Family history,cannabisuse in adolescence, problems during pregnancy, childhood adversity, birth in late winter or early spring, older father, being born or raised in a city[5][6]
Based on observed behavior, reported experiences, and reports of others familiar with the person[7]
About 0.3% to 0.7% of people are affected by schizophrenia during their lifetime.[14]In 2017, there were an estimated 1.1 million new cases and in 2019 a total of 20 million cases globally.[15][2]Males are more often affected and on average have an earlier onset.[2]The causes of schizophrenia includegeneticandenvironmentalfactors.[5]Genetic factors include a variety of common and raregenetic variants.[16]Possible environmental factors include being raised in acity,cannabisuse during adolescence, infections, the ages of a person's mother orfather, and poornutrition during pregnancy.[5][17]
About half of those diagnosed with schizophrenia will have a significant improvement over the long term with no further relapses, and a small proportion of these will recover completely.[7][18]The other half will have a lifelong impairment,[19]and severe cases may be repeatedly admitted to hospital.[18]Social problems such as long-term unemployment, poverty, homelessness, exploitation, and victimization are common consequences of schizophrenia.[20][21]Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and morephysical health problems,[22][23]leading to an average decreasedlife expectancyof 20 years.[10]In 2015, an estimated 17,000 deaths were caused by schizophrenia.[12]
The mainstay of treatment is anantipsychoticmedication, along withcounselling, job training, andsocial rehabilitation.[5]Up to a third of people do not respond to initial antipsychotics, in which case the antipsychoticclozapinemay be used.[24]In situations where there is a risk of harm to self or others, a shortinvoluntary hospitalizationmay be necessary.[25]Long-term hospitalization may be needed for a small number of people with severe schizophrenia.[26]In countries where supportive services are limited or unavailable, long-term hospital stays are more typical.[27]
My Eyes at the Moment of the Apparitionsby German artistAugust Natterer, who had schizophrenia
Schizophrenia is amental disordercharacterized by significant alterations inperception, thoughts, mood, and behavior.[28]Symptoms are described in terms ofpositive,negative, andcognitive symptoms.[3][29]The positive symptoms of schizophrenia are the same for anypsychosisand are sometimes referred to as psychotic symptoms. These may be present in any of the different psychoses, and are often transient making early diagnosis of schizophrenia problematic. Psychosis noted for the first time in a person who is later diagnosed with schizophrenia is referred to as afirst-episode psychosis(FEP).[30][31]
Negative symptomsare deficits of normal emotional responses or of other thought processes.[36]The five recognised domains of negative symptoms are:emotional blunting– showing flat expressions or little emotion;alogia– a poverty of speech;anhedonia– an inability to feel pleasure;asociality– the lack of desire to form relationships, andavolition– a lack ofmotivationandapathy.[37]Other related symptoms are social withdrawal,[38]self-neglectparticularly in hygiene, and self-care, and loss of judgment.[36]Negative symptoms appear to contribute more to poor quality of life, functional impairment, and to the burden on others than do positive symptoms.[19][39]People with greater negative symptoms often have a history of poor adjustment before the onset of illness.[38]Negative symptoms are less responsive to medication, and are the most difficult to treat.[40][41]
Cognitive deficitsare the earliest and most constantly found symptoms in schizophrenia. They are often evident long before the onset of illness in theprodromal stage, and may be present in early adolescence, or childhood.[42][43]They are a core feature but not considered to be core symptoms, as are positive and negative symptoms.[44][45]However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms.[42]Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.[46][47]
The deficits incognitionare seen to drive the negative psychosocial outcome in schizophrenia, and are claimed to equate to a possible reduction in IQ from the norm of 100 to 70–85.[48][49]Cognitive deficits may be ofneurocognition(nonsocial) or ofsocial cognition.[50]Neurocognition is the ability to receive and remember information, and includes verbal fluency,memory,reasoning,problem solving,speed of processing, andauditoryandvisual perception.[47]Verbal memoryand attention are seen to be the most affected.[51][49]Verbal memoryimpairment is associated with a decreased level ofsemantic processing(relating meaning to words).[52]Another memory impairment is that ofepisodic memory.[53]An impairment in visual perception that is consistently found in schizophrenia is that ofvisual backward masking.[47]Visual processingimpairments include an inability to perceive complexvisual illusions.[54]Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world.[50][47]This is also an associated impairment, andfacial emotion perceptionis often found to be difficult.[55][56]Facial perception is critical for ordinary social interaction.[57]Cognitive impairments do not usually respond to antipsychotics, and there are a number ofinterventionsthat are used to try to improve them.
Onset typically occurs between the late teens and early 30s, with the peak incidence occurring in males in the early to mid twenties, and in females in the late twenties.[3][7][11]Onset before the age of 17 is known as early-onset,[58]and before the age of 13, as can sometimes occur is known aschildhood schizophreniaor very early-onset.[59][7]A later stage of onset can occur between the ages of 40 and 60, known as late-onset schizophrenia.[50]A later onset over the age of 60 which may be difficult to differentiate as schizophrenia, is known as very-late-onset schizophrenia-like psychosis.[50]Late onset has shown that a higher rate of females are affected; they have less severe symptoms, and need lower doses of antipsychotics.[50]The earlier favouring of onset in males is later seen to be balanced by apost-menopausalincrease in the development in females.Estrogenproduced pre-menopause, has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload.[60]There has been a dramatic increase in the numbers of older adults with schizophrenia.[61]An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset, and late-onset illness.[50][62]There has been a dramatic increase in the numbers of older adults with schizophrenia.[61]An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset, and late-onset illness.[50][62]
Onset may happen suddenly, or may occur after the slow and gradual development of a number of signs and symptoms in a period known as theprodromal stage.[7]Up to 75% of those with schizophrenia go through a prodromal stage.[63]The negative and cognitive symptoms in the prodrome can precede FEP by many months, and up to five years.[64][46]The period from FEP and treatment is known as the duration of untreated psychosis (DUP) which is seen to be a factor in functional outcome. The prodromal stage is the high-risk stage for the development of psychosis.[47]Since the progression to first episode psychosis, is not inevitable an alternative term is often preferred ofat risk mental state[47]Recognition and early intervention at the prodromal stage would minimize the disruption to educational and social development associated with schizophrenia, and has been the focus of many studies.[64][46]It is suggested that the use of anti-inflammatory compounds such asD-serinemay prevent the transition to schizophrenia.[46]Cognitive symptoms are not secondary to positive symptoms, or to the side effects of antipsychotics.[47]
Cognitive impairments in the prodromal stage become worse after first episode psychosis (after which they return to baseline and then remain fairly stable), making early intervention to prevent such transition of prime importance.[46]Early treatment with cognitive behavioral therapies are the gold standard.[64]Neurological soft signsof clumsiness and loss of fine motor movement are often found in schizophrenia, and these resolve with effective treatment of FEP.[65][11]
Genetic, environmental, and vulnerability factors are involved in the development of schizophrenia.[66][5]The interactions of theserisk factorsare complex, as numerous and diverseinsultsfrom conception to adulthood can be involved.[66]A genetic predisposition on its own, without interacting environmental factors, will not give rise to the development of schizophrenia.[67][66]Schizophrenia is described as aneurodevelopmental disorderthat lacks a precise boundary in its definition.[68][67]
Genetic
Estimates of theheritabilityof schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics.[69][16]These estimates vary because of thedifficulty in separatinggenetic and environmental influences, and their accuracy has been queried.[70][71]The greatest risk factor for developing schizophrenia is having afirst-degree relativewith the disease (risk is 6.5%); more than 40% ofidentical twinsof those with schizophrenia are also affected.[72]If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%.[69]However,DSM-5points out that most people with schizophrenia have no family history of psychosis.[7]Results ofcandidate genestudies of schizophrenia have generally failed to find consistent associations,[73]and thegenetic lociidentified bygenome-wide association studiesas associated with schizophrenia explain only a small fraction of the variation in the disease.[74]
Manygenesare known to be involved in schizophrenia, each with small effect and unknowntransmissionandexpression.[16][75]The summation of these effect sizes into apolygenic risk scorecan explain at least 7% of the variability in liability for schizophrenia.[76]Around 5% of cases of schizophrenia are understood to be at least partially attributable to rarecopy-number variations(CNVs); thesestructural variationsare associated with known genomic disorders involvingdeletionsat22q11.2(DiGeorge syndrome), duplications at16p11.216p11.2 duplication(most frequently found) and deletions at15q11.2(Burnside-Butler syndrome).[77]Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.[77]
The genesCRHR1andCRHBPhave been shown to be associated with a severity of suicidal behavior. These genes code for stress response proteins needed in the control of theHPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in thefunction of the HPA axispossibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviors.[67]
The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected thatgenetic variantsthat increase the risk of schizophrenia would be selected against due to their negative effects onreproductive fitness. A number of potential explanations have been proposed, including thatallelesassociated with schizophrenia risk confers a fitness advantage in unaffected individuals.[78][79]While some evidence has not supported this idea,[71]others propose that a large number of alleles each contributing a small amount can persist.[80]
Environmental factors, each associated with a slight risk of developing schizophrenia in later life includeoxygen deprivation, infection,prenatal maternal stress, and malnutrition in the mother duringfetal development.[22]A risk is also associated with maternal obesity, in increasingoxidative stress, and dysregulating the dopamine and serotonin pathways.[81]Both maternal stress and infection have been demonstrated to alter fetalneurodevelopmentthrough an increase of pro-inflammatorycytokines.[82]There is a slighter risk associated with being born in the winter or spring possibly due tovitamin D deficiency[83]or aprenatalviral infection.[72]Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections byToxoplasma gondiiandChlamydia.[84]The increased risk is about five to eight percent.[85]Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.[86]
Adverse childhood experiences(ACEs), severe forms of which are classed aschildhood trauma, range from being bullied or abused, to the death of a parent.[87]Many adverse childhood experiences can causetoxic stressand increase the risk of psychosis.[88][89][87]Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.[90]
Living in anurban environmentduring childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two,[22][91]even after taking into accountdrug use,ethnic group, and size ofsocial group.[92]A possible link between the urban environment andpollutionhas been suggested to be the cause of the elevated risk of schizophrenia.[93]
Other risk factors of importance includesocial isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions.[72][94]Having afather older than 40 years, or parents younger than 20 years are also associated with schizophrenia.[5][95]
Cannabis-usemay be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk.[17]The increased risk may require the presence of certain genes within an individual.[17]Its use is associated with doubling the rate.[101]The use of more potent strains of cannabis having a high level of its active ingredienttetrahydrocannabinol(THC), increases the risk further. One of these strains is well known asskunk.[102][103]
The mechanisms of schizophrenia are unknown, and a number of models have been put forward to explain the link between altered brain function and schizophrenia.[22]One of the most common is thedopamine model, which attributespsychosisto the mind's faulty interpretation of the misfiring ofdopaminergic neurons.[104]This has been directly related to the symptoms of delusions and hallucinations.[22][105][106][107]Abnormal dopamine signaling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis.[108][109]A decrease inD1receptorsin thedorsolateral prefrontal cortexmay also be responsible for deficits inworking memory.[110][111]
There are often impairments in cognition,social skills, and motor skills before the onset of schizophrenia, which suggests aneurodevelopmental model.[119]Such frameworks have hypothesized links between these biological abnormalities and symptoms.[120]Furthermore, problems before birth such as maternal infection, maternal malnutrition and complications during pregnancy all increase risk for schizophrenia.[5][121]Schizophrenia usually emerges 18-25, an age period that overlaps with certain stages ofneurodevelopmentthat are implicated in schizophrenia.[122]
Deficits inexecutive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are dissociable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to utilize this to direct cognition and behavior.[123][124]These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby thedorsolateral prefrontal cortexis activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reducedneuropil, evidenced by increasedpyramidal celldensity and reduceddendritic spinedensity. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reducedgrey mattervolume in association with deficits in working memory tasks.[125]
Positive symptoms have been linked to reduced cortical thickness in thesuperior temporal gyrus.[126]Severity of negative symptoms has been linked to reduced thickness in the left medialorbitofrontal cortex.[127]Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests thathedonic responsesare intact in schizophrenia,[128]and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward.[129]Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses.[130]
It has been hypothesized that in some people, development of schizophrenia is related tointestinal tractdysfunction such as seen withnon-celiac gluten sensitivityor abnormalities in thegut microbiota.[131]A subgroup of persons with schizophrenia present an immune response toglutendifferently from that found in people withceliac, with elevated levels of certain serum biomarkers of gluten sensitivity such asanti-gliadin IgGoranti-gliadin IgAantibodies.[132]
Another theory links abnormalbrain lateralizationto the development ofbeing left-handedwhich is significantly more common in those with schizophrenia.[133]This abnormal development of hemispheric asymmetry is noted in schizophrenia.[134]Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralization and schizophrenia.[133][135]
Bayesian models of brain functioninghave been utilized to link abnormalities in cellular functioning to symptoms.[136][137]Both hallucinations and delusions have been suggested to reflect improper encoding ofprior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models ofcircuitsthat mediatepredictive coding, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.[138][139][140]
There is no objective test orbiomarkerto confirm diagnosis.Psychosescan occur in several conditions and are often transient making early diagnosis of schizophrenia difficult. Psychosis noted for the first time in a person that is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP).
DSM-5 states that to be diagnosed with schizophrenia, two diagnostic criteria have to be met over the period of one month, with a significant impact on social or occupational functioning for at least six months. One of the symptoms needs to be either delusions, hallucinations, or disorganized speech. A second symptom could be one of the negative symptoms, or severely disorganized orcatatonic behaviour.[7]A different diagnosis ofschizophreniform disordercan be made before the six months needed for the diagnosis of schizophrenia.[7]
In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning.[143]In the UK diagnosis is based on having the symptoms for most of the time for one month, with symptoms that significantly affect the ability to work, study, or to carry on ordinary daily living, and with other similar conditions ruled out.[144]
The ICD criteria are typically used in European countries; the DSM criteria are used predominantly in the United States and Canada, and are prevailing in research studies. In practice, agreement between the two systems is high.[145]The current proposal for theICD-11criteria for schizophrenia recommends addingself-disorderas a symptom.[34]
A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome.WHOfor ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis.[44]
Changes made
Both manuals have adopted the chapter heading ofSchizophrenia spectrum and other psychotic disorders; ICD modifying this asSchizophrenia spectrum and other primary psychotic disorders.[44]The definition of schizophrenia remains essentially the same as that specified by the 2000 text revised DSM-IV (DSM-IV-TR). However, with the publication of DSM-5, the APA removed allsub-classificationsof schizophrenia.[44]ICD-11 has also removed subtypes. The removed subtype from both, ofcatatonichas been relisted in ICD-11 as apsychomotor disturbancethat may be present in schizophrenia.[44]
Another major change was to remove the importance previously given toSchneider's first-rank symptoms.[146]DSM-5 still uses the listing ofschizophreniform disorderbut ICD-11 no longer includes it.[44]DSM-5 also recommends that a better distinction be made between a current condition of schizophrenia and its historical progress, to achieve a clearer overall characterization.[146]
A dimensional assessment has been included in DSM-5 covering eight dimensions of symptoms to be rated (using theScale to Assess the Severity of Symptom Dimensions) – these include the five diagnostic criteria plus cognitive impairments, mania, and depression.[44]This can add relevant information for the individual in regard to treatment, prognosis, and functional outcome; it also enables the response to treatment to be more accurately described.[44][147]
Many people with schizophrenia have one or moreother disordersthat often includes ananxiety disordersuch aspanic disorder, anobsessive-compulsive disorder, or asubstance use disorder. These are separate disorders that need separate treatments.[7]Sleep disordersare commonly found with schizophrenia, and are early signs of illness and also of relapse.[148]Sleep disorders are linked with positive symptoms that includedisorganized thinkingand can adversely affect neocorticalplasticityand cognition.[148]The consolidation of memories is disrupted in sleep disorders.[149]They are associated with severity of illness, a poor prognosis, and poor quality of life.[150][151]Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not.[150]There is also aclozapine-inducedsomnolence. A related condition is antipsychotic-inducedrestless legs syndrome. Genetic variations have been found associated with these conditions involving thecircadian rhythm, dopamine andhistamine metabolism, and signal transduction.[152]
Psychotic symptomslasting less than a month may be diagnosed asbrief psychotic disorder, and various conditions may be classed aspsychotic disordernot otherwise specified;schizoaffective disorderis diagnosed if symptoms ofmood disorderare substantially present alongside psychotic symptoms. If the psychotic symptoms are the direct physiological result of a general medical condition or a substance, then the diagnosis is one of a psychosis secondary to that condition. Schizophrenia is not diagnosed if symptoms ofpervasive developmental disorderare present unless prominent delusions or hallucinations are also present.[7]
Preventionof schizophrenia is difficult as there are no reliable markers for the later development of the disorder.[155]There is tentative though inconclusive evidence for the effectiveness ofearly interventionto prevent schizophrenia in theprodrome phase.[156]There is some evidence that early intervention in those with first-episode psychosis may improve short-term outcomes, but there is little benefit from these measures after five years.[22]Cognitive behavioral therapymay reduce the risk of psychosis in those at high risk after a year[157]and is recommended in this group, by theNational Institute for Health and Care Excellence (NICE).[28]Another preventive measure is to avoid drugs that have been associated with development of the disorder, includingcannabis,cocaine, andamphetamines.[72]
Antipsychotics are prescribed following a first-episode psychosis, and following remission apreventive maintenance useis continued to avoid relapse. However, it is recognised that some people do recover following a single episode and that long-term use of antipsychotics will not be needed but there is no way of identifying this group.[158]
Voluntaryorinvoluntaryadmittance to hospital may be needed to treat a severe episode, however, hospital stays are as short as possible. In the UK large mental hospitals termed asylums began to be closed down in the 1950s with the advent of antipsychotics, and with an awareness of the negative impact of long-term hospital stays on recovery.[20]This process was known asdeinstitutionalization, and community and supportive services were developed in order to support this change. Many other countries followed suit with the US starting in the 60s.[162]There will still remain a few people who do not improve enough to be discharged.[20][26]In those countries that lack the necessary supportive and social services long-term hospital stays are more usual.[27]
The first-line treatment for schizophrenia is anantipsychotic. The first-generation antipsychotics, now calledtypical antipsychotics, aredopamine antagoniststhat block D2 receptors, and affect theneurotransmissionofdopamine. Those brought out later, the second-generation antipsychotics known asatypical antipsychotics, can also have effect on another neurotransmitterserotonin. Antipsychotics can reduce the symptoms of anxiety within hours of their use but for other symptoms they may take several days or weeks to reach their full effect.[30][163]They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications.[164]There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people.[165]Stopping medication may be considered after a single psychotic episode where there has been a full recovery with no symptoms for twelve months. Repeated relapses worsen the long-term outlook and the risk of relapse following a second episode is high, and long-term treatment is usually recommended.[166][167]
Tobacco smokingincreases themetabolismof some antipsychotics, by strongly activitatingCYP1A2the enzyme that breaks them down, and a significant difference is found in these levels between smokers and non-smokers.[168][169][170]It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%.[169]The result of stopping smoking can lead to an increased concentration of the antipsychotic that may result in toxicity, so that monitoring of effects would need to take place with a view to decreasing the dosage; many symptoms may be noticeably worsened, and extreme fatigue, and seizures are also possible with a risk of relapse. Likewise those who resume smoking may need their dosages adjusted accordingly.[171][168]The altering effects are due tocompoundsin tobacco smoke and not to nicotine; the use ofnicotine replacement therapytherefore has the equivalent effect of stopping smoking and monitoring would still be needed.[168]
About 30 to 50 percent of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment.[172]For those who are unwilling or unable to take medication regularly,long-acting injectionsof antipsychotics may be used,[173]which reduce the risk of relapse to a greater degree than oral medications.[174]When used in combination with psychosocial interventions, they may improve long-termadherenceto treatment.[175]
Research findings suggested that other neurotransmission systems including serotonin, glutamate, GABA, and acetycholine were implicated in the development of schizophrenia, and that a more inclusive medication was needed.[170]A new first-in-class antipsychotic that targets multiple neurotransmitter systems calledlumateperone(ITI-007), was trialed and approved by theFDAin December 2019 for the treatment of schizophrenia in adults.[176][177][170]Lumateperone is a small molecule agent that shows improved safety, and tolerance. It interacts with dopamine, serotonin, and glutamate in a complex, uniquely selective manner, and is seen to improve negative symptoms, and social functioning. Lumateperone was also found to reduce potential metabolic dysfunction, have lower rates of movement disorders, and have lower cardiovascular side effects such as afast heart rate.[170]
Side effects
Typical antipsychoticsare associated with a higher rate ofmovement disordersincludingakathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk ofmetabolic syndrome.[178]Risperidone(atypical) has a similar rate ofextrapyramidal symptomstohaloperidol(typical).[178]A rare but potentially lethal condition ofneuroleptic malignant syndrome(NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention.[179]Another less rare condition oftardive dyskinesiacan occur due to long-term use of antipsychotics, developing after many months or years of use. It is more often reported with use of typical antipsychotics.[180]
Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects includeseizures, NMS,neutropenia, andagranulocytosis(loweredwhite blood cellcount) and its use needs careful monitoring.[181][182]Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfullyrechallenged(restarted) with clozapine.[183][184]
Clozapine is also associated withthromboembolism(includingpulmonary embolism),myocarditis, andcardiomyopathy.[185][186]A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using aprevention therapy for venous thromboembolismafter starting treatment with clozapine, and continuing this for six months.[186]Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead toileusandbowel ischemiaresulting in many fatalities.[181]
However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression.[187][188]Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction.[72]Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies.[189]Unwanted side effects cause people to stop treatment, resulting in relapses.[190]
Treatment resistant schizophrenia
About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning.[191]However, positive symptoms persist in up to a third of people. Following two trials of different antipsychotics over six weeks, that also prove ineffective, they will be classed as having treatment resistant schizophrenia (TRS), andclozapinewill be offered.[192][24]Clozapine is of benefit to around half of this group although it has the potentially serious side effect ofagranulocytosis(loweredwhite blood cellcount) in less than 4% of people.[22][72][193]Between 12 and 20 per cent will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia.[192][194]ECTmay be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit.[194]A review concluded that this use only has an effect on medium-term TRS and that there is not enough evidence to support its use other than for this group.[195]
TRS is often accompanied by a low quality of life, and greater social dysfunction.[196]TRS may be the result of inadequate rather than inefficient treatment; it also may be a false label due to medication not being taken regularly, or at all.[188]About 16 per cent of people who had initially been responsive to treatment later develop resistance. This could relate to the length of time on APs, with treatment becoming less responsive.[197]This finding also supports the involvement of dopamine in the development of schizophrenia.[188]Studies suggest that TRS may be a more heritable form.[198]
TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies.[196]This variation is seen to possibly indicate an underlying neurobiology such as dopamine supersensitivity (DSS), glutamate or serotonin dysfunction, inflammation andoxidative stress.[192]Studies have found that dopamine supersensitivity is found in up to 70% of those with TRS.[199]The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes.[192][198]It is further suggested that if the subtypes could be distinguished at an early stage significant implications could follow for treatment considerations, and for research.[194]Neuroimaging studies have found a significant decrease in the volume of grey matter in those with TRS with no such change seen in those who are treatment responsive.[194]In those with ultra treatment resistance the decrease in grey matter volume was larger.[192][194]
A link has been made between thegut microbiotaand the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These includeliver enzyme genesthat control theavailability of a drugto brain targets, and genes responsible for the structure and function of these targets. In thecolonthe bacteria encode a hundred times more genes than exist in thehuman genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in theportal circulation. This small fraction is then subject to themetabolic actionof many communities of bacteria. Activation of the drug depends on the composition and enzymes of the bacteria and of the specifics of the drug, and therefore a great deal of individual variation can affect both the usefulness of the drug and its tolerability. It is suggested thatparenteral administrationof antipsychotics would bypass the gut and be more successful in overcoming TRS. The composition of gut microbiota is variable between individuals, but they are seen to remain stable. However, phyla can change in response to many factors including ageing, diet, substance-use, and medications – especially antibiotics, laxatives, and antipsychotics. In FEP, schizophrenia has been linked to significant changes in the gut microbiota that can predict response to treatment.[200]
Other support services for education, employment, and housing are usually offered. For people suffering from severe schizophrenia, and discharged from a stay in hospital, these services are often brought together in an integrated approach to offer support in the community away from the hospital setting. In addition to medicine management, housing, and finances, assistance is given for more routine matters such as help with shopping and using public transport. This approach is known asassertive community treatment(ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life.[205][206]Another more intense approach is known asintensive care management(ICM). ICM is a stage further than ACT and emphasises support of high intensity in smaller caseloads, (less than twenty). This approach is to provide long-term care in the community. Studies show that ICM improves many of the relevant outcomes including social functioning.[207]
Some studies have shown little evidence for the effectiveness ofcognitive behavioral therapy(CBT) in either reducing symptoms or preventing relapse.[208][209]However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and has been recommended in Canada, but it has been seen here to have no effect on social function, relapse, or quality of life.[210]In the UK it is recommended as an add-on therapy in the treatment of schizophrenia, but is not supported for use in treatment resistant schizophrenia.[209][211]Arts therapiesare seen to improve negative symptoms in some people, and are recommended by NICE in the UK.[163][212]This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example.[212][213][214]Peer support, in which people withpersonal experienceof schizophrenia, provide help to each other, is of unclear benefit.[215]
Other
Exercise therapyhas been shown to improve positive and negative symptoms, cognition, and improve quality of life.[216]Aerobic exercise has been shown to improvecognitive deficitsof working memory and attention.[217]Exercise has also been shown to increase the volume of thehippocampusin those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease.[216]However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity.[218]Supervised sessions are recommended.[217]In the UK healthy eating advice is offered alongside exercise programs.[219]
An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those offolate, andvitamin Dare linked to the risk factors for the development of schizophrenia and for early death including heart disease.[220]Those with schizophrenia possibly have the worst diet of all the mental disorders. Lower levels of folate and vitamin D have been noted as significantly lower in first episode psychosis.[220]The use of supplemental folate is recommended.[221]Azinc deficiencyhas also been noted.[222]Vitamin B12is also often deficient and this is linked to worse symptoms. Supplementation with B vitamins has been shown to significantly improve symptoms, and to put in reverse some of the cognitive deficits.[220]It is also suggested that the noted dysfunction in gut microbiota might benefit from the use ofprobiotics.[222]
Schizophrenia has great human and economic costs.[5]It results in a decreased life expectancy of 20 years.[10][4]This is primarily because of its association withobesity, poor diet, asedentary lifestyle, andsmoking, with an increased rate ofsuicideplaying a lesser role.[10][223]Side effects of antipsychotics may also increase the risk.[10]These differences in life expectancy increased between the 1970s and 1990s.[224]An Australian study puts the rate of early death at 25 years, and views the main cause to be related to heart disease.[185]Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia.[225][226]This may lead tohyponatremiawhich can be life-threatening. Antipsychotics can lead to adry mouth, but there are several other factors that may contribute to the disorder. It is suggested to lead to a reduction in life expectancy by 13 per cent.[226]A study has suggested that real barriers to improving the mortality rate in schizophrenia are poverty, overlooking the symptoms of other illnesses, stress, stigma, and medication side effects, and that these need to be changed.[227]
Schizophrenia is a major cause ofdisability. In 2016 it was classed as the 12th most disabling condition.[228]Approximately 75% of people with schizophrenia have ongoing disability with relapses[40]and 16.7 million people globally are deemed to have moderate or severe disability from the condition.[229]Some people do recover completely and others function well in society.[230]Most people with schizophrenia live independently with community support.[22]About 85% are unemployed.[5]In people with a first episode of psychosis in scizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%.[231]Males are affected more often than females, and have a worse outcome.[232]Outcomes for schizophrenia appear better in thedevelopingthan thedeveloped world.[233]These conclusions have been questioned.[234]Social problems, such as long-term unemployment, poverty, homelessness, exploitation,stigmatizationand victimization are common consequences, and lead tosocial exclusion.[20][21]
There is a higher than averagesuicide rateassociated with schizophrenia estimated at around 5% to 6%, most often occurring in the period following onset or first hospital admission.[23][11]Several times more (20 to 40%) attempt suicide at least once.[7][235]There are a variety of risk factors, including male gender, depression, a highIQ,[235]heavy smoking,[236]and substance abuse.[100]Repeated relapse is linked to an increased risk of suicidal behavior.[158]The use ofclozapinecan reduce the risk of suicide and aggression.[188]
Schizophrenia and smokinghave shown a strong association in studies worldwide.[237][238]Use of cigarettes is especially high in those diagnosed with schizophrenia, with estimates ranging from 80 to 90% being regular smokers, as compared to 20% of the general population.[238]Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content.[33]Some propose that this is in an effort to improve symptoms.[239]Among people with schizophrenia use ofcannabisis also common.[100]
Deaths per million persons due to schizophrenia in 2012.
0–0
1–1
2–2
3–3
4–6
7–20
In 2017, theGlobal Burden of Disease Studyestimated there were 1.1 million new cases, and in 2019WHOreported a total of 20 million cases globally.[15][2]Schizophrenia affects around 0.3–0.7% of people at some point in their life.[14]It occurs 1.4 times more frequently in males than females and typically appears earlier in men[72]– the peak ages of onset are 25 years for males and 27 years for females.[240]Onset in childhood, before the age of 13 can sometimes occur.[7][59]A later onset can occur between the ages of 40 and 60, known as late onset, and also after 60 known as very late onset.[50]
Worldwide, schizophrenia is the most commonpsychotic disorder.[62]The frequency of schizophrenia varies across the world,[7][241]within countries,[242]and at the local and neighborhood level.[243]This variation has been estimated to be fivefold.[5]It causes approximately one percent of worldwidedisability adjusted life years[72]and resulted in 17,000 deaths in 2015.[12]
In 2000, theWorld Health Organizationfound the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardized prevalence per 100,000 ranging from 343 in Africa to 544 in Japan and Oceania for men, and from 378 in Africa to 527 in Southeastern Europe for women.[244]About 1.1% of adults have schizophrenia in the United States.[245]However, in areas of conflict this figure can rise to between 4.0 and 6.5%.[246]
The term "schizophrenia" was coined byEugen Bleuler.
The history of schizophrenia is complex and does not lend itself easily to a linear narrative.[247]Accounts of a schizophrenia-likesyndromeare rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809.[248]Dementia praecox, meaning prematuredementiawas used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 byArnold Pickin a case report ofhebephrenia. In 1893Emil Kraepelinused the term in making a distinction, known as theKraepelinian dichotomy, between the two psychoses – dementia praecox, and manic depression (now calledbipolar disorder).[10]Kraepelin believed thatdementia praecoxwas probably caused by asystemic diseasethat affected many organs and nerves, affecting the brain after puberty in a final decisive cascade.[249]It was thought to be an early form of dementia, a degenerative disease.[10]When it became evident that the disorder was not degenerative it was renamed schizophrenia byEugen Bleulerin 1908.[250]
The wordschizophreniatranslates roughly as "splitting of the mind" and isModern Latinfrom theGreekrootsschizein(σχίζειν, "to split") andphrēn, (φρεν, "mind")[251]Its use was intended to describe the separation of function betweenpersonality,thinking,memory, andperception.[250]
The term schizophrenia used to be associated withsplit personalityby the general population but that usage went into decline whensplit personalitybecame known as a separate disorder, first asmultiple identity disorder, and later asdissociative identity disorder.[252]In 2002 in Japan the name was changed tointegration disorder, and in 2012 in South Korea, the name was changed toattunement disorderto reduce thestigma, both with good results.[22][253][254]
A molecule ofchlorpromazine, the first antipsychotic developed in the 1950s.
In the early 20th century, the psychiatristKurt Schneiderlisted the psychotic symptoms of schizophrenia into two groups of hallucinations, and delusions. The hallucinations were listed as specific to auditory, and the delusional included thought disorders. These were seen as the symptoms of first-rank importance and were termedfirst-rank symptoms. Whilst these were also sometimes seen to be relevant to the psychosis in manic-depression, they were highly suggestive of schizophrenia and typically referred to as first-rank symptoms of schizophrenia. The most common first-rank symptom was found to belong to thought disorders.[255][256]In 2013 the first-rank symptoms were excluded from theDSM-5criteria.[146]First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.[257]
In the early 1970s in the US, the diagnostic model used for schizophrenia was broad and clinically-based using DSM II. It had been noted that schizophrenia was diagnosed far more in the US than in Europe which had been using the ICD-9 criteria. The US model was criticised for failing to demarcate clearly those people with a mental illness, and those without. In 1980 DSM III was published and showed a shift in focus from the clinically-basedbiopsychosocial modelto a reason-based medical model.[264]DSM IV showed an increased focus to an evidence-based medical model.[265]
Subtypes of schizophrenia are no longer recognized as separate conditions from schizophrenia byDSM-5[266]orICD-11.[267]Before 2013, the subtypes of schizophrenia were classified as paranoid, disorganized, catatonic, undifferentiated, and residual type.[268]The subtypes of schizophrenia were eliminated because of a lack of clear distinction among the subtypes and low validity of classification.[267][269]
In 2002, the term for schizophrenia in Japan was changed fromseishin-bunretsu-byō(精神分裂病, lit. "mind-split disease")totōgō-shitchō-shō(統合失調症, lit. "integration-dysregulation syndrome")to reducestigma.[270]The new name also interpreted as "integration disorder" was inspired by thebiopsychosocial model; it increased the percentage of people who were informed of the diagnosis from 37 to 70% over three years.[253]A similar change was made in South Korea in 2012 toattunement disorder.[254]A professor of psychiatry,Jim van Os, has proposed changing the English term topsychosis spectrum syndrome.[271]In 2013 with the reviewed DSM-5, the DSM-5 committee was in favor of giving a new name to schizophrenia but they referred this to WHO.[272]
In the United States, the cost of schizophrenia – including direct costs (outpatient, inpatient, drugs, and long-term care) and non-health care costs (law enforcement, reduced workplace productivity, and unemployment) – was estimated to be $62.7 billion in 2002.[273]In the UK the cost in 2016 was put at £11.8 billion per year with a third of that figure directly attributable to the cost of hospital and social care, and treatment.[5]
People with severe mental illness, including schizophrenia, are at a significantly greater risk of being victims of both violent and non-violent crime.[276]Schizophrenia has been associated with a higher rate of violent acts, but most appear to be related to associatedsubstance abuse.[277]Rates ofhomicidelinked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region.[278]What role schizophrenia has on violence independent of drug misuse is controversial, but certain aspects of individual histories or mental states may be factors.[279]About 11% of people in prison for homicide have schizophrenia and 21% havemood disorders.[needs update][280]Another study found about 8-10% of people with schizophrenia had committed a violent act in the past year compared to 2% of the general population.[needs update][280]
Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence.[277]In a large, representative sample from a 1999 study, 12.8% of Americans believed that those with schizophrenia were "very likely" to do something violent against others, and 48.1% said that they were "somewhat likely" to. Over 74% said that people with schizophrenia were either "not very able" or "not able at all" to make decisions concerning their treatment, and 70.2% said the same of money-management decisions.[needs update][281]The perception of people with psychosis as violent more than doubled between the 1950s and 2000, according to one meta-analysis.[282]
Schizophrenia is not believed to occur in other animals[283]but it may be possible to develop a pharmacologically induced non-human primate model of schizophrenia.[284]
Effects of early intervention is an active area of research.[156]One important aspect of this research is early detection of at-risk individuals. This includes development of risk calculators[285]and methods for large-scale population screening.[286]
Various agents have been explored for possible effectiveness in treating negative symptoms, for which antipsychotics have been of little benefit.[287]There have been trials on medications with anti-inflammatory activity, based on the premise that inflammation might play a role in the pathology of schizophrenia.[288]
Research has found a tentative benefit in usingminocycline, abroad-spectrum antibiotic, as an add-on treatment for schizophrenia. Reviews have found that minocycline as an add-on therapy appears to be effective in improving all dimensions of symptoms, and has been found to be safe and well tolerated, but larger studies are called for.[289][290]
A review of the effects ofnidotherapy– efforts to change the environment to improve functional ability was inconclusive, and it was suggested that it be treated as an experimental approach.[291]
Another active area of research is the study of a variety of potentialbiomarkersthat would be of invaluable help not only in the diagnosis but also in the treatment and prognosis of schizophrenia. Possible biomarkers include markers of inflammation, neuroimaging,BDNF, genetics, and speech analysis. Some inflammatory markers such asC-reactive proteinare useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. However, other inflammatorycytokinesare found to be elevated in first episode psychosis and acute relapse that are normalized after treatment with antipsychotics, and these may be considered as state markers.[295]Deficits insleep spindlesin schizophrenia may serve as a marker of an impairedthalamocortical circuit, and a mechanism for memory impairment.[149]
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