Jump to content

Risk factors of schizophrenia

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Notpayingthepsychiatrist (talk | contribs) at 10:59, 10 September 2008 (→‎Specific Symptoms: Deleted section which was replicated below - most of the material was my doing anyway). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction. A person experiencing schizophrenia is typically characterized as demonstrating disorganized thought and language, and as experiencing delusions or hallucinations, in particular auditory hallucinations.[1]

The causes of schizophrenia have been the subject of much debate over many decades with various factors proposed and discounted. 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. In the absence of a confirmed specific pathology underlying the diagnosis, some question the legitimacy of schizophrenia's status as a disease. Furthermore, some propose that the perceptions and feelings involved are meaningful and do not necessarily involve impairment.

Although no common cause of schizophrenia has been identified in all individuals diagnosed with the condition, currently most researchers and clinicians believe it results from a combination of both brain vulnerabilities (either inherited or acquired) and life events. This widely-adopted approach is known as the 'stress-vulnerability' model, and much scientific debate now focuses on how much each of these factors contributes to the development and maintenance of schizophrenia. Schizophrenia is most commonly first diagnosed during late adolescence or early adulthood suggesting it is often the end process of childhood and adolescent development. There is on average a somewhat earlier onset for men than women, with the possible influence of the female hormone oestrogen being one hypothesis and sociocultural influences another.[citation needed]

Genes

While the reliability of the schizophrenia diagnosis introduces difficulties in measuring the effect of genes (for example, symptoms overlap to some extent with severe bipolar disorder or major depression), evidence suggests that genetic vulnerability and environmental factors can act in combination to result in diagnosis of schizophrenia.[2] Schizophrenia is likely to be a diagnosis of complex inheritance. Thus, it is likely that several genes interact to generate risk for schizophrenia or for the separate components that can co-occur to lead to a diagnosis.[3] This, combined with disagreements over which research methods are best, or how data from genetic research should be interpreted, has led to differing estimates over genetic contribution.

Both individual twin studies and meta-analyses of twin studies estimate 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). Adoption studies have also indicated a somewhat increased risk in those with a parent with schizophrenia even when raised apart. Studies suggest that the phenotype is genetically influenced but not genetically determined; that the variants in genes are generally within the range of normal human variation and have low risk associated with them each individually; and that some interact with each other and with environmental risk factors; and that they may not be specific to schizophrenia.[4] Some twin studies[5][6] have found rates as low as 11.0%–13.8% among monozygotic twins, and 1.8%–4.1% among dizygotic twins, however. In addition, some scientists criticize the methodology of the twin studies, and have argued that the genetic basis of schizophrenia is still largely unknown or open to different interpretations.[citation needed]

There is currently a great deal of effort being put into molecular genetic studies of schizophrenia, which attempt to identify specific genes which may increase risk. Because of this, the genes that are thought to be most involved can change as new evidence is gathered. A 2003 review of linkage studies listed seven genes as likely to increase risk for a later diagnosis of the disorder.[2] Two more recent reviews[3][4] have suggested that the evidence is currently strongest for two genes known as dysbindin (DTNBP1) and neuregulin (NRG1), with a number of other genes (such as COMT, RGS4, PPP3CC, ZDHHC8, DISC1, and AKT1) showing some early promising results that have not yet been fully replicated. Variations near the gene FXYD6 have been associated with schizophrenia in the UK[7][8] but not in Japan.[9] 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.[10]

Recent research has suggested that a greater than average number of rare deletions or duplications of tiny DNA sequences within genes (known as copy number variants) are linked to increased risk for schizophrenia, especially in those "sporadic" cases not linked to family history of schizophrenia, and that the genetic factors and developmental pathways can thus be different in different individuals.[11][12]

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, has reported no 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.[13]

Obstetric events

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 25–30% 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.[14]

One epidemiological finding is that people diagnosed with schizophrenia are more likely to have been born in winter or spring[15] (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.[16] 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.[17] 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.[18]

Fetal growth

Lower than average birth weight has been one of the most consistent findings, indicating slowed fetal growth possibly mediated by genetic effects. Almost any factor adversely affecting the fetus will affect growth rate, however, so the association has been described as not particularly informative regarding causation.[14] 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.[19]

Animal models have suggested links between intrauterine growth restriction and specific neurological abnormalities similar to those that may be involved in the development of schizophrenia, including ventricular enlargement and reduced hippocampal volume in guinea pigs.[20]

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.[21][22] This has been recently described as one of the most important of the external factors that influence susceptability, although studies have been mainly epidemiological. 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.[23] 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 and/or vascular expression".[24]

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.[25] 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.[26] 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.[27] 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.[28] 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.[29]

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".[30][31] 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.[32]

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%).[33]

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 parental age has been linked[4], possibly due to prenatal complications increasing the risk of genetic mutations. Maternal-fetal rhesus or genotype incompatibility has also been linked, via increasing the risk of an adverse prenatal environment. And, 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.[14]

Infections

Numerous viral infections, in utero or in childhood, have been associated with an increased risk of later developing schizophrenia.[34] Schizophrenia is somewhat more common in those born in winter to early spring, when infections are more common.[35]

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.[36] This result was corroborated by a later British study of the same pandemic,[37], but not by a 1994 study of the pandemic in Croatia.[38] A Japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic.[39]

Polio, measles, varicella-zoster, rubella, herpes simplex virus type 2, maternal genital infections, and more recently Toxoplasma gondii, have been correlated with the later development of schizophrenia.[40] However, studies of postmortem brain tissue have reported equivocal or negative results, including no evidence of herpesvirus or T. Gondii DNA in schizophrenia in a recent study.[41]

Psychiatrists E. Fuller Torrey and R.H. Yolken have hypothesized that the common parasite Toxoplasma gondii contributes to some if not many cases of schizophrenia.[42] Studies have tended to find moderately higher levels of Toxoplasma antibodies in those with schizophrenia[43][44] and possibly higher rates of prenatal or early postnatal exposure to Toxoplasma gondii, but not to acute infection. Causal mechanisms remain speculative.[40]

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[45] and direct studies have linked dysfunctional immune status to some of the clinical features of schizophrenia.[46][47]

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. 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.[19]

A prospective study found average diffferences 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.[48]

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.[49] The early subtle motor signs persisted to some extent, showing a small link to later school performance in adolescence.[50] 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).[51] 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.[52] 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.[26]

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.[25] 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.[53]

Some small studies on offspring of individuals with schizophrenia have identified various neurobehavioral deficits,[54] a poorer family environment and disruptive school behaviour,[55] poor peer engagement, immaturity or unpopularity[56] or poorer social competence and increasing schizophrenic symptomology emerging during adolescence.[57]

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.[58]

Substance use

The relationship between schizophrenia and drug use is complex, meaning that a clear causal connection between drug use and schizophrenia has been difficult to tease apart. There is strong evidence that using certain drugs can trigger either the onset or relapse of schizophrenia in some people. It may also be the case, however, that people with schizophrenia use drugs to overcome negative feelings associated with both the commonly prescribed antipsychotic medication and the condition itself, where negative emotion, paranoia and anhedonia are all considered to be core features.

The rate of substance use is known to be particularly high in this group. In a recent study, 60% of people with schizophrenia were found to use substances and 37% would be diagnosable with a substance use disorder.[59]

Amphetamines

As amphetamines trigger the release of dopamine and excessive dopamine function is believed to be responsible for many symptoms of schizophrenia (known as the dopamine hypothesis of schizophrenia), amphetamines may worsen schizophrenia symptoms.[citation needed]

Hallucinogens

Schizophrenia can sometimes be triggered by heavy use of hallucinogenic or stimulant drugs,[60] although some claim that a predisposition towards developing schizophrenia is needed for this to occur. There is also some evidence suggesting that people suffering schizophrenia but responding to treatment can have relapse because of subsequent drug use.

Drugs such as ketamine, PCP, and LSD have been used to mimic schizophrenia for research purposes. Using LSD and other psychedelics as a model has now fallen out of favor with the scientific research community, as the differences between the drug induced states and the typical presentation of schizophrenia have become clear. The dissociatives ketamine and PCP are still considered to produce states that are remarkably similar however.

Cannabis

There is evidence that cannabis use can contribute to schizophrenia. Some studies suggest that cannabis is neither a sufficient nor necessary factor in developing schizophrenia, but that cannabis may significantly increase the risk of developing schizophrenia and may be, among other things, a significant causal factor. Nevertheless, some previous research in this area has been criticised as it has often not been clear whether cannabis use is a cause or effect of schizophrenia. To address this issue, a recent review of studies from which a causal contribution to schizophrenia can be assessed has suggested that cannabis statistically doubles the risk of developing schizophrenia on the individual level, and may, assuming a causal relationship, be responsible for up to 8% of cases in the population.[61]

An older longitudinal study, published in 1987, suggested six-fold increase of schizophrenia risks for high consumers of cannabis (use on more than fifty occasions) in Sweden.[62]

Clues from 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.[63][64] 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.[65] An older study found that as much as 88% of outpatients with schizophrenia were smokers.[66]

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.[67]

A recent study of over 50,000 Swedish conscripts found that there was a small but significant protective effect of smoking cigarettes on the risk of developing schizophrenia later in life.[68] While the authors of the study stressed that the risks of smoking far outweigh these minor benefits, this study provides further evidence for the 'self-medication' theory of smoking in schizophrenia and may give clues as to how schizophrenia might develop at the molecular level. Furthermore, many people with schizophrenia have smoked tobacco products long before they are diagnosed with the illness, and some groups advocate that the chemicals in tobacco have actually contributed to the onset of the illness and have no benefit of any kind.[citation needed]

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.[citation needed]

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.[69] 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.[69]

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.[70][71] Stressful life events generally precede the onset of schizophrenia.[72] 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.[73][74] Childhood experiences of abuse or trauma are risk factors for a diagnosis of schizophrenia later in life.[75][76][77][78] Recent large-scale general population studies indicate the relationship is a causal one, with an increasing risk with additional experiences of maltreatment,[79] although a critical review suggests conceptual and methodological issues require further research.[80] There is some evidence that adversities may lead to cognitive biases and/or altered dopamine neurotransmission, a process that has been termed "sensitization".[81] 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.[82]

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.[83] A recent study of 4.4 million men and women in Sweden found an 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.[84] The effect does not appear to be due to a higher incidence of obstetric complications in urban environments.[85] 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.[86] 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.[87]

Close relationships

Evidence is consistent that 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).[88] 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.[89][90]

Neural processes

Structural

Differences in the size and structure of certain brain areas have been found in some adults diagnosed with schizophrenia. Early findings came from the discovery of ventricular enlargement in people diagnosed with schizophrenia with negative symptoms most prominent.[91] However, this finding has not proved particularly reliable on the level of the individual person, with considerable variation between patients.

More recent studies have shown a large number of differences in brain structure between people with and without diagnoses of schizophrenia.[92] However, as with earlier studies, many of these differences are only reliably detected when comparing groups of people, and are unlikely to predict any differences in brain structure of an individual person with schizophrenia.

A 2005 meta-analysis reported that 69% of the 15 studies used found volumetric deficits in the left medial temporal lobe; 57% in the left superior temporal gyrus; and 50% in the left medial frontal gyrus, left parahippocampal gyrus, right superior temporal gyrus, and left inferior frontal gyrus.[93]

Studies of the rare childhood-onset schizophrenia (prior to age 13) indicate a greater-than-normal loss of grey matter over several years, progressing from the back of the brain to the front, levelling out in early adulthood. Such a pattern of "pruning" occurs as part of normal brain development but appears to be exaggerated in childhood-onset psychotic disorders, particularly in schizophrenia. Abnormalities in the volume of the ventricles or frontal lobes have also been found in some studies, but not in others. Volume changes are most likely glial and vascular rather than purely neuronal, and reduction in grey matter may primarily reflect a reduction of neuropil rather than a deficit in the total number of neurons. Studies to date have been based on small numbers of the most severe and treatment-resistant patients taking antipsychotics.[94]

Functional magnetic resonance imaging and other brain imaging technologies allow for the study of differences in brain activity among people diagnosed with schizophrenia.

Functional

Some studies using neuropsychological tests and brain imaging technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes.[95] Abnormalities of the kind shown are linked to the same neurocognitive deficits often associated with schizophrenia, particularly in areas of memory,[96] attention, problem solving, executive function, and social cognition.[citation needed] Observations of the frontal lobe in patients with schizophrenia are inconsistent: While many studies have found abnormalities, others have found no[97] or only a statistically insignificant[98] difference. Data from a PET study[99] suggests that the less the frontal lobes are activated during a working memory task, the greater the increase in abnormal dopamine activity in the striatum, thought to be related to the neurocognitive deficits in schizophrenia.

Electroencephalograph (EEG) recordings of persons with schizophrenia performing perception oriented tasks showed an absence of gamma band activity in the brain, indicating weak integration of critical neural networks in the brain.[100] Those who experienced intense hallucinations, delusions and disorganized thinking showed the lowest frequency synchronization. None of the drugs taken by the persons scanned had moved neural synchrony back into the gamma frequency range. Gamma band and working memory alterations may be related to alterations in interneurons that produce the neurotransmitter GABA.

Dopamine

Main article: Dopamine hypothesis of schizophrenia

Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. An influential theory, known as the "dopamine hypothesis of schizophrenia", proposed that a malfunction involving dopamine pathways was therefore the cause of (the positive symptoms of) schizophrenia. Evidence for this theory includes[101] findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors;[102] and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia;[103][104] and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum.

However, there was controversy and conflicting findings over whether post-mortem findings resulted from chronic antipsychotic treatment. Studies using SPET and PET methods in drug naive patients have generally failed to find any difference in dopamine D2 receptor density compared to controls. Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful.[105][106] In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity.

It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them.[107] Increased dopamine sensitivity may be a common final pathway.[108]

Another reliable finding is that there is an excess of binding sites insensitive to a certain testing agent (raclopride) [109]

Another one of Philip Seeman's findings was that the dopamine D2 receptor protein looked abnormal in schizophrenia. Proteins change states by flexing. The activating of the protein by folding could be permanent or fluctuating,[110] just like the courses of patients' illnesses waxes and wanes. Increased folding of a protein leads to increased risk of 'additional fragments' forming [111]The schizophrenic d2 receptor has a unique additional fragment when digested by papain in the test-tube in the FASEB experiment above, but none of the controls exhibited the same fragment. The D2 receptor in schizophrenia are thus in a highly active state as found by Philip Seeman et al.[112]

Glutamate

Main article: Glutamate hypothesis of schizophrenia

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia[113] and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.[114] The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.[115] Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia.[116]

Other

Dyregulation of neural calcium homeostasis has been hypothesized to be a link between the glutamate and dopaminergic abnormalities[117] and some small studies have indicated that calcium channel blocking agents can lead to improvements on some measures in schizophrenia with tardive dyskinesia.[118]

There is evidence of irregular cellular metabolism and oxidative stress in the prefrontal cortex in schizophrenia, involving increased glucose demand and/or cellular hypoxia.[119]


Development of specific delusions

Andrew Sims has said that the top two 'Factors mainly concerned in the germination of delusions' are:1. Disorder of brain functioning and 2. background influences of temperament and personality[120].

Higher levels of dopamine qualify as the 'disorders of brain function'. They are needed to sustain certain delusions is confirmed by a study on delusional disorder (another psychotic syndrome). "...pHVA [homovanillic acid] was employed as a "state marker" of the [delusional] disorder...": Delusions of persecution and delusions of jealousy were able to be differentiated by the amount of acid that was released when the dopamine was digested."... From these findings, it seems that pHVA varies depending upon the subtype and course of schizophrenia, and it is also strongly influenced by neuroleptic treatment."[121] This is confirmed in that very high recreational use of amphetamine produces Gender Identity Disorder delusions (which the DSM says are rare)[122], while medical doses of amphetamine can produce morbid jealousy[123]

Sims examines certain personality traits that are commonly associated with delusions.

Cultural factors have "a decisive factor in shaping delusions". [124] For example, delusions of guilt and punishment are frequesnt in a Western, Christian country like Austria, but not in Pakistan - where it is more likely persecution. It says cultural factors have a decisive influence in shaping delusions. [125] . Frequent delusions of guilt and punishment are shown in Austria as well and this is with Parkinson's patients treated with l-dopa.[126]

Cognition and emotion

A number of cognitive biases or deficits have been found in people diagnosed with schizophrenia. These include jumping to conclusions when faced with limited or contradictory information; specific biases in reasoning about social situations, for example assuming other people cause things that go wrong (external attribution); difficulty distinguishing inner speech from speech from an external source (source monitoring); difficulty in adjusting speech to the needs of the hearer, related to theory of mind difficulties; difficulties in the very earliest stages of processing visual information (including reduced latent inhibition); difficulty with attention e.g. being more easily distracted, attentional bias towards threat. Some of these tendencies have been shown to worsen or appear when under emotional stress or in confusing situations. As with the related neurological findings, they are not shown by all individuals with a diagnosis of schizophrenia and it is not clear how specific they are to schizophrenia or to particular symptoms.[127] However, the findings regarding cognitive difficulties in schizophrenia are reliable and consistent enough for some researchers to argue that they are diagnostic.[128] 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.[129] Similar cognitive features have been identified in close relatives of people diagnosed with schizophrenia.[130]

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.[131] Some theories suggest positive symptoms of schizophrenia can result from or be worsened by negative emotions, including depressed feelings and low self-esteem[132] and feelings of vulnerability, inferiority or loneliness.[133] Chronic negative feelings and maladaptive coping skills may explain some of the association between psychosocial stressors and symptomology.[134] Critical and controlling behaviour by significant others (high expressed emotion) causes increased emotional arousal[135] and lowered self-esteem[136] 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.[137] Holding minority or poorly understood sociocultural beliefs, for example due to ethnic background, has been linked to increased diagnosis of schizophrenia. The way an individual personally understands and attributes their delusions or hallucinations (e.g. as threatening or as potentially positive) has also been found to influence functioning and recovery.[138]

Information processing disorders - backed up by Andrzej Jakubik "Personality disorders" (ISBN 83-200-2087-5). pages 218 and following, suggests that in paranoid schizophrenia short term memory organization levels and data processing structures related are impaired, especially selection, structuralisation and recall related functional circuits. His references are :[139][140][141][142][143][144][145][146][147][148][149][150][151][152][153]

Notes

  1. ^ American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th Edition TR Washington, DC: American Psychiatric Association.
  2. ^ a b Harrison PJ, Owen MJ. (2003). Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet, 361(9355), 417–9. PMID 12573388
  3. ^ a b Owen MJ, Craddock N, O'Donovan MC. (2005). Schizophrenia: genes at last? Trends in Genetics, 21(9), 518–25. PMID 16009449
  4. ^ a b c Riley B, Kendler KS (2006). Molecular genetic studies of schizophrenia. Eur J Hum Genet, 14 (6), 669–80. PMID 16721403
  5. ^ Koskenvuo M, Langinvainio H, Kaprio J, Lonnqvist J, Tienari P (1984). Psychiatric hospitalization in twins. Acta Genet Med Gemellol (Roma), 33(2),321–32. PMID 6540965
  6. ^ Hoeffer A, Pollin W. (1970). Schizophrenia in the NAS-NRC panel of 15,909 veteran twin pairs. Archives of General Psychiatry, 1970 Nov; 23(5):469–77. PMID 5478575
  7. ^ Getting Crowded on Chromosome 11q22—Make Way for Phosphohippolin. Schizophrenia Research Forum, 14 March 2007. Retrieved on 2007-05-16
  8. ^ Choudhury K, McQuillin A, Puri V, Pimm J, et al (2007). Am J Hum Genet. Apr;80(4):664-72. PMID 17357072
  9. ^ Ito Y, Nakamura Y, Takahashi N, Saito S, Aleksic B, Iwata N, Inada T, Ozaki N. (2008) A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population. Neurosci Lett. 2008 Jun 13;438(1):70-5. PMID 18455306
  10. ^ Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O'Donovan M, O'Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A (2008). "Genome-Wide Association Identifies a Common Variant in the Reelin Gene That Increases the Risk of Schizophrenia Only in Women". PLoS Genetics. 4 (2): e28. doi:10.1371/journal.pgen.0040028. PMID 18282107.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  11. ^ Walsh T (2008). "Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia". Science. 320 (5875): 539–43. doi:10.1126/science.1155174. PMID 18369103. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  12. ^ Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008 Jul;40(7):880-5. PMID 18511947
  13. ^ Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C; et al. (2008). "No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics". American Journal of Psychiatry. 165 (4): 497–506. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Comment:
  14. ^ a b c Mary Catherine Clarke, Michelle Harley and Mary Cannon (2006) The Role of Obstetric Events in Schizophrenia Schizophrenia Bulletin 2006 32(1):3-8; doi:10.1093/schbul/sbj028
  15. ^ Davies G, Welham J, Chant D, Torrey EF, McGrath J. (2003). A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophrenia Bulletin, 29 (3), 587–93. PMID 14609251
  16. ^ Gobet, F. & Chassy, P. (2008). Season of birth and chess expertise. Journal of Biosocial Science, 40, 313-316. Available online at http://bura.brunel.ac.uk/bitstream/2438/736/1/Seasonality+and+chess.pdfPDF (65.8 KiB) Retrieved 22 July 2007.
  17. ^ Susser E, Neugebauer R, Hoek HW, et al (1996). Schizophrenia after prenatal famine. Further evidence. Archives of General Psychiatry, 53(1), 25–31. PMID 8540774
  18. ^ Huttunen MO, Niskanen P. (1978). Prenatal loss of father and psychiatric disorders. Archives of General Psychiatry, 35(4), 429–31. PMID 727894
  19. ^ a b Welham J, Isohanni M, Jones P, McGrath J. The Antecedents of Schizophrenia: A Review of Birth Cohort Studies. Schizophr Bull. 2008 Jul 24. PMID 18658128
  20. ^ Mallard, E.C., Rehn, A., Rees, S., Tolcos, M. and Copolov, D. (1999). Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia Schizophrenia Research, 40, 1, 11-21.
  21. ^ R.A. Hanford, Brain Hypoxia, minimal brain dysfunction and schizophrenia, American Journal of Psychiatry 132:2 1975 p192 PMID 1111324
  22. ^ The above reference is cited in a 2006 work, in giving a history of minimal brain dysfunction saying: "It was also noted that individuals who experienced perinatal brain hypoxia constituted a population at risk for minimal brain dysfunction, and that children attending psychiatric clinics often presented with illnesses or perinatal complications of a sort known to be associated with neurological brain damage (Handford 1975)."Disorganized Children : A Guide for Parents and Professionals Jessica Kingsley Publishers Ltd. Stein, Samuel M.p135
  23. ^ van Erp, T. G.M., Saleh, P. A., Rosso, I. M., Huttunen, M., Lonnqvist, J., Pirkola, T., Salonen, O., Valanne, L., Poutanen, V.-P., Standertskjold-Nordenstam, C.-G., Cannon, T. D. (2002). "Contributions of Genetic Risk and Fetal Hypoxia to Hippocampal Volume in Patients With Schizophrenia or Schizoaffective Disorder, Their Unaffected Siblings, and Healthy Unrelated Volunteers," American Journal of Psychiatry, 159:1514-1520
  24. ^ Schmidt-Kastner R, van Os J, Steinbusch HWM, Schmitz C. (2006). Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia Schizophrenia Research, 84(2-3), 253-271.
  25. ^ a b Mary Cannon, MD, PhD; Avshalom Caspi, PhD; Terrie E. Moffitt, PhD; HonaLee Harrington, BS; Alan Taylor, MSc; Robin M. Murray, MD, DSc; Richie Poulton, PhD (2002) Evidence for Early-Childhood, Pan-Developmental Impairment Specific to Schizophreniform Disorder: Results From a Longitudinal Birth Cohort (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 59, MAY 2002 p449
  26. ^ a b Rosso, I.M., Bearden, C.E., Hollister, J.M., Gasperoni, T.L., Sanchez, L.E., Hadley, T. and Cannon, T.D. (2000) Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study Schizophrenia Bulletin, 26(2), 371-374.
  27. ^ Kunugi, H., Urushibara, T., Murray, R.M., Nanko, S., and Hirose, T. (2003). Prenatal underdevelopment and schizophrenia: A case report of monozygotic twins Psychiatry and Clinical Neurosciences, 57, 271–274.
  28. ^ Murray, Robin M., and Fearon, Paul (1999). The developmental 'risk factor' model of schizophrenia," Journal of Psychiatric Research, 33, 497-499. PMID 10628525
  29. ^ Cannon, M. and Murry, R. Neonatal origins of schizophrenia Arch. Dis. Child. 1998;78;1-3
  30. ^ Hava Golan and Mahmoud Huleihel (2006) The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent models Developmental Science 9:4 (2006), pp 338–349
  31. ^ Golan H., Kashtutsky, I., Hallack, M., Sorokin, Y., Huleihel, M. (2004) Maternal Hypoxia during pregnancy delays the development of motor reflexes in newborn mice. Developmental Neuroscience, 26:24-29.
  32. ^ Ellman, LM and Cannon TD, "Chapter 7. Environmental pre- and preinatal influences in etiology" in Clinical Handbook of Schizophrenia by Kim T. Mueser, Dilip V. Jeste New York : Guilford Press, ©2008 p69
  33. ^ Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: A 19-year longitudinal study Gwen L Zornberg, Stephen L Buka, Ming T Tsuang. The American Journal of Psychiatry. Washington: Feb 2000. Vol. 157, Iss. 2; p. 196 (7 pages), p198
  34. ^ Brown, Alan S. (2008) "The Risk for Schizophrenia From Childhood and Adult Infections," Am J Psychiatry 165:7-10
  35. ^ Torrey EF, Miller J, Rawlings R, Yolken RH (1997). "Seasonality of births in schizophrenia and bipolar disorder: A review of the literature," Schizophrenia Research, 28:1–38.
  36. ^ Mednick SA, Machon RA, Huttunen MO, Bonett D (1988). "Adult schizophrenia following prenatal exposure to an influenza epidemic," Arch Gen Psychiatry, 45:189–192
  37. ^ Cooper, SJ (1992). "Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic," The British Journal of Psychiatry, 161: 394-396
  38. ^ Erlenmeyer-Kimling, L.; Folnegovic, Z.; Hrabak-Zerjavic, V.; Borcic, B.; Folnegovic-Smalc, V.; and Susser, E. (1994). "Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia," Am J Psychiatry, 151:1496-1498
  39. ^ Mino, Yoshio; Oshimab, Iwao; Tsudaa, Toshihide; and Okagami, Kazuo (2000). "No relationship between schizophrenic birth and influenza epidemics in Japan," Journal of Psychiatric Research, 34(2):133-138
  40. ^ a b Mortensen PB, Nørgaard-Pedersen B, Waltoft BL, Sørensen TL, Hougaard D, Yolken RH. Early infections of Toxoplasma gondii and the later development of schizophrenia. Schizophr Bull. 2007 May;33(3):741-4.
  41. ^ Conejero-Goldberg C, Torrey EF, Yolken RH. Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients. Schizophr Res. 2003 Mar 1;60(1):65-9. PMID 12505139
  42. ^ Torrey EF, Yolken RH (2003). "Toxoplasma gondii and schizophrenia," Emerging Infectious Diseases, 9 (11), 1375–80. PMID 14725265
  43. ^ Torrey, EF; Bartko, John J.; Lun, Zhao-Rong; and Yolken, Robert H. (2007). "Antibodies to Toxoplasma gondii in Patients With Schizophrenia: A Meta-Analysis," Schizophrenia Bulletin, 33(3):729-736
  44. ^ Wang HL, Wang GH, Li QY, Shu C, Jiang MS, Guo Y (2006). "Prevalence of Toxoplasma infection in first-episode schizophrenia and comparison between Toxoplasma-seropositive and Toxoplasma-seronegative schizophrenia," Acta Psychiatrica Scandinavica, 114 (1), 40–48. PMID 16774660
  45. ^ Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, Mortensen PB (2006). Association of Schizophrenia and Autoimmune Diseases: Linkage of Danish National Registers. American Journal of Psychiatry 163, 521–528. PMID 16513876
  46. ^ Jones AL, Mowry BJ, Pender MP, Greer JM. (2005). Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol, 83 (1), 9–17. PMID 15661036
  47. ^ Strous RD, Shoenfeld Y (2006). Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. Journal of Autoimmunity 2006 Sep;27(2):71–80. PMID 16997531
  48. ^ Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort Jones, Peter; Rodgers, Bryan; Murray, Robin; Marmot, Michael The Lancet; Nov 19, 1994; 344, 8934 pg. 1398 PMID 7968076
  49. ^ M. Isohanni, P.B. Jones, K. Moilanen, P. Rantakallio, J. Veijola, H. Oja, M. Koiranen, J. Jokelainen, T. Croudace, M-R. Jarvelin. (2001) "Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort" Schizophrenia Research 52 p2 PMID 11595387
  50. ^ Isohanni, M., Murraya, G.K., Jokelainenc, J., Croudaceb, T., & Jones, P.B. The persistence of developmental markers in childhood and adolescence and risk for schizophrenic psychoses in adult life. A 34-year follow-up of the Northern Finland 1966 birth cohort Schizophrenia Research Volume 71, Issues 2-3, 1 December 2004, Pages 213-225
  51. ^ Cannon, M, Jones, P, Huttunen, M.O., Tanskanen, A, Murray, R. (1999) Motor Co-ordination Deficits as Predictors of Schizophrenia Among Finnish School Children Hum. Psychopharmacol. Clin. Exp. 14, 491±497
  52. ^ Isohanni, M., Isohanni, I., Nieminen, P., Jokelainen, J. and Järvelin, M.-R., 2000. School predictors of schizophrenia. Letter to the editor. Arch. Gen. Psychiatry 57, p. 813.
  53. ^ I. Helling, A. Öhman, C. M. Hultman School achievements and schizophrenia: a case–control study Acta Psychiatrica Scandinavica Volume 108 Issue 5, Pages 381 - 386
  54. ^ Hans SL, Marcus J, Nuechterlein KH, et al (1999). Neurobehavioral deficits at adolescence in children at risk for schizophrenia: The Jerusalem Infant Development Study. Arch Gen Psychiatry. 56(8):741–8. PMID 10435609
  55. ^ Carter JW, Schulsinger F, Parnas J, Cannon T, Mednick SA. (2002). A multivariate prediction model of schizophrenia. Schizophrenia Bulletin 28(4):649–82. PMID 12795497
  56. ^ Hans SL, Auerbach JG, Asarnow JR, Styr B, Marcus J. (2000). Social adjustment of adolescents at risk for schizophrenia: the Jerusalem Infant Development Study. J Am Acad Child Adolesc Psychiatry. 39(11):1406–14. PMID 11068896
  57. ^ Dworkin RH, Bernstein G, Kaplansky LM, et al (1991). Social competence and positive and negative symptoms: a longitudinal study of children and adolescents at risk for schizophrenia and affective disorder. Am J Psychiatry. Sep;148(9):1182–8. PMID 1882996
  58. ^ Galderisi S, Maj M, Mucci A, Cassano GB, Invernizzi G, Rossi A, Vita A, Dell'Osso L, Daneluzzo E, Pini S. (2002) Historical, psychopathological, neurological, and neuropsychological aspects of deficit schizophrenia: a multicenter study Am J Psychiatry. 2002 Jun;159(6):983-90.
  59. ^ Swartz MS, Wagner HR, Swanson JW, et al (2006). Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study. Journal of Nervous and Mental Disease, 194(3), 164–72. PMID 16534433
  60. ^ Mueser KT, Yarnold PR, Levinson DF, et al (1990). Prevalence of substance abuse in schizophrenia: demographic and clinical correlates. Schizophrenic Bulletin, 16(1), 31–56. PMID 2333480
  61. ^ Arseneault L, Cannon M, Witton J, Murray RM (2004). Causal association between cannabis and psychosis: examination of the evidence. British Journal of Psychiatry, 184, 110-7. PMID 14754822 Full text available.
  62. ^ Andreasson S, Allebeck P, Engstrom A, and Rydberg U (1987). Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet, 1987, Dec 26, 2(8574), 1483–6. PMID 2892048
  63. ^ McNeill, Ann (2001). "Smoking and mental health — a review of the literature" (PDF). SmokeFree London Programme. Retrieved 2006-12-14. {{cite journal}}: Cite journal requires |journal= (help)
  64. ^ Meltzer H, Gill B, Petticrew M, Hinds K. (1995). "OPCS Surveys of Psychiatric Morbidity Report 3: Economic Activity and Social Functioning of Adults With Psychiatric Disorders". London, Her Majesty’s Stationery Office. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link) Available for fee.
  65. ^ Kelly, C (1999). "Smoking Habits, Current Symptoms, and Premorbid Characteristics of Schizophrenic Patients in Nithsdale, Scotland". The American Journal of Psychiatry. 156. American Psychiatric Association: 1751–1757. PMID 10553739. Retrieved 2006-12-14. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  66. ^ Hughes, JR (1986). "Prevalence of smoking among psychiatric outpatients". The American Journal of Psychiatry. 143. American Psychiatric Association: 993–997. PMID 3487983. Retrieved 2006-12-14. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  67. ^ "Conditions in Occupational Therapy: effect on occupational performance." ed. Ruth A. Hansen and Ben Atchison (Baltimore: Lippincott Williams & Williams, 2000), 54–74. ISBN 0-683-30417-8
  68. ^ Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingsson T, Lewis G (2003). Investigating the association between cigarette smoking and schizophrenia in a cohort study. American Journal of Psychiatry, 160 (12), 2216–21. PMID 14638593
  69. ^ a b Compton, Michael T. (2005-11-16). "Cigarette Smoking in Individuals with Schizophrenia". Medscape Psychiatry & Mental Health. Retrieved 2007-05-17. {{cite web}}: Check date values in: |date= (help)
  70. ^ Wicks S, Hjern A, Gunnell D, Lewis G, Dalman C. Social adversity in childhood and the risk of developing psychosis: a national cohort study Am J Psychiatry. 2005 Sep;162(9):1652-7.
  71. ^ Mueser KT, McGurk SR (2004). "Schizophrenia". The Lancet. 363 (9426): 2063–72. doi:10.1016/S0140-6736(04)16458-1. PMID 15207959.
  72. ^ Day R, Nielsen JA, Korten A, Ernberg G, et al (1987). Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization. Culture, Medicine and Psychiatry, 11 (2), 123–205. PMID 3595169
  73. ^ Selten JP, Cantor-Graae E, Kahn RS (2007). "Migration and schizophrenia". Current Opinion in Psychiatry. 20 (2): 111–115. doi:10.1097/YCO.0b013e328017f68e. PMID 17278906. Retrieved 2008-07-06. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  74. ^ Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review Am J Psychiatry. 2005 Jan;162(1):12-24.
  75. ^ Harriet L. MacMillan, Jan E. Fleming, David L. Streiner, et al (2001). Childhood Abuse and Lifetime Psychopathology in a Community Sample. American Journal of Psychiatry,158, 1878–83. PMID 11691695
  76. ^ Schenkel LS, Spaulding WD, Dilillo D, Silverstein SM (2005). Histories of childhood maltreatment in schizophrenia: Relationships with premorbid functioning, symptomatology, and cognitive deficits. Schizophrenia Research Jul 15;76(2–3):273–286. PMID 15949659Full-text available for purchase, Retrieved on 2007-05-16
  77. ^ Janssen I, Krabbendam L, Bak M, Hanssen M, et al (2004). Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatrica Scandinavica, 109, 38–45. PMID 14674957
  78. ^ Read J, Perry BD, Moskowitz A, Connolly J (2001). The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry, 64, 319-45. PMID 11822210Full text) (PDF), Retrieved on 2007-05-16
  79. ^ J. Read, J. van Os, A. P. Morrison, C. A. Ross Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications Acta Psychiatrica Scandinavica Volume 112 Issue 5, Pages 330 - 350
  80. ^ Morgan C, Fisher H. (2007) Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma--a critical review Schizophr Bull. 2007 Jan;33(1):3-10.
  81. ^ Collip D, Myin-Germeys I, Van Os J. Does the concept of "sensitization" provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull. 2008 Mar;34(2):220-5 PMID 18203757
  82. ^ Bentall RP, Fernyhough C. Social Predictors of Psychotic Experiences: Specificity and Psychological Mechanisms Schizophr Bull. 2008 Aug 14.
  83. ^ Van Os J. (2004). Does the urban environment cause psychosis? British Journal of Psychiatry, 184 (4), 287–288. PMID 15056569
  84. ^ Sundquist K, Frank G, Sundquist J. (2004). Urbanisation and incidence of psychosis and depression: Follow-up study of 4.4 million women and men in Sweden. British Journal of Psychiatry, 184 (4), 293–298. PMID 15056572
  85. ^ Eaton WW, Mortensen PB, Frydenberg M. Obstetric factors, urbanization and psychosis. Schizophr Res. 2000 Jun 16;43(2-3):117-23. PMID 10858630
  86. ^ Carsten Bøcker Pedersen; Preben Bo Mortensen Evidence of a Dose-Response Relationship Between Urbanicity During Upbringing and Schizophrenia Risk Arch Gen Psychiatry. 2001;58:1039-1046.
  87. ^ Krabbendam L, van Os J. Schizophrenia and urbanicity: a major environmental influence--conditional on genetic risk. Schizophr Bull. 2005 Oct;31(4):795-9.
  88. ^ Bebbington PE, Kuipers E (1994). The predictive utility of expressed emotion in schizophrenia: an aggregate analysis. Psychological Medicine, 24, 707–718. PMID 7991753
  89. ^ Bentall RP (2007). "Prospects for a cognitive-developmental account of psychotic experiences". Br J Clin Psychol. 46 (Pt 2): 155–73. doi:10.1348/014466506X123011. PMID 17524210. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  90. ^ Subotnik, KL (2002). "Are Communication Deviance and Expressed Emotion Related to Family History of Psychiatric Disorders in Schizophrenia?". Schizophrenia Bulletin. 28 (4): 719–29. PMID 12795501. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  91. ^ Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L. (1976). Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet, 30;2 (7992), 924–6. PMID 62160
  92. ^ Flashman LA, Green MF (2004). Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment. Psychiatric Clinics of North America, 27 (1), 1–18, vii. PMID 15062627
  93. ^ Honea R., Crow T., Passingham D., Mackay C. (2005). "Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies," Am J Psychiatry, 162:2233-2245
  94. ^ Arango C, Moreno C, Martínez S; et al. (2008). "Longitudinal brain changes in early-onset psychosis". Schizophr Bull. 34 (2): 341–53. doi:10.1093/schbul/sbm157. PMID 18234701. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  95. ^ Green, M.F. (2001) Schizophrenia Revealed: From Neurons to Social Interactions. New York: W.W. Norton. ISBN 0-393-70334-7
  96. ^ Park S, Holzman PS (1992). "Schizophrenics show spatial working memory deficits," Arch Gen Psychiat, 49:975–982.
  97. ^ Wible CG, Shenton ME, Hokama H, Kikinis R, Jolesz FA, Metcalf D, McCarley RW (1995) Prefrontal cortex and schizophrenia. A quantitative magnetic resonance imaging study. Arch Gen Psychiat 52:279–288.
  98. ^ Selemon LD, Rajkowska G, Goldman-Rakic PS (1998) Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional stereologic counting method. J Comp Neurol 392:402–412.
  99. ^ Meyer-Lindenberg A, Miletich RS, Kohn PD, et al (2002). Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nature Neuroscience, 5, 267–71. PMID 11865311
  100. ^ Spencer KM, Nestor PG, Perlmutter R, et al (2004). Neural synchrony indexes disordered perception and cognition in schizophrenia. Proceedings of the National Academy of Sciences, 101, 17288-93. PMID 15546988 Full text, Retrieved 2007-05-16.
  101. ^ Stefan, Martin (2002). An Atlas of Schizophrenia, p. 54
  102. ^ Creese I, Burt DR, Snyder SH (1976). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs," Science:19:481–3
  103. ^ Angrist B, van Kammen DP (1984). "CNS stimulants as a tool in the study of schizophrenia," Trends in Neurosciences, 7:388–90
  104. ^ Lieberman JA, Kane JM, Alvir J (1987). "Provocative tests with psychostimulant drugs in schizophrenia," Psychopharmacology, 91:415–33
  105. ^ Laruelle M. (1998) "Imaging dopamine transmission in schizophrenia. A review and meta-analysis," Quarterly Journal of Nuclear Medicine, 42:211–21
  106. ^ Stone, James M.; Morrison, Paul D.; Pilowsky, Lyn S. (2006), "Review: Glutamate and dopamine dysregulation in schizophrenia a synthesis and selective review", Journal of Psychopharmacology, 21 (4): 440, doi:10.1177/0269881106073126, PMID 17259207{{citation}}: CS1 maint: multiple names: authors list (link)
  107. ^ Abi-Dargham A, Moore H (2003). "Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia". Neuroscientist. 9 (5): 404–16. PMID 14580124. {{cite journal}}: Unknown parameter |month= ignored (help)
  108. ^ P SEEMAN, J SCHWARZ, J CHEN, H SZECHTMAN, M PERREAULT, G. S MCKNIGHT, J C. RODER, R QUIRION, P BOKSA, L K. SRIVASTAVA, K YANAI, D WEINSHENKER AND T SUMIYOSHI (2006) Psychosis Pathways Converge via D2High Dopamine Receptors, SYNAPSE 60:319–346.
  109. ^ Albert Hung Choy Wonga, Hubert H.M. Van Tol (2003) "Schizophrenia: from phenomenology to neurobiology" Neuroscience and Biobehavioral Reviews 27, p276
  110. ^ Philip Seeman & H. B. Niznik (1990). "Dopamine receptors and transporters in Parkinson's disease and schizophrenia". FASEB Journal. 4: 2737–2744.
  111. ^ (prior to degradation, "neither constituent unfolded prior to the onset of proteolysis"Rote, Kevin V. and Rechsteiner, Martin (1986). "Degradation of proteins microinjected into HeLa cells. The role of substrate flexibility," Journal of Biological Chemistry, 261(33), 15430-15436. )
  112. ^ P. Seeman, J SCHWARZ, J CHEN, H SZECHTMAN, M PERREAULT, G. S MCKNIGHT, J C. RODER, R QUIRION, P BOKSA, L K. SRIVASTAVA, K YANAI, D WEINSHENKER AND T SUMIYOSHI (2006). "Psychosis Pathways Converge via D2High Dopamine Receptors". Synapse. 60: 319–346.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  113. ^ Konradi C, Heckers S. (2003). Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacology and Therapeutics, 97(2), 153–79. PMID 12559388
  114. ^ Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. (2001). Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology, 25(4), 455–67. PMID 11557159
  115. ^ Coyle JT, Tsai G, Goff D. (2003). Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Annals of the New York Academy of Sciences, 1003, 318–27. PMID 14684455
  116. ^ Tuominen HJ, Tiihonen J, Wahlbeck K. (2005). Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophrenia Research, 72:225–34. PMID 15560967
  117. ^ Yarlagadda A. Role of calcium regulation in pathophysiology model of schizophrenia and possible interventions. Med Hypotheses. 2002 Feb;58(2):182-6. PMID 11812200
  118. ^ Yamada K, Ashikari I, Onishi K, Kanba S, Yagi G, Asai M. (1995). Effectiveness of nilvadipine in two cases of chronic schizophrenia. Psychiatry Clin Neurosci. Aug;49(4):237–8. PMID 9179944
  119. ^ Prabakaran, S., Swatton, J. E., Ryan, M. M., Huffaker, S. J., Huang, J. T., Griffin, J. L., Wayland, M., Freeman, T., Dudbridge, F., Lilley, K. S., Karp, N. A., Hester, S., Tkachev, D., Mimmack, M. L., Yolken, R. H., Webster, M. J., Torrey, E. F. and Bahn, S. (2004). Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress Molecular Psychiatry, 9, 684-697.
  120. ^ Symptoms in the Mind: An Introduction to Descriptive Psychopathology By Andrew Sims Published by Elsevier Health Sciences, 2002 ISBN 0702026271, 9780702026270 p127
  121. ^ http://www.nature.com/npp/journal/v26/n6/full/1395864a.html as at 8-09-08 Neuropsychopharmacology (2002) 26 794-801.10.1038/S0893-133X(01)00421-3 Delusional Disorder: Molecular Genetic Evidence for Dopamine Psychosis Kiyoshi Morimoto MD, Ph.D, Ryosuke Miyatake MD, Ph.D, Mitsuo Nakamura MD, Ph.D, Takemi Watanabe MD, Ph.D, Toru Hirao MD, Ph.D and Hiroshi Suwaki MD, Ph.D
  122. ^ J Nerv Ment Dis. 1982 Sep;170(9):568-71.Amphetamine abuse and transsexualism. Lothstein LM
  123. ^ Psychostimulants, adult attention deficit hyperactivity disorder and morbid jealousy. By: Pillai, Krishna; Kraya, Niazi. Australian & New Zealand Journal of Psychiatry, Feb2000, Vol. 34 Issue 1, p160,
  124. ^ Behaviour Research and Therapy Volume 41, Issue 7, July 2003, Pages 755-776 Assessment of psychopathology across and within cultures: issues and findings, Juris G. Draguns and Junko Tanaka-Matsumi
  125. ^ http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=224276&Ausgabe=226529&ArtikelNr=29094 Comparison of Delusions among Schizophrenics in Austria and in Pakistan T. Stompea, A. Friedmana, G. Ortweinb, R. Strobla, H.R. Chaudhryc, N. Najamc, M.R. Chaudhryc, Psychopathology Vol. 32, No. 5, 1999
  126. ^ http://www.springerlink.com/index/N11474QQ25R5U236.pdf The balance of biogenic amines as condition for normal behaviour W. Birkmayer, W. Danielczyk, E. Neumayer and P. Riederer, Journal of Neural Transmission, Volume 33, Number 2 / June, 1972.
  127. ^ Broome MR, Woolley JB, Tabraham P, Johns LC, et al (2005). What causes the onset of psychosis? Schizophrenia Research, 79(1), 23–34. PMID 16198238
  128. ^ Lewis R (2004). Should cognitive deficit be a diagnostic criterion for schizophrenia? Journal of Psychiatry and Neuroscience March; 29(2): 102–113. PMID 15069464
  129. ^ Brune M, Abdel-Hamid M, Lehmkamper C, Sonntag C (2007). Mental state attribution, neurocognitive functioning, and psychopathology: What predicts poor social competence in schizophrenia best? Schizophrenia Research. Mar 6 PMID 17346931
  130. ^ Sitskoorn MM, Aleman A, Ebisch SJH, Appels MCM, Khan RS (2004). Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophrenia Research, Volume 71, Issue 2, Pages 285–295. PMID 15474899
  131. ^ Cohen & Docherty (2004). Affective reactivity of speech and emotional experience in patients with schizophrenia. Schizophrenia Research, 1;69(1):7–14. PMID 15145465
  132. ^ Smith B, Fowler DG, Freeman D, et al (2006). Emotion and psychosis: links between depression, self-esteem, negative schematic beliefs and delusions and hallucinations. Schizophrenia Research. Sep;86(1–3):181–8. PMID 16857346
  133. ^ Beck, AT (2004). A Cognitive Model of Schizophrenia, Journal of Cognitive Psychotherapy, 18 (3), 281–288. Retrieved on 2007-05-16.
  134. ^ Horan WP, Blanchard JJ (2003). Emotional responses to psychosocial stress in schizophrenia: the role of individual differences in affective traits and coping. Schizophrenia Research. April 1;60(2–3):271–83. PMID 12591589
  135. ^ Tarrier & Turpin (1992). Psychosocial factors, arousal and schizophrenic relapse. The psychophysiological data. Br J Psychiatry. 161:3–11. PMID 1638327
  136. ^ Barrowclough C, Tarrier N, Humphreys L, Ward J, Gregg L, Andrews B (2003). Self-esteem in schizophrenia: relationships between self-evaluation, family attitudes, and symptomatology. J Abnorm Psychol. 112(1):92–9. PMID 12653417
  137. ^ Birchwood M, Meaden A, Trower P, Gilbert P, Plaistow J (2000). The power and omnipotence of voices: subordination and entrapment by voices and significant others. Psychol Med. Mar;30(2):337–44. PMID 10824654
  138. ^ Honig A, Romme MA, Ensink BJ, Escher SD, Pennings MH, deVries MW (1998). Auditory hallucinations: a comparison between patients and nonpatients J Nerv Ment Dis. Oct;186(10):646–51. PMID 9788642
  139. ^ Hamlin R., Folsom A.:Impairment in abstract responses of schizophrenic, neurotic, and brain-damaged patients. Journal of Abnormal Psychology, 1977, 86, 483-491
  140. ^ Grzywa.A.: Myslenie chorych na schizofrenie jako wyraz zaburzen w procesie przetwarzania informacji. Psychiatria Polska, 1986, 20,215-224 (Thinking of schizophrenic patients as expression of disorders in information metabolism process)
  141. ^ Grzywa A.: Psychologiczne mechanizmy ksztaltowania sie przekonan urojeniowych. Postepy Psychiatrii Neurologicznej, 1992, 1,34-41. (Psychological mechanisms of delusional beliefs creation)
  142. ^ Grzywa A., Chlewinski Z.:Zwiazek przetwarzania informacji z pamiecia krotko i dlugotrwala u chorych na schizofrenie paranoidalna. Psychiatria Polska, 1984a, 18, 219-224. (Relation of information processing with short and long term memory in paranoid schizophrenic sufferers)
  143. ^ Grzywa A.,Chlewinski Z.:Analiza bledow w transformacji pojec abstrakcyjnych u chorych na schizofrenie paranoidalna. Psychiatria Polska, 1984b, 333-338. (Analysis of errors in transformation of abstract defintions in paranoid schizophrenia sufferers)
  144. ^ Grzywa A.,Chlewinski Z.:Myslenie urojeniowe - definicje i proby klasyfikacji. Psychiatria Polska, 1986,20, 269-276. (Delusional thinking - definitions and attempts of classification)
  145. ^ Harvey P.D.,Earle-Boyer E.A.,Weilgus M.S.,Levinson J.C.:Encoding, memory, and thought disorder in schizophrenia and mania. Schizophrenia Bulletin, 1986, 12, 252-261.
  146. ^ Koch S.D.Kayton L.,Peterson R.:Affective encoding and consequent remembering in schizophrenic young adults. Journal of Abnormal Psychology, 1976, 85,156-166.
  147. ^ Koch S.D.,Marusarz T.Z.,Rosen A.:Remembering of sentences by schizophrenic young adults. Journal of Abnormal Psychology, 1980, 89, 291-294.
  148. ^ Oltmans T.S.:Selective attention in schizophrenia and manic psychoses: the effect of distraction on information processing. Journal of Abnormal Psychology, 1978, 87, 212-225.
  149. ^ Pogue-Geile M.F.Oltmans T.S.:Sentence-perception and distractiblity in schizophrenia. Journal of Abnormal Psychology, 1980, 89, 115-124.
  150. ^ Phishkin V., Williams N.V.:Cognitive deficit in schizophrenia. Journal of Nervous and Mental Disorders, 1983, 171, 24-29.
  151. ^ Puszczewicz B.:Organizacja pamieci u chorych na schizofrenie paranoidalna. WSPS, Warszawa 1987 (praca magisterska) (Memory organisation in schizophrenia sufferers)
  152. ^ Weiss K.M., Vrtunski P.B., Simpson D.M.:Information overload disrupts digit recall performance in schizophrenics. Schizophrenia Research , 1988, 1, 299-303.
  153. ^ Forgus R.H.De Wolfe A.S.:Coding of cognitive input in delusional patients. Journal of Abnormal Psychology , 1974, 83, 278-284.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Risk_factors_of_schizophrenia&oldid=237475099"