Schizophrenia

Schizophrenia
A white cloth with seemingly random, unconnected text sewn into it using multiple colors of thread
Cloth embroidered by a person diagnosed with schizophrenia
Pronunciation
SpecialtyPsychiatry
SymptomsDelusions, confused thinking, hallucinations (usually hearing voices)[2][3]
ComplicationsSuicide, heart disease, lifestyle diseases[4]
Usual onsetAges 16 to 30[3]
DurationChronic[3]
CausesEnvironmental and genetic factors[5]
Risk factorsFamily history, cannabis use, problems during pregnancy, being raised in a city, older father[5]
Diagnostic methodBased on observed behavior, reported experiences, and reports of others familiar with the person[6]
Differential diagnosisSubstance abuse, Huntington's disease, mood disorders (bipolar disorder), autism[7] borderline personality disorder[8]
ManagementCounseling, job training[2][5]
MedicationAntipsychotics[5]
Prognosis20 years shorter life expectancy[9][4]
Frequency~0.5%[10]
Deaths~17,000 (2015)[11]

Schizophrenia is a mental illness characterized by relapsing episodes of psychosis.[5] Major symptoms include hallucinations (most usually hearing voices), delusions (false beliefs), and disordered thinking.[5] Other symptoms may include social withdrawal, decreased emotional expression, and lack of motivation.[5] Symptoms typically come on gradually, begin in young adulthood, and in many cases never resolve.[3] There is no objective diagnostic test; diagnosis is based on observed behavior, and a history that includes the person's reported experiences, and reports of others familiar with the person. To be diagnosed with schizophrenia, symptoms and functional impairment need to be present for six months.[6][12] People with schizophrenia often have other mental health problems like anxiety disorders such as obsessive-compulsive disorder, depression, or a substance-use disorder.[13]

About 0.3% to 0.7% of people are affected by schizophrenia during their lifetimes.[10] In 2017, there were an estimated 1.1 million new cases and a total of 19.8 million cases globally.[14] Males are more often affected and onset is on average earlier in age.[2] The causes of schizophrenia include environmental and genetic factors.[5] Possible environmental factors include being raised in a city, cannabis use during adolescence, certain infections, the ages of a person's parents, and poor nutrition during pregnancy.[5][15] Genetic factors include a variety of common and rare genetic variants.[16]

About half of people with schizophrenia either recover completely, or have a significant improvement over the long term with no further relapses.[17][6] The other half will have a lifelong impairment,[18] and some will need repeated stays in hospital.[17] Social problems, such as long-term unemployment, poverty, and homelessness, are common consequences.[6][19] Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and more physical health problems,[10][20] leading to an average decreased life expectancy of 20 years.[9] In 2015, an estimated 17,000 people worldwide died from behavior related to, or caused by, schizophrenia.[11]

The mainstay of treatment is an antipsychotic medication, along with counselling, job training, and social rehabilitation.[5] In those who do not improve with other antipsychotics, clozapine may be tried.[5] In situations where there is a risk of harm to self or others, involuntary hospitalization may be necessary, although hospital stays are shorter and less frequent than they once were.[21]

Video summary (script)

Signs and symptoms

My Eyes at the Moment of the Apparitions by German artist August Natterer, who had schizophrenia

Schizophrenia is a major mental disorder characterized by significant alterations in perception, thoughts, mood, and behavior.[22] Symptoms are described in terms of positive, negative, and cognitive symptoms.[3][23] The positive symptoms of schizophrenia are the same for any psychosis and 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 a first-episode psychosis (FEP).[12][24]

Positive symptoms

Positive symptoms are those symptoms that are not normally experienced, but are present in people during a psychotic episode in schizophrenia. They include delusions, and hallucinations, typically regarded as manifestations of psychosis, and disordered thoughts and speech.[12] Hallucinations can involve any of the senses including taste, sight, touch, and most commonly hearing as hearing voices.[25] They are also typically related to the content of the delusional theme.[26] Delusions are bizarre or persecutory in nature. Thought disorders can include disorganized thinking and speech, speech that is not understandable known as word salad, and thought blocking.[3][27] Positive symptoms generally respond well to medication.[26]

Negative symptoms

Negative symptoms are deficits of normal emotional responses or of other thought processes.[28] The five recognised domains of negative symptoms are: blunted affect – 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, and avolition – a lack of motivation and apathy.[29] Negative symptoms appear to contribute more to poor quality of life, functional impairment, and to the burden on others than do positive symptoms.[18][30] People with greater negative symptoms often have a history of poor adjustment before the onset of illness. Other related symptoms are social withdrawal,[31] self-neglect particularly in hygiene, and self-care, and loss of judgment.[28] Distortions of self-experience such as feeling as if one's thoughts or feelings are not really one's own, to believing that thoughts are being inserted into one's mind, sometimes termed passivity phenomena, are also common.[32] Negative symptoms are less responsive to medication.[33]

Cognitive symptoms

Cognitive deficits are the earliest and most constantly found symptoms in schizophrenia.[34][35] The presence and degree of cognitive dysfunction has been reported to be a better indicator of functionality than the presentation of positive or negative symptoms.[36] The deficits impacting cognitive function are found in many areas: working memory, long-term memory,[37][38] verbal declarative memory,[39] semantic processing,[40] episodic memory,[41] attention,[18] and learning (particularly verbal learning)[37] and speed of processing.[10] Deficits in verbal memory are the most pronounced in someone with schizophrenia, and are not accounted for by deficit in attention. Verbal memory impairment has been linked to a decreased ability to semantically encode (process information relating to meaning), which is cited as a cause for another known deficit in long-term memory.[37] From a list of words people usually tend to remember positive words, but in schizophrenia all words are remembered equally, suggesting that anhedonia impairs the semantic encoding of words.[37] These deficits have been found in people before the onset of the illness to some extent.[36][42][43] First-degree relatives of those with schizophrenia and other high-risk people also show a degree of deficit in cognitive abilities, specifically in working memory.[43] A review of the literature on cognitive deficits in people with schizophrenia shows that the deficits may be present in early adolescence, or as early as childhood.[36] The deficits presented tend to remain the same over time, or follow an identifiable course based upon environmental variables.[36][37]

Although the evidence that cognitive deficits remain stable over time is reliable and abundant,[37][41] much of the research in this domain focuses on methods to improve attention and working memory.[37][38] Efforts to improve learning ability in people with schizophrenia using a high-reward versus low-reward condition, and an instruction-absent or instruction-present condition revealed that increasing reward leads to poorer performance, while providing instruction leads to improved performance, highlighting that some treatments may exist to increase cognitive performance.[37] Training people with schizophrenia to alter their thinking, attention, and language behaviors by verbalizing tasks, engaging in cognitive rehearsal, giving self-instructions, giving coping statements to the self to handle failure, and providing self-reinforcement for success, improves performance on recall tasks.[37] This type of training, known as self-instructional (SI) training, produced benefits such as lower number of nonsense verbalizations and improved recall when distracted.[37]

Impairment in social cognition is associated with schizophrenia.[44][45] People with schizophrenia often find facial emotion perception to be difficult.[46]

Onset

Late adolescence and early adulthood are peak periods for the onset of schizophrenia,[10] critical years in a young adult's social and vocational development.[47] In 40% of men and 23% of women diagnosed with schizophrenia, the condition manifested itself before the age of 19.[48] The most general symptoms of schizophrenia tend to appear between ages 16 and 30.[3][6] The onset of the disorder is usually between ages 18 and 25 for men and between 25 and 35 for women.[49] To minimize the developmental disruption associated with schizophrenia, much work has been done to identify and treat the prodromal (pre-onset) phase, which has been detected up to 30 months before the onset of symptoms.[47] Those who go on to develop schizophrenia may experience transient or self-limiting psychotic symptoms[50] and the non-specific symptoms of social withdrawal, irritability, dysphoria,[51] and clumsiness before the onset of the disease.[52] People who have a transient psychosis as well as family history of schizophrenia have a 20–40% chance of being diagnosed one year later.[53] Children who go on to develop schizophrenia may also demonstrate decreased intelligence, decreased motor development (reaching milestones such as walking slowly), isolated play preference, social anxiety, and poor school performance.[54][55][56]

Causes

Genetic vulnerability and environmental factors are key issues in the development of schizophrenia;[10][57] their interactions are complex as numerous and diverse insults from conception to adulthood can be involved.[58]

Genetic

Estimates of the heritability of schizophrenia are around 80%, which implies that 80% of the individual differences in risk to schizophrenia is associated with genetics.[59][60] These estimates vary because of the difficulty in separating genetic and environmental influences and some have labeled these estimates inaccurate.[61][62] The greatest single risk factor for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of identical twins of those with schizophrenia are also affected.[57] If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%.[59] Results of candidate gene studies of schizophrenia have generally failed to find consistent associations,[63] and the genetic loci identified by genome-wide association studies as associated with schizophrenia explain only a small fraction of the variation in the disease.[64]

Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression.[16][65] The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia.[66] Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare copy-number variations (CNVs); these structural variations are associated with known genomic disorders involving deletions at 22q11.2 (DiGeorge syndrome), duplications at 16p11.2 16p11.2 duplication (most frequently found) and deletions at 15q11.2 (Burnside-Butler syndrome).[67] 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.[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 that genetic variants that increase the risk of schizophrenia would be selected against due to their negative effects on reproductive fitness. A number of potential explanations have been proposed, including that alleles associated with schizophrenia risk confers a fitness advantage in unaffected individuals.[68][69] While some evidence has not supported this idea,[62] others propose that a large number of alleles each contributing a small amount can persist.[70]

Environment

Environmental factors associated with the development of schizophrenia include the living environment, drug use, and prenatal stressors.[10]

Factors such as oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during fetal development, may result in a slight increase in the risk of schizophrenia later in life.[10] as has maternal obesity. Both maternal stress and infection have been demonstrated to alter fetal neurodevelopment through pro-inflammatory proteins such as IL-8 and TNF.[71][72] There is a slighter risk associated with being born in the winter or spring possibly due to a prenatal viral infection.[57] Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections by Toxoplasma gondii and Chlamydia.[73] The increased risk is about five to eight percent.[74] Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.[75]

Childhood trauma, death of a parent, and being bullied or abused increase the risk of psychosis.[76][77] Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two,[10][57] even after taking into account drug use, ethnic group, and size of social group.[78] Other factors that play an important role include social isolation and immigration related to social adversity, racial discrimination, family dysfunction, unemployment, and poor housing conditions.[57][79] Having a father older than 40 years, or parents younger than 20 years are also seen to be risk factors.[5]

Substance use

Cannabis may be a contributory factor in schizophrenia, potentially increasing the risk of the disease in those who are already at risk.[15] The increased risk may require the presence of certain genes within an individual.[15] Among those who are at risk of psychosis, it is associated with twice the rate.[80]

About half of those with schizophrenia use recreational drugs, including cannabis, nicotine, and alcohol excessively.[81][82] Recreational drugs include stimulants such as amphetamine and cocaine that can lead to a temporary stimulant psychosis, which presents very similarly to schizophrenia. Rarely, alcohol use can also result in a similar alcohol-related psychosis.[57][83] Drugs may be also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness.[81][84]

Mechanisms

While the mechanisms of schizophrenia are unknown, a number of attempts have been made to explain the link between altered brain function and schizophrenia.[10] One of the most common is the dopamine hypothesis, which attributes psychosis to the mind's faulty interpretation of the misfiring of dopaminergic neurons.[10] Other possible mechanisms include glutaminergic neurotransmission and neurodevelopment. Frameworks have hypothesized links between these biological abnormalities and symptoms.[85]

Abnormal dopamine signalling has been implicated in schizophrenia based on the usefulness of medications that effect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis.[86][87] Abnormalities in dopamine signalling have been hypothesized to underlie delusions.[88][89][90] A decrease in D1 receptors in the prefrontal cortex may also be responsible for deficits in working memory.[91][92][93][94]

Studies demonstrate reduced NMDA receptor expression and NMDA receptor blockers mimic both schizophrenia symptoms and the physiological abnormalities associated with schizophrenia.[95][96][97] Post-mortem studies consistently find that a subset of these neurons fail to express GAD67,[98] in addition to abnormalities in morphology. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles that is necessary during working memory tasks, a process that is electrophysiologically reflected in gamma frequency (30–80 Hz) oscillations. Both working memory tasks and gamma oscillations are impaired in schizophrenia, which may reflect abnormal interneuron functionality.[98][99][100][101]

There are often impairments in cognition, social functioning, and motor skills before the onset of schizophrenia, which suggests there is a neurodevelopmental component.[102] Furthermore, problems before birth such as maternal infection,[103][104] maternal malnutrition and complications during pregnancy all increase risk for schizophrenia.[71] Schizophrenia usually emerges 18-25, an age period that overlaps with certain stages of neurodevelopment that are implicated in schizophrenia.[105]

Deficits in executive 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.[106][107] 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 the dorsolateral prefrontal cortex is 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 reduced neuropil, evidenced by increased pyramidal cell density and reduced dendritic spine density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.[108]

Positive and negative symptoms have been linked to reduced cortical thickness in the superior temporal lobe,[109] and orbitofrontal cortex, respectively.[110] Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia,[111] and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward.[112] 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.[113]

Bayesian models of brain functioning have been utilized to link abnormalities in cellular functioning to symptoms.[114][115] Both hallucinations and delusions have been suggested to reflect improper encoding of prior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of circuits that mediate predictive coding, hypoactive NMDA receptor activation, similar to that seen in schizophrenia, could theoretically result in classic symptoms of schizophrenia such as delusions and hallucinations.[116][117]

Diagnosis

There is no objective test or biomarker to confirm diagnosis. Psychoses can 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). Diagnosis of schizophrenia needs a period of six months where symptoms are noted, however a different diagnosis of schizophreniform disorder can be made before the six months needed for schizophrenia.[118]

Schizophrenia is diagnosed based on criteria in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association or the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization. These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a psychiatric assessment. The mental status examination is an important part of the assessment.[119] Symptoms associated with schizophrenia occur along a continuum in the population and must reach a certain severity and level of impairment before a diagnosis is made.[57] An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS).[120] This has been seen to have shortcomings relating to negative symptoms, and other scales – the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS) have been introduced.[121]

Criteria

In 2013, the fifth edition of the DSM (DSM-5) was published. 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. The person had to be suffering from delusions, hallucinations, or disorganized speech. A second symptom could be negative symptoms, or severely disorganized or catatonic behaviour.[118] The definition of schizophrenia remains essentially the same as that specified by the 2000 version of DSM (DSM-IV-TR), but DSM-5 makes a number of changes.

  • Subtype classifications – such as catatonic and paranoid schizophrenia  – are removed. These were retained in previous revisions largely for reasons of tradition, but had subsequently proved to be of little worth.[122]
  • Catatonia is no longer so strongly associated with schizophrenia.[123]
  • In describing a person's schizophrenia, it is recommended that a better distinction be made between the current state of the condition and its historical progress, to achieve a clearer overall characterization.[122]
  • Special treatment of Schneider's first-rank symptoms is no longer recommended.[122]
  • Schizoaffective disorder is better defined to demarcate it more cleanly from schizophrenia.[122]
  • An assessment covering eight domains of psychopathology – such as whether hallucination or mania is experienced – is recommended to help clinical decision-making.[124]

The ICD-10 criteria are typically used in European countries; the DSM criteria are used in the United States and some other countries, and are prevailing in research studies. The ICD-10 criteria put more emphasis on Schneiderian first-rank symptoms. In practice, agreement between the two systems is high.[125] The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.[32]

If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied. Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, and various conditions may be classed as psychotic disorder not otherwise specified; schizoaffective disorder is diagnosed if symptoms of mood disorder are 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.[118] Schizophrenia is not diagnosed if symptoms of pervasive developmental disorder are present unless prominent delusions or hallucinations are also present.[118]

Subtypes

With the publication of DSM-5, the APA removed all sub-classifications of schizophrenia.[126] The five sub-classifications included in DSM-IV-TR were:[127][128]

  • Paranoid type: Delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not. Delusions are persecutory and/or grandiose, but in addition to these, other themes such as jealousy, religiosity, or somatization may also be present. (DSM code 295.3/ICD code F20.0)
  • Disorganized type: Named hebephrenic schizophrenia in the ICD. Where thought disorder and flat affect are present together. (DSM code 295.1/ICD code F20.1)
  • Catatonic type: The subject may be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility. (DSM code 295.2/ICD code F20.2)
  • Undifferentiated type: Psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. (DSM code 295.9/ICD code F20.3)
  • Residual type: Where positive symptoms are present at a low intensity only. (DSM code 295.6/ICD code F20.5)

The ICD-10 defines additional subtypes:[127]

  • Post-schizophrenic depression: A depressive episode arising in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present. (ICD code F20.4)
  • Simple schizophrenia: Insidious and progressive development of prominent negative symptoms with no history of psychotic episodes. (ICD code F20.6)
  • Other schizophrenia include cenesthopathic schizophrenia and schizophreniform disorder NOS (ICD code F20.8).[129]

Differential diagnosis

Psychotic symptoms may be present in several other mental disorders, including bipolar disorder,[7] borderline personality disorder,[8] substance intoxication, and substance-induced psychosis. Non-bizarre delusions are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizotypal personality disorder has symptoms that are similar but less severe than those of schizophrenia.[6] Schizophrenia occurs along with obsessive-compulsive disorder (OCD) considerably more often than could be explained by chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia.[130]

A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbance, systemic infection, syphilis, AIDS dementia complex, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementias such as Alzheimer's disease, Huntington's disease, frontotemporal dementia, and the Lewy body dementias may also be associated with schizophrenia-like psychotic symptoms.[131] It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication. In children hallucinations must be separated from typical childhood fantasies.[6]

Prevention

Prevention of schizophrenia is difficult as there are no reliable markers for the later development of the disorder.[132] There is tentative though inconclusive evidence for the effectiveness of early interventions to prevent schizophrenia in the prodrome phase.[133] There is some evidence that early intervention in those with a psychotic episode may improve short-term outcomes, but there is little benefit from these measures after five years.[10] Cognitive behavioral therapy may reduce the risk of psychosis in those at high risk after a year[134] and is recommended in this group, by the National Institute for Health and Care Excellence (NICE).[22] Another preventive measure is to avoid drugs that have been associated with development of the disorder, including cannabis, cocaine, and amphetamines.[57]

Management

The primary treatment of schizophrenia is antipsychotic medications, often in combination with psychological and social supports.[10] Community support services including drop-in centers, visits by members of a community mental health team, supported employment[135] and support groups are common. Hospitalization may occur for severe episodes either voluntarily or (if mental health legislation allows it) involuntarily. Long-term hospitalization is uncommon since deinstitutionalization beginning in the 1950s, although it still occurs.[21] The time between the onset of symtoms to being given treatment – the duration of untreated psychosis (DUP) is corellated with worse outcome.[24]

Exercise therapy has been shown to improve positive and negative symptoms, cognition, and improve quality of life.[136] Aerobic exercise has been shown to improve cognitive deficits of working memory and attention.[137] Exercise has also been shown to increase the volume of the hippocampus in those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease.[136] However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity.[138] Supervised sessions are recommended.[137]

Medication

Risperidone (trade name Risperdal) is a common atypical antipsychotic medication.

The first-line treatment for schizophrenia is an antipsychotic medication. Antipsychotics block the effects of dopamine a neurotransmitter. The first-generation antipsychotics, now called typical antipsychotics, only affect dopamine levels. Those brought out later, the second-generation antipsychotics known as atypical antipsychotics, can also have effect on another neurotransmitter serotonin. 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.[139][12] They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications.[140]

After a first-episode psychosis where there has been a full recovery with no symptoms for twelve months, stopping medication may be considered. Up to 40% in these cases remain well though some may need to continue on low doses. Where there has been a second relapse but with no further symptoms after a full year, antipsychotics may be reduced. Repeated psychotic episodes worsen the long-term outlook and the risk of relapse following a second episode is high, and long term treatment is usually recommended.[141][142] Antipsychotics may need to be stopped or switched, if a person fails to improve adequately or has associated adverse effects. This needs to be closely monitored, and should take place over weeks or months, except in urgent situations such as the development of agranulocytosis from the use of clozapine. In this type of abrupt stoppage a more severe rebound psychosis can occur.[141]

There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people.[143] Atypical antipsychotics such as amisulpride, olanzapine, risperidone, and clozapine may be more effective but are associated with greater side effects.[144] There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people.[33] Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),[145] but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.[10][57][146]

Most people on antipsychotics have side effects. People on typical antipsychotics tend to have a higher rate of movement disorders including akathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. This is most pronounced with olanzapine; risperidone and quetiapine are also associated with weight gain.[144] Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.[144] It remains unclear whether the newer antipsychotics reduce the chances of developing neuroleptic malignant syndrome or tardive dyskinesia, a rare but serious neurological disorder.[147]

About 30 to 50 percent of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment.[148] For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used, either monthly or three-monthly.[149] They reduce the risk of relapse to a greater degree than oral medications.[150] When used in combination with psychosocial interventions, they may improve long-term adherence to treatment.[151]

Supplements

Disruption of the gut microbiota has been linked to inflammation, and disorders of the central nervous system. This includes schizophrenia, and probiotic supplementation has been proposed to improve its symptoms. A review found no evidence to support this but it concludes that probiotics may be of benefit in regulating bowel movements and lessening the metabolic effects of antipsychotics.[152]

Interventions

A number of interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy,[153] group therapy, cognitive remediation therapy,[154] cognitive behavioral therapy, and metacognitive training.[155] Skills training, and help with substance use, and weight management– often needed as a side effect of an antipsychotic, are also offered.[156] In the US, interventions for first episode psychosis have been brought together in an overall approach known as coordinated speciality care (CSC) and also includes support for education.[12] In the UK care across all phases is a similar approach that covers many of the treament guidelines recommended.[22] The aim is to reduce the number of relapses and stays in hospital.[153]

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 as assertive community treatment (ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life.[157][158] Another more intense approach is known as intensive 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.[159]

Some studies have shown little evidence for the effectiveness of cognitive behavioral therapy (CBT) in either reducing symptoms or preventing relapse.[160][161] Other studies have found that CBT improves overall psychotic symptoms, but has no effect on social function, relapse, or quality of life.[162] 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.[161][163] Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK.[164][165] This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example.[165][166][167] Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.[168]

Prognosis

Disability-adjusted life years lost due to schizophrenia per 100,000 inhabitants in 2004.

Schizophrenia has great human and economic costs.[10] It results in a decreased life expectancy of 20 years.[9][4] This is primarily because of its association with obesity, poor diet, sedentary lifestyles, and smoking, with an increased rate of suicide playing a lesser role.[10][9][169] Antipsychotic medications may also increase the risk.[9] These differences in life expectancy increased between the 1970s and 1990s.[170] Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia.[171][172] This may lead to hyponatremia which can be life-threatening. Antipsychotics can lead to a dry 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.[172]

Schizophrenia is a major cause of disability, with active psychosis ranked as the third-most-disabling condition after quadriplegia and dementia and ahead of paraplegia and blindness.[173] Approximately 75% of people with schizophrenia have ongoing disability with relapses[33] and 16.7 million people globally are deemed to have moderate or severe disability from the condition.[174] Some people do recover completely and others function well in society.[175] Most people with schizophrenia live independently with community support.[10] About 85% are unemployed.[5] In people with a first episode of psychosis a good long-term outcome occurs in 42%, an intermediate outcome in 35% and a poor outcome in 27%.[176] Outcomes for schizophrenia appear better in the developing than the developed world.[177] These conclusions have been questioned.[178][179]

There is a higher than average suicide rate associated with schizophrenia. This had been cited at 10%, but has been revised to an estimate of 4.9%, most often occurring in the period following onset or first hospital admission.[20][180] Several times more (20 to 40%) attempt suicide at least once.[6][181] There are a variety of risk factors, including male gender, depression, and a high IQ.[181]

Schizophrenia and smoking have shown a strong association in studies worldwide.[182][183] 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.[183] Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content.[184] Some propose that this is in an effort to improve symptoms.[185] Among people with schizophrenia use of cannabis is also common.[81]

Epidemiology

Deaths per million persons due to schizophrenia in 2012.
  0–0
  1–1
  2–2
  3–3
  4–6
  7–20

In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases and a total of 19.8 million cases globally.[14] Schizophrenia affects around 0.3–0.7% of people at some point in their life.[10] It occurs 1.4 times more frequently in males than females and typically appears earlier in men[57]—the peak ages of onset are 25 years for males and 27 years for females.[186] Onset in childhood is much rarer,[187] as is onset in middle or old age.[188]

Despite the prior belief that schizophrenia occurs at similar rates worldwide, its frequency varies across the world,[6][189] within countries,[190] and at the local and neighborhood level.[191] This variation has been estimated to be fivefold.[5] It causes approximately one percent of worldwide disability adjusted life years[57] and resulted in 17,000 deaths in 2015.[11] The rate of schizophrenia varies up to threefold depending on how it is defined.[10]

In 2000, the World Health Organization found 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.[192] About 1.1% of adults have schizophrenia in the United States.[193]

History

The term "schizophrenia" was coined by Eugen Bleuler.

The history of schizophrenia is complex and does not lend itself easily to a linear narrative.[194] Accounts of a schizophrenia-like syndrome are rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809.[195] Dementia praecox, meaning premature dementia was used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 by Arnold Pick in a case report of hebephrenia. In 1893 Emil Kraepelin used the term in making a distinction, known as the Kraepelinian dichotomy, between the two psychoses – praecox dementia, and manic depression.[196] Kraepelin believed that dementia praecox was probably caused by a long-term, smouldering systemic or "whole body" disease process that affected many organs and peripheral nerves in the body but which affected the brain after puberty in a final decisive cascade.[197] It was thought to be an early form of dementia, a degenerative disease.[198] When it became evident that the disorder was not degenerative it was renamed schizophrenia by Eugen Bleuler in 1908.

The word schizophrenia—which translates roughly as "splitting of the mind" and comes from the Greek roots schizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-, "mind")[199] and was intended to describe the separation of function between personality, thinking, memory, and perception. American and British interpretations of Bleuler led to the claim that he described its main symptoms as four A's: flattened affect, autism, impaired association of ideas, and ambivalence.[200][201]

The term schizophrenia used to be associated with split personality by the general population but that usage went into decline when it became known as a separate disorder, first as multiple identity disorder , and later as dissociative identity disorder.[202]

A molecule of chlorpromazine, the first antipsychotic developed in the 1950s.

In the early 20th century, the psychiatrist Kurt Schneider listed the forms of psychotic symptoms that he thought distinguished schizophrenia from other psychotic disorders. [203] These are called first-rank symptoms that are mostly covered in the updated use of positive symptoms. They are no longer included in DSM-5. First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.[204]

Treatment was revolutionized in the mid-1950s with the development and introduction of the first typical antipsychotic, chlorpromazine.[205]

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-based biopsychosocial model to a reason-based medical model.[206] DSM IV showed an increased focus to an evidence-based medical model.[207] DSM-5 was published in 2013 and introduced changes to DSM IV.

Society and culture

John Nash, an American mathematician and joint recipient of the 1994 Nobel Prize for Economics, who had schizophrenia. His life was the subject of the 1998 book, A Beautiful Mind by Sylvia Nasar.

In 2002, the term for schizophrenia in Japan was changed from seishin-bunretsu-byō (精神分裂病, lit. "mind-split disease") to tōgō-shitchō-shō (統合失調症, lit. "integration-dysregulation syndrome") to reduce stigma.[10] The new name also interpreted as "integration disorder" was inspired by the biopsychosocial model; it increased the percentage of people who were informed of the diagnosis from 37 to 70% over three years.[208] A similar change was made in South Korea in 2012.[209] A professor of psychiatry, Jim van Os, has proposed changing the English term to "psychosis spectrum syndrome".[210]

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.[211]

The book A Beautiful Mind chronicled the life of John Forbes Nash who had been diagnosed with schizophrenia but who went on to win the Nobel Prize for Economics. This was later made into the film with the same name. An earlier documentary was made with the title A Brilliant Madness.

In 1964 a lengthy case study of three males diagnosed with paranoid schizophrenia who each had the delusional belief that they were Jesus Christ was published as a book. This has the title of The Three Christs of Ypsilanti, and has later (2017) been made into a film called Three Christs.

Violence

People with severe mental illness, including schizophrenia, are at a significantly greater risk of being victims of both violent and non-violent crime.[212] Schizophrenia has been associated with a higher rate of violent acts, but most appear to be related to associated substance abuse.[213] Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region.[214] What role schizophrenia has on violence independent of drug misuse is controversial, but certain aspects of individual histories or mental states may be factors.[215] About 11% of people in prison for homicide have schizophrenia and 21% have mood disorders.[216] 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.[216]

Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence.[213] 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.[217] The perception of people with psychosis as violent has more than doubled in prevalence since the 1950s, according to one meta-analysis.[218]

Research directions

Schizophrenia is not believed to occur in non-human species[219] but it may be possible to develop a pharmacologically induced nonhuman primate model of schizophrenia.[220]

It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the intestinal flora.[221] A subgroup of persons with schizophrenia present an immune response to gluten differently from that found in people with celiac, with elevated levels of certain serum biomarkers of gluten sensitivity such as anti-gliadin IgG or anti-gliadin IgA antibodies.[222]

Research has found a tentative benefit in using minocycline, a broad-spectrum antibiotic, to treat schizophrenia.[223] Nidotherapy or efforts to change the environment of people with schizophrenia to improve their ability to function, is also being studied but there is not enough evidence yet to make conclusions about its effectiveness.[224] Various agents have been explored for possible effectiveness in treating negative symptoms, for which medications have been of little benefit.[225] 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.[226]

Various brain stimulation techniques are being studied to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs).[227][228] A 2015 Cochrane review found unclear evidence of benefit.[229] Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS).[228] Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.[228]

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https://en.wikipedia.org/wiki/Schizophrenia