The causes of schizophrenia have been the subject of much debate, with various factors proposed and discounted or modified.
The language of schizophrenia research under the medical model is scientific. Such studies suggest that genetics, prenatal development, early environment, neurobiology, and psychological and social processes are important contributory factors.
Current psychiatric research into the development of the disorder is often based on a neurodevelopmental model (proponents of which see schizophrenia as a syndrome.) However, schizophrenia is diagnosed on the basis of symptom profiles. Neural correlates do not provide sufficiently useful criteria. "Current research into schizophrenia has remained highly fragmented, much like the clinical presentation of the disease itself". The one thing that researchers can agree on is that schizophrenia is a complicated and variable condition. It is best thought of as a syndrome, a cluster of symptoms that may or may not have related causes, rather than a single disease.
It is possible for schizophrenia to develop at any age, but it mostly happens to people within the ages of 16–30 (generally males aged 16–25 years and females 25–30 years); about 75 percent of people living with the illness developed it in these age-ranges. There is a likelihood of children developing schizophrenia, though it is quite rare before the age 12. Also, new cases are uncommon after age 40. In addition, about 1 percent of the world's population will develop schizophrenia over their lifetime, therefore out of all the people born, 1 in 100 will develop schizophrenia by age 55. There is on average a somewhat earlier onset for men than women, with the possible influence of the female sex hormone estrogen being one hypothesis and socio-cultural influences another.
Studies have found that people born during the months of late winter and early spring have a higher likelihood of developing schizophrenia, a phenomenon known as the “seasonality effect”. Factors responsible are thought to be related to various viral epidemics, vitamin D deficiencies, population densities, prenatal malnutrition, substance abuse, and additional interaction and protective factors.
The language of schizophrenia research under the medical model is scientific. Such studies suggest that genetics, prenatal development, early environment, neurobiology, and psychological and social processes are important contributory factors.
Current psychiatric research into the development of the disorder is often based on a neurodevelopmental model (proponents of which see schizophrenia as a syndrome.) However, schizophrenia is diagnosed on the basis of symptom profiles. Neural correlates do not provide sufficiently useful criteria. "Current research into schizophrenia has remained highly fragmented, much like the clinical presentation of the disease itself". The one thing that researchers can agree on is that schizophrenia is a complicated and variable condition. It is best thought of as a syndrome, a cluster of symptoms that may or may not have related causes, rather than a single disease.
It is possible for schizophrenia to develop at any age, but it mostly happens to people within the ages of 16–30 (generally males aged 16–25 years and females 25–30 years); about 75 percent of people living with the illness developed it in these age-ranges. There is a likelihood of children developing schizophrenia, though it is quite rare before the age 12. Also, new cases are uncommon after age 40. In addition, about 1 percent of the world's population will develop schizophrenia over their lifetime, therefore out of all the people born, 1 in 100 will develop schizophrenia by age 55. There is on average a somewhat earlier onset for men than women, with the possible influence of the female sex hormone estrogen being one hypothesis and socio-cultural influences another.
Studies have found that people born during the months of late winter and early spring have a higher likelihood of developing schizophrenia, a phenomenon known as the “seasonality effect”. Factors responsible are thought to be related to various viral epidemics, vitamin D deficiencies, population densities, prenatal malnutrition, substance abuse, and additional interaction and protective factors.
Genetics
Heritability
Evidence
suggests that genetic vulnerability with environmental factors can act
in combination resulting in the development of schizophrenia.
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. Recent research suggests that genetic vulnerability to schizophrenia is multifactorial, caused by interactions of several genes.
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%. Concordance rates between monozygotic twins vary in different studies, approximately 50%; whereas dizygotic twins was 17%.
Some twin studies 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.
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.
Genetic candidates
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).
Candidate gene studies
An older 2003 review of linkage studies also listed seven genes as likely to increase risk for a later diagnosis of the disorder. Two reviews 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. Variations near the gene FXYD6 have also been associated with schizophrenia in the UK but not in Japan. 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.
Still another review found evidence that the protein phosphatase 2B
(calcineurin) might be involved in susceptibility to schizophrenia.
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.
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.
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.
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."
Genome-wide association studies
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.
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.
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.
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.
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.
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.
Copy-number variations
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.
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.
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.
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.
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.
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. This study further supported genetic involvement for excitatory neurotransmission.
Overlap with other disorders
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.
Evolutionary psychology
Schizophrenia has been considered an evolutionary puzzle due to the
combination of high heritability, relatively high prevalence, and
reduced reproductive success. One explanation could be increased
reproductive success by close relatives without symptoms but this does
not seem to be the case. Still, it has been argued that it is possible
that a low amount of schizotypy
increasing genes may increase reproductive success by increasing such
traits such as creativity, verbal ability, and emotional sensitivity.
Another evolutionary explanation is the "imprinted brain theory" which argues that psychosis and autism are contrasting disorders on a number of different variables. This is argued to be caused by an unbalanced genomic imprinting favoring paternal genes in the case of autism and maternal genes in the case of psychosis.
Before birth
It is well established that obstetric
complications or events are associated with an increased chance of the
child later developing schizophrenia, although overall they constitute a
non-specific risk factor with a relatively small effect. Obstetric
complications occur in approximately 25 to 30% of the general population
and the vast majority do not develop schizophrenia, and likewise the
majority of individuals with schizophrenia have not had a detectable
obstetric event. Nevertheless, the increased average risk is
well-replicated, and such events may moderate the effects of genetic or
other environmental risk factors. The specific complications or events
most linked to schizophrenia, and the mechanisms of their effects, are
still under examination.
One epidemiological 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. Explanations have included a greater
prevalence of viral infections at that time, or a greater likelihood of vitamin D
deficiency. A similar effect (increased likelihood of being born in
winter and spring) has also been found with other, healthy populations,
such as chess players.
Women who were pregnant during the Dutch famine of 1944, where many people were close to starvation (experiencing malnutrition) had a higher chance of having a child who would later develop schizophrenia. Studies of Finnish mothers who were pregnant when they found out that their husbands had been killed during the Winter War
of 1939–1940 have shown that their children were significantly more
likely to develop schizophrenia when compared with mothers who found out
about their husbands' death after pregnancy, suggesting that maternal stress may have an effect.
Fetal growth
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.
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.
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.
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.
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.
Hypoxia
It has been hypothesized since the 1970s that brain hypoxia (low oxygen levels) before, at or immediately after birth may be a risk factor for the development of schizophrenia.
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.
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. 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.
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.
A longitudinal study found that obstetric complications involving
hypoxia were one factor associated with neurodevelopmental impairments
in childhood and with the later development of schizophreniform disorders.
Fetal hypoxia has been found to predict unusual movements at age 4 (but
not age 7) among children who go on to develop schizophrenia,
suggesting that its effects are specific to the stage of
neurodevelopment. 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.
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.
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.
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".
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. One paper restated that cerebellum neurological disorders were frequently found in schizophrenics and speculated hypoxia may cause the subsequent cognitive dysmetria
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.
Other factors
There is an emerging literature on a wide range of prenatal risk factors, such as prenatal stress, intrauterine (in the womb) malnutrition, and prenatal infection. Increased paternal age has been linked to schizophrenia, possibly due to "chromosomal aberrations and mutations of the aging germline." 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. References for many of these environmental risk factors have been collected in an online database.
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.
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.
A meta-analysis found that high neuroticism increases the risk of psychosis and schizophrenia.
Infections and immune system
Numerous
viral infections, in utero or in childhood, 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.
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. This result was corroborated by a later British study of the same pandemic, but not by a 1994 study of the pandemic in Croatia. A Japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic.
Polio, measles, varicella-zoster, rubella, herpes simplex virus type 2, maternal genital infections, Borna disease virus, and more recently Toxoplasma gondii have been correlated with the later development of schizophrenia. 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.
In a meta-analysis of several studies, they found moderately higher levels of Toxoplasma antibodies in those with schizophrenia 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.
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 and direct studies have linked dysfunctional immune status to some of the clinical features of schizophrenia.
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).
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.
Recent findings support the hypothesis that schizophrenia is associated with alterations of the tryptophane-kynurenine metabolic pathway due to activation of specific sections of the immune system.
The relevance of some auto-antibodies that act against the NMDAR and VGKC is being studied. Current estimates suggest that between 1.5 - 6.5% 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.
Childhood antecedents
In
general, the antecedents of schizophrenia are subtle and those who will
go on to develop schizophrenia do not form a readily identifiable
subgroup - 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.
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.
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. The early subtle motor signs persisted to some extent, showing a small link to later school performance in adolescence.
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).
(Patients in this age group with these symptoms were significantly less
likely to progress to high school, despite academic ability.)
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.
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.
However, another study found that unusual motor coordination scores at
7 years of age were associated in adulthood with both those with
schizophrenia and their unaffected siblings, while unusual movements at
ages 4 and 7 predicted adult schizophrenia but not unaffected sibling
status.
A birth cohort study in New Zealand found that children who went on to develop schizophreniform disorder
had, as well as emotional problems and interpersonal difficulties
linked to all adult psychiatric outcomes measured, significant
impairments in neuromotor, receptive language, and cognitive development.
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.
Some small studies on offspring of individuals with schizophrenia have identified various 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.
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.
There is evidence that childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.
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.
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.
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. Some substances can induce psychosis.
The use of various drugs makes a diagnosis of schizophrenia more
complicated. A person cannot be diagnosed unless symptoms persist after
drug use has ended.
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.
Cannabis
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.
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. 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.
Cannabis use is also suspected to contribute to the hyperdopaminergic state that is characteristic of schizophrenia. Compounds found in cannabis, such as THC, have been shown to increase the activity of dopamine pathways in the brain, 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.
Amphetamines and other stimulants
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.
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.
Concerns have been raised that long-term therapy with stimulants for ADHD might cause paranoia, schizophrenia and behavioral sensitization.
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. 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.
Hallucinogens
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.
Alcohol
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.
Tobacco use
People with schizophrenia tend to smoke significantly more tobacco
than the general population. The rates are exceptionally high amongst
institutionalized patients and homeless people. In a UK census from 1993, 74% of people with schizophrenia living in institutions were found to be smokers. 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 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.
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.
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. However, some researchers have questioned whether self-medication is really the best explanation for the association.
A study from 1989 and a 2004 case study 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.
This gives credence to the idea tobacco could be used to self-medicate
by limiting effects of the illness, the medication, or both.
Life experiences
Social adversity
The chance of developing schizophrenia has been found to increase with the number of adverse social factors (e.g. indicators of socioeconomic disadvantage or social exclusion) present in childhood. Stressful life events generally precede the onset of schizophrenia.
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.
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.
Childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.
Recent large-scale general population studies indicate the relationship
is a causal one, with an increasing risk with additional experiences of
maltreatment, although a critical review suggests conceptual and methodological issues require further research.
There is some evidence that adversities may lead to cognitive biases
and altered dopamine neurotransmission, a process that has been termed
"sensitization".
Childhood trauma, and bereavement or separation in families, have been
found to be risk factors for schizophrenia and psychosis.
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.
Urbanicity
A particularly stable and replicable finding has been the association between living in an urban environment and the development of schizophrenia, even after factors such as drug use, ethnic group and size of social group have been controlled for. 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.
The effect does not appear to be due to a higher incidence of obstetric complications in urban environments.
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.
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.
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).
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.
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. Social support systems are very important for schizophrenics and the people with whom they are in relationships. Recovery from schizophrenia is possible when one develops a healthy self and establishes firm psychological
boundaries with each of their parents.
Synergistic effects
Experiments
on mice have provided evidence that several stressors can act together
to increase the risk of schizophrenia. In particular, the combination of
a maternal infection during pregnancy followed by heightened stress at
the onset of sexual maturity markedly increases the probability that a
mouse develops symptoms of schizophrenia, whereas the occurrence of one
of these factors without the other does not.
Other views
Schizophrenia
is suggested to be a brain disorder rather than a mental illness. It is
labeled as a mental illness because the symptoms align as such and the
causes of the disorder are not completely known and understood. Psychiatrists R. D. Laing, Silvano Arieti, Theodore Lidz
and others have argued that the symptoms of what is called mental
illness are comprehensible reactions to impossible demands that society
and particularly family life places on some sensitive individuals.
Laing, Arieti and Lidz were notable in valuing the content of psychotic
experience as worthy of interpretation, rather than considering it
simply as a secondary and essentially meaningless marker of underlying
psychological or neurological distress. Laing described eleven case
studies of people diagnosed with schizophrenia and argued that the
content of their actions and statements was meaningful and logical in
the context of their family and life situations.
In 1956, Gregory Bateson and his colleagues Paul Watzlawick, Donald Jackson, and Jay Haley articulated a theory of schizophrenia, related to Laing's work, as stemming from double bind
situations where a person receives different or contradictory messages.
Madness was therefore an expression of this distress and should be
valued as a cathartic and transformative experience. In the books Schizophrenia and the Family and The Origin and Treatment of Schizophrenic Disorders Lidz and his colleagues explain their belief that parental behaviour can result in mental illness in children. Arieti's Interpretation of Schizophrenia won the 1975 scientific National Book Award in the United States.
The concept of schizophrenia as a result of civilization has been developed further by psychologist Julian Jaynes in his 1976 book The Origin of Consciousness in the Breakdown of the Bicameral Mind;
he proposed that until the beginning of historic times, schizophrenia
or a similar condition was the normal state of human consciousness. This would take the form of a "bicameral mind"
where a normal state of low affect, suitable for routine activities,
would be interrupted in moments of crisis by "mysterious voices" giving
instructions, which early people characterized as interventions from the
gods. Psychohistorians, on the other hand, accept the psychiatric diagnoses. However, unlike the current medical model of mental disorders they may argue that poor parenting in tribal societies causes the shaman's schizoid personalities. Commentators such as Paul Kurtz
and others have endorsed the idea that major religious figures
experienced psychosis, heard voices and displayed delusions of grandeur.
Modern clinical psychological research has indicated a number of
processes which may cause or bring on episodes of schizophrenia.
A number of cognitive biases
and deficits have been identified. These include attribution biases in
social situations, difficulty distinguishing inner speech from speech
from an external source (source monitoring), difficulty in adjusting
speech to the needs of the hearer, difficulties in the very earliest
stages of processing visual information (including reduced latent inhibition), and an attentional bias towards threats.
Some of these tendencies have been shown to worsen or appear when
under emotional stress or in confusing situations. As with 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.
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, and 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 socio-cultural beliefs, for example due to ethnic
background, has been linked to increased diagnosis of schizophrenia. The
way an individual interprets his or her delusions and hallucinations
(e.g. as threatening or as potentially positive) has also been found to
influence functioning and recovery.
Some experts think autonomy vs. intimacy is a motivation for schizophrenic symptoms.
Other lines of work relating to the self in schizophrenia have linked it to psychological dissociation or abnormal states of awareness and identity as understood from phenomenological, such as in self-disorders, and other perspectives.
Psychiatrist Tim Crow has argued that schizophrenia may be the evolutionary price we pay for a left brain hemisphere specialization for language.
Since psychosis is associated with greater levels of right brain
hemisphere activation and a reduction in the usual left brain hemisphere
dominance, our language abilities may have evolved at the cost of
causing schizophrenia when this system breaks down.
In alternative medicine, some practitioners believe that there are a vast number of physical causes of what ends up being diagnosed as schizophrenia.
While some of these explanations may stretch credulity, others (such as
heavy metal poisoning and nutritional imbalances) have been supported
at least somewhat by research.
However, it is not entirely clear how many (if any) patients initially
diagnosed with schizophrenia these alternative explanations may account
for.
Psychological stress may worsen schizophrenia.
