 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 those 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.[166] Social support systems are very important for those with schizophrenia and the people with whom they are in relationships.[167] Recovery from schizophrenia is possible when one develops a healthy self and establishes firm psychological boundaries with each of their parents.[166]