Fear of Rain (2021)

Introduction

Fear of Rain (also titled I Saw a Man with Yellow Eyes) is an upcoming American psychological thriller film written and directed by Castille Landon and starring Katherine Heigl, Madison Iseman, Israel Broussard, Eugenie Bondurant, and Harry Connick Jr.

Outline

A girl living with schizophrenia struggles with terrifying hallucinations as she begins to suspect her neighbour has kidnapped a child. The only person who believes her is Caleb – a boy she is not even sure exists.

Cast

  • Madison Iseman as Rain Burroughs.
  • Katherine Heigl as Michelle Burroughs.
  • Israel Broussard as Caleb.
  • Eugenie Bondurant as Dani McConnell.
  • Harry Connick Jr. as John Burroughs.

Production

Principal photography began in April 2019 in Tampa, Florida, and St. Petersburg, Florida. In November 2019, it was announced that the film was in post-production.

Production & Filming Details

  • Director(s): Castille London.
  • Producer(s):
    • Lori Abrams … co-producer / executive producer.
    • Kevin Adler … executive producer.
    • Nicolas Chartier … executive producer.
    • Lisa D’Ambrosio … executive producer.
    • Jonathan Deckter … executive producer.
    • Tommy Kelly … executive producer.
    • Dominic Medina … assistant producer.
    • Don Miggs … executive producer.
    • Robert Molloy … producer.
    • Dori A. Rath … producer (p.g.a.).
    • Joseph Restaino … producer (p.g.a.).
    • Joe Riley … producer.
    • Jessica Steinbrenner … executive producer.
    • Tony Stopperan … executive producer.
  • Writer(s): Castille London.
  • Music: Jamie Muhoberac.
  • Cinematography: Joshua Reis.
  • Editor(s): Morgan Halsey.
  • Production:
    • Sweet Tomato Films.
    • Zero Gravity Management.
    • Buzzfeed.
    • Hungry Bull Productions.
    • Mirror Image Films.
    • Pinstripe Productions.
  • Distributor(s):
    • GEM Entertainment (2020) (Non-US) (all media) (multi-territory).
    • The Searchers (2021) (Netherlands) (theatrical).
    • Front Row Filmed Entertainment (2020) (United Arab Emirates) (all media) (Middle East, North Africa and Iran).
    • Lionsgate (2021) (USA) (all media).
    • Storm Pictures Korea (2021) (South Korea) (all media).
    • The Searchers (2021) (Belgium) (all media).
  • Release Date: 12 February 2021.
  • Running Time: 104 minutes.
  • Rating: PG-13.
  • Country: US.
  • Language: English.

Video Link

On This Day … 08 February

People (Deaths)

  • 1964 – Ernst Kretschmer, German psychiatrist and author (b. 1888).
  • 2007 – Ian Stevenson, Canadian-American psychiatrist and academic (b. 1918).

Ernst Kretschmer

Ernst Kretschmer (08 October 1888 to 08 February 1964) was a German psychiatrist who researched the human constitution and established a typology.

Life

Kretschmer was born in Wüstenrot near Heilbronn. He attended Cannstatt Gymnasium, one of the oldest Latin schools in Stuttgart area. From 1906 to 1912 he studied theology, medicine, and philosophy at the universities of Tübingen, Munich and Hamburg. From 1913 he was assistant of Robert Gaupp in Tübingen, where he received his habilitation in 1918. He continued as assistant medical director until 1926.

In 1926 he became the director of the psychiatric clinic at Marburg University.

Kretschmer was a founding member of the International General Medical Society for Psychotherapy (AÄGP) which was founded on 12 January 1927. He was the president of AÄGP from 1929. In 1933 he resigned from the AÄGP for political reasons.

From 1946 until 1959, Kretschmer was the director of the psychiatric clinic of the University of Tübingen. He died, aged 75, in Tübingen.

Cooperating with the Nazis

After he resigned from the AÄGP, he started to support the SS and signed the “Vow of allegiance of the professors of the German universities and high-schools to Adolf Hitler and the National Socialistic state.” (German: “Bekenntnis der Professoren an den deutschen Universitäten und Hochschulen zu Adolf Hitler und dem nationalsozialistischen Staat”).

Persistent Vegetative State and Sensitive Paranoia Research

Kretschmer was the first to describe the persistent vegetative state which has also been called Kretschmer’s syndrome. Another medical term coined after him is Kretschmer’s sensitive paranoia. This classification has the merit of singling out “a type of paranoia that was unknown” prior to Kretschmer, and which “does not resemble the stereotypical image […] of sthenic paranoia”. Furthermore, between 1915 and 1921 he developed a differential diagnosis between schizophrenia and manic depression.

Ian Stevenson

Ian Pretyman Stevenson (31 October 1918 to 08 February 2007) was a Canadian-born American psychiatrist. He worked for the University of Virginia School of Medicine for fifty years, as chair of the department of psychiatry from 1957 to 1967, Carlson Professor of Psychiatry from 1967 to 2001, and Research Professor of Psychiatry from 2002 until his death.

As founder and director of the university’s Division of Perceptual Studies, which investigates the paranormal, Stevenson became known for his research into cases he considered suggestive of reincarnation, the idea that emotions, memories, and even physical bodily features can be transferred from one life to another. Over a period of forty years in international fieldwork, he investigated three thousand cases of children who claimed to remember past lives. His position was that certain phobias, philias, unusual abilities and illnesses could not be fully explained by heredity or the environment. He believed that, in addition to genetics and the environment, reincarnation might possibly provide a third, contributing factor.

Stevenson helped found the Society for Scientific Exploration in 1982 and was the author of around three hundred papers and fourteen books on reincarnation, including Twenty Cases Suggestive of Reincarnation (1966), Cases of the Reincarnation Type (four volumes, 1975-1983) and European Cases of the Reincarnation Type (2003). His most ambitious work was the 2,268-page, two-volume Reincarnation and Biology: A Contribution to the Etiology of Birthmarks and Birth Defects (1997). This reported two hundred cases in which birthmarks and birth defects seemed to correspond in some way to a wound on the deceased person whose life the child recalled. He wrote a shorter version of the same research for the general reader, Where Reincarnation and Biology Intersect (1997).

Reaction to his work was mixed. In an obituary for Stevenson in The New York Times, Margalit Fox wrote that Stevenson’s supporters saw him as a misunderstood genius but that most scientists had simply ignored his research and that his detractors regarded him as earnest but gullible. His life and work became the subject of three supportive books, Old Souls: The Scientific Search for Proof of Past Lives (1999) by Tom Shroder, a Washington Post journalist, Life Before Life (2005) by Jim B. Tucker, a psychiatrist and colleague at the University of Virginia, and Science, the Self, and Survival after Death (2012), by Emily Williams Kelly. Critics, particularly the philosophers C.T.K. Chari (1909-1993) and Paul Edwards (1923-2004), raised a number of issues, including claims that the children or parents interviewed by Stevenson had deceived him, that he had asked them leading questions, that he had often worked through translators who believed what the interviewees were saying, and that his conclusions were undermined by confirmation bias, where cases not supportive of his hypothesis were not presented as counting against it.

What is Schizophrenia?

Introduction

Schizophrenia is a psychiatric disorder characterised by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganised thinking. Other symptoms include social withdrawal, decreased emotional expression, and apathy. Symptoms typically come on gradually, begin in young adulthood, and in many cases never resolve. There is no objective diagnostic test; diagnosis is based on:

  • Observed behaviour;
  • 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 (DSM-5) or one month (ICD-11). Many people with schizophrenia have other mental disorders that often includes an anxiety disorder such as panic disorder, an obsessive compulsive disorder (OCD), or a substance use disorder.

About 0.3% to 0.7% of people are affected by schizophrenia during their lifetime. In 2017, there were an estimated 1.1 million new cases and in 2019 a total of 20 million cases globally. Males are more often affected and on average have an earlier onset. The causes of schizophrenia include genetic and environmental factors. Genetic factors include a variety of common and rare genetic variants. Possible environmental factors include being raised in a city, cannabis use during adolescence, infections, the ages of a person’s mother or father, and poor nutrition during pregnancy.

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. The other half will have a lifelong impairment, and severe cases may be repeatedly admitted to hospital. Social problems such as long-term unemployment, poverty, homelessness, exploitation, and victimisation are common consequences of schizophrenia. Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and more physical health problems, leading to an average decrease in life expectancy by 20 years. In 2015, an estimated 17,000 deaths were caused by schizophrenia.

The mainstay of treatment is antipsychotic medication, along with counselling, job training, and social rehabilitation. Up to a third of people do not respond to initial antipsychotics, in which case the antipsychotic clozapine may be used. In situations where there is a risk of harm to self or others, a short involuntary hospitalisation may be necessary. Long-term hospitalisation may be needed for a small number of people with severe schizophrenia. In countries where supportive services are limited or unavailable, long-term hospital stays are more typical.

Epidemiology

In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases, and in 2019 the World Health Organisation (WHO) reported a total of 20 million cases globally. Schizophrenia affects around 0.3-0.7% of people at some point in their life. It occurs 1.4 times more frequently in males than females and typically appears earlier in men – the peak ages of onset are 25 years for males and 27 years for females. Onset in childhood, before the age of 13 can sometimes occur. 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.

Worldwide, schizophrenia is the most common psychotic disorder. The frequency of schizophrenia varies across the world, within countries, and at the local and neighbourhood level. This variation has been estimated to be fivefold. It causes approximately 1% of worldwide disability adjusted life years and resulted in 17,000 deaths in 2015.

In 2000, the WHO found the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardised 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. About 1.1% of adults have schizophrenia in the United States. However, in areas of conflict this figure can rise to between 4.0 and 6.5%.

Brief History

Accounts of a schizophrenia-like syndrome are rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809. 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 – dementia praecox, and manic depression (now called bipolar disorder). Kraepelin believed that dementia praecox was probably caused by a systemic disease that affected many organs and nerves, affecting the brain after puberty in a final decisive cascade. It was thought to be an early form of dementia, a degenerative disease. When it became evident that the disorder was not degenerative it was renamed schizophrenia by Eugen Bleuler in 1908.

The word schizophrenia translates roughly as “splitting of the mind” and is Modern Latin from the Greek roots schizein (σχίζειν, “to split”) and phrēn, (φρεν, “mind”) Its use was intended to describe the separation of function between personality, thinking, memory, and perception.

The term schizophrenia used to be associated with split personality by the general population but that usage went into decline when split personality became known as a separate disorder, first as multiple identity disorder , and later as dissociative identity disorder. In 2002 in Japan the name was changed to integration disorder, and in 2012 in South Korea, the name was changed to attunement disorder to reduce the stigma, both with good results.

In the early 20th century, the psychiatrist Kurt Schneider listed 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 termed first-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. In 2013 the first-rank symptoms were excluded from the DSM-5 criteria. First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.]

The earliest attempts to treat schizophrenia were psychosurgical, involving either the removal of brain tissue from different regions or the severing of pathways. These were notably frontal lobotomies and cingulotomies which were carried out from the 1930s. In the 1930s a number of shock therapies were introduced which induced seizures (convulsions) or comas. Insulin shock therapy involved the injecting of large doses of insulin in order to induce comas, which in turn produced hypoglycaemia and convulsions. The use of electricity to induce seizures was developed, and in use as electroconvulsive therapy (ECT) by 1938. Stereotactic surgeries were developed in the 1940s. Treatment was revolutionized in the mid-1950s with the development and introduction of the first typical antipsychotic, chlorpromazine. In the 1970s the first atypical antipsychotic clozapine, was introduced followed by the introduction of others.

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. DSM IV showed an increased focus to an evidence-based medical model.

Subtypes of schizophrenia classified as paranoid, disorganized, catatonic, undifferentiated, and residual type were difficult to distinguish between and are no longer recognised as separate conditions by DSM-5 (2013) or ICD-11.

Signs and Symptoms

Schizophrenia is a mental disorder characterized by significant alterations in perception, thoughts, mood, and behaviour. Symptoms are described in terms of positive, and negative, and cognitive symptoms. 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).

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, hallucinations, and disorganised thoughts and speech, typically regarded as manifestations of psychosis. Hallucinations most commonly involve the sense of hearing as hearing voices but can sometimes involve any of the other senses of taste, sight, smell, and touch. They are also typically related to the content of the delusional theme. Delusions are bizarre or persecutory in nature. 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. Thought disorders can include thought blocking, and disorganised speech – speech that is not understandable is known as word salad. Positive symptoms generally respond well to medication, and become reduced over the course of the illness, perhaps related to the age-related decline in dopamine activity.

Negative Symptoms

Negative symptoms are deficits of normal emotional responses, or of other thought processes. 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.

Avolition and anhedonia are seen as motivational deficits resulting from impaired reward processing. Reward is the main driver of motivation and this is mostly mediated by dopamine. It has been suggested that negative symptoms are multidimensional and they have been categorised into two subdomains of apathy or lack of motivation, and diminished expression. Apathy includes avolition, anhedonia, and social withdrawal; diminished expression includes blunt effect, and alogia. Sometimes diminished expression is treated as both verbal and non-verbal. Apathy accounts for around 50% of the most often found negative symptoms and affects functional outcome and subsequent quality of life. Apathy is related to disrupted cognitive processing affecting memory and planning including goal-directed behaviour. The two subdomains has suggested a need for separate treatment approaches. A lack of distress – relating to a reduced experience of depression and anxiety is another noted negative symptom. A distinction is often made between those negative symptoms that are inherent to schizophrenia, termed primary; and those that result from positive symptoms, from the side effects of antipsychotics, substance abuse, and social deprivation – termed secondary negative symptoms. Negative symptoms are less responsive to medication and the most difficult to treat. However if properly assessed, secondary negative symptoms are amenable to treatment.

Scales for specifically assessing the presence of negative symptoms, and for measuring their severity, and their changes have been introduced since the earlier scales such as the PANNS that deals with all types of symptoms. These scales are the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS) also known as second-generation scales. In 2020, ten years after its introduction a cross-cultural study of the use of BNSS found valid and reliable psychometric evidence for the five-domain structure cross-culturally. The BNSS is designed to assess both the presence and severity and change of negative symptoms of the five recognised domains, and the additional item of reduced normal distress. BNSS can register changes in negative symptoms in relation to psychosocial and pharmacological intervention trials. BNSS has also been used to study a proposed non-D2 treatment called SEP-363856. Findings supported the favouring of five domains over the two-dimensional proposition.

Cognitive Symptoms

Cognitive deficits are the earliest and most constantly found symptoms in schizophrenia. They are often evident long before the onset of illness in the prodromal stage, and may be present in early adolescence, or childhood. They are a core feature but not considered to be core symptoms, as are positive and negative symptoms. However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms. Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.

The deficits in cognition are 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. Cognitive deficits may be of neurocognition (non-social) or of social cognition. Neurocognition is the ability to receive and remember information, and includes verbal fluency, memory, reasoning, problem solving, speed of processing, and auditory and visual perception. Verbal memory and attention are seen to be the most affected. Verbal memory impairment is associated with a decreased level of semantic processing (relating meaning to words). Another memory impairment is that of episodic memory. An impairment in visual perception that is consistently found in schizophrenia is that of visual backward masking. Visual processing impairments include an inability to perceive complex visual illusions. Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world. This is also an associated impairment, and facial emotion perception is often found to be difficult. Facial perception is critical for ordinary social interaction. Cognitive impairments do not usually respond to antipsychotics, and there are a number of interventions that are used to try to improve them; cognitive remediation therapy has been found to be of particular help.

Onset

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. Onset before the age of 17 is known as early-onset, and before the age of 13, as can sometimes occur, is known as childhood schizophrenia or very early-onset. A later stage of onset can occur between the ages of 40 and 60, known as late-onset schizophrenia. 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. Late onset has shown that a higher rate of females are affected; they have less severe symptoms and need lower doses of antipsychotics. The tendency for earlier onset in males is later seen to be balanced by a post-menopausal increase in the development in females. Oestrogen produced pre-menopause has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload. There has been a dramatic increase in the numbers of older adults with schizophrenia. An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset and late-onset illness.

Onset may happen suddenly or may occur after the slow and gradual development of a number of signs and symptoms, a period known as the prodromal stage. Up to 75% of those with schizophrenia go through a prodromal stage. The negative and cognitive symptoms in the prodrome stage can precede FEP by many months and up to five years. 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. Since the progression to first episode psychosis is not inevitable, an alternative term is often preferred of at risk mental state Cognitive dysfunction at an early age impact a young person’s usual cognitive development. Recognition and early intervention at the prodromal stage would minimize the associated disruption to educational and social development and has been the focus of many studies. It is suggested that the use of anti-inflammatory compounds such as D-serine may prevent the transition to schizophrenia. Cognitive symptoms are not secondary to positive symptoms or to the side effects of antipsychotics.

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. Early treatment with cognitive behavioural therapies are the gold standard. Neurological soft signs of clumsiness and loss of fine motor movement are often found in schizophrenia, which may resolve with effective treatment of FEP.

Risk Factors

Schizophrenia is described as a neurodevelopmental disorder with no precise boundary, or single cause, and is thought to develop from gene-environment interactions with involved vulnerability factors. The interactions of these risk factors are complex, as numerous and diverse insults from conception to adulthood can be involved. A genetic predisposition on its own, without interacting environmental factors, will not give rise to the development of schizophrenia. The genetic component means that prenatally brain development is disturbed, and environmental influence affects the postnatal development of the brain. Evidence suggests that genetically susceptible children are more likely to be vulnerable to the effects of environmental risk factors.

Genetic

Estimates of the heritability of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics. These estimates vary because of the difficulty in separating genetic and environmental influences, and their accuracy has been queried. The greatest 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. If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%. However, DSM-5 points out that most people with schizophrenia have no family history of psychosis. Results of candidate gene studies of schizophrenia have generally failed to find consistent associations, and the genetic loci identified by genome-wide association studies explain only a small fraction of the variation in the disease.

Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression. The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia. 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). 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.

The genes CRHR1 and CRHBP have been shown to be associated with a severity of suicidal behaviour. These genes code for stress response proteins needed in the control of the HPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in the function of the HPA axis possibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviours.

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. While some evidence has not supported this idea, others propose that a large number of alleles each contributing a small amount can persist.

Environmental

Environmental factors, each associated with a slight risk of developing schizophrenia in later life include oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during prenatal development. A risk is also associated with maternal obesity, in increasing oxidative stress, and dysregulating the dopamine and serotonin pathways. Both maternal stress and infection have been demonstrated to alter foetal neurodevelopment through an increase of pro-inflammatory cytokines. There is a slighter risk associated with being born in the winter or spring possibly due to vitamin D deficiency or a prenatal viral infection. 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. The increased risk is about 5-8%. Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.

Adverse childhood experiences (ACEs), severe forms of which are classed as childhood trauma, range from being bullied or abused, to the death of a parent. Many adverse childhood experiences can cause toxic stress and increase the risk of psychosis. Chronic trauma can promote lasting inflammatory dysregulation throughout the nervous system. It is suggested that early stress may contribute to the development of schizophrenia through these alterations in the immune system. Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.

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, even after taking into account drug use, ethnic group, and size of social group. A possible link between the urban environment and pollution has been suggested to be the cause of the elevated risk of schizophrenia.

Other risk factors of importance include social isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions. Having a father older than 40 years, or parents younger than 20 years are also associated with schizophrenia. It has been suggested that apart from gene-environment interactions, environment-environment interactions also be taken into account as each environmental risk factor on its own is not enough.

Substance Use

About half of those with schizophrenia use recreational drugs, including cannabis, tobacco, and alcohol excessively. Use of stimulants such as amphetamine and cocaine 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. Drugs may also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness. The use of cannabis and tobacco are not associated with the development of cognitive deficits, and sometimes a reverse relationship is found where their use improves these symptoms. However, substance abuse is associated with an increased risk of suicide, and a poor response to treatment.

Cannabis-use may be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk. The increased risk may require the presence of certain genes within an individual. Its use is associated with doubling the rate. The use of more potent strains of cannabis having a high level of its active ingredient tetrahydrocannabinol (THC), increases the risk further. One of these strains is well known as skunk.

Mechanisms

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. The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the interaction between genes and the environment. Extensive studies support this model. Maternal infections, malnutrition and complications during pregnancy and childbirth are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18-25 a period that overlaps with certain stages of neurodevelopment. Gene-environment interactions lead to deficits in the neural circuitry that affect sensory and cognitive functions.

The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia. The most common model put forward was the dopamine hypothesis of schizophrenia, which attributes psychosis to the mind’s faulty interpretation of the misfiring of dopaminergic neurons. This has been directly related to the symptoms of delusions and hallucinations. Abnormal dopamine signalling 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. A decrease in D1 receptors in the dorsolateral prefrontal cortex may also be responsible for deficits in working memory.

The glutamate hypothesis of schizophrenia links alterations between glutamatergic neurotransmission and the neural oscillations that affect connections between the thalamus and the cortex. Studies have shown that a reduced expression of a glutamate receptor – NMDA receptor, and glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia. Post-mortem studies consistently find that a subset of these neurons fail to express GAD67 (GAD1), in addition to abnormalities in brain morphometry. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronising of neural ensembles needed during working memory tasks. These give the neural oscillations produced as gamma waves that have a frequency of between 30 and 80 hertz. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality.

Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, 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 behaviour. 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.

Positive symptoms have been linked to cortical thinning in the superior temporal gyrus. Severity of negative symptoms has been linked to reduced thickness in the left medial orbitofrontal cortex. 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, and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward. Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behaviour required to obtain rewards, despite normal hedonic responses.

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 gut microbiota. 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.

Another theory links abnormal brain lateralization to the development of being left-handed which is significantly more common in those with schizophrenia. This abnormal development of hemispheric asymmetry is noted in schizophrenia. Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralisation and schizophrenia.

An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of astrocytes. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia.

Bayesian models of brain functioning have been utilised to link abnormalities in cellular functioning to symptoms. 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, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.

Diagnosis

Refer to Diagnosis of Schizophrenia.

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).

Criteria

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 behaviour, followed by a psychiatric assessment. The mental status examination is an important part of the assessment. An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS). 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. The DSM-5, published in 2013, gives a Scale to Assess the Severity of Symptom Dimensions outlining eight dimensions of symptoms.

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 disorganised speech. A second symptom could be one of the negative symptoms, or severely disorganised or catatonic behaviour. A different diagnosis of schizophreniform disorder can be made before the six months needed for the diagnosis of schizophrenia.

In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning. 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.

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. The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.

A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome. WHO for ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis.

Changes Made

Both manuals have adopted the chapter heading of Schizophrenia spectrum and other psychotic disorders; ICD modifying this as Schizophrenia spectrum and other primary psychotic disorders. 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 all sub-classifications of schizophrenia. ICD-11 has also removed subtypes. The removed subtype from both, of catatonic has been relisted in ICD-11 as a psychomotor disturbance that may be present in schizophrenia.

Another major change was to remove the importance previously given to Schneider’s first-rank symptoms. DSM-5 still uses the listing of schizophreniform disorder but ICD-11 no longer includes it. 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 characterisation.

A dimensional assessment has been included in DSM-5 covering eight dimensions of symptoms to be rated (using the Scale to Assess the Severity of Symptom Dimensions) – these include the five diagnostic criteria plus cognitive impairments, mania, and depression. 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.

Two of the negative symptoms – avolition and diminished emotional expression, have been given more prominence in both manuals.

Comorbidities

Many people with schizophrenia may have one or more other mental disorders, such as panic disorder, OCD, or substance use disorder. These are separate disorders that require treatment. When comorbid with schizophrenia, substance use disorder and antisocial personality disorder both increase the risk for violence. Comorbid substance abuse also increases risk for suicide.

Sleep disorders often co-occur with schizophrenia, and may be an early sign of relapse. Sleep disorders are linked with positive symptoms such as disorganised thinking and can adversely affect cortical plasticity and cognition. The consolidation of memories is disrupted in sleep disorders. They are associated with severity of illness, a poor prognosis, and poor quality of life. Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not. Genetic variations have been found associated with these conditions involving the circadian rhythm, dopamine and histamine metabolism, and signal transduction. Limited positive evidence has been found for the use of acupuncture as an add-on.

Differential Diagnosis

To make a diagnosis of schizophrenia other possible causes of psychosis need to be excluded. Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, or as schizophreniform disorder. Psychosis is noted in Other specified schizophrenia spectrum and other psychotic disorders as a DSM-5 category. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Psychosis that results from a general medical condition or substance is termed secondary psychosis. Psychotic symptoms may be present in several other conditions, including bipolar disorder, borderline personality disorder, substance intoxication, substance-induced psychosis, and a number of drug withdrawal syndromes. 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. Schizophrenia occurs along with 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. There can be considerable overlap with the symptoms of post-traumatic stress disorder.

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, HIV-associated neurocognitive disorder, 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. 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. It is difficult to distinguish childhood schizophrenia from autism.

Prevention

Prevention of schizophrenia is difficult as there are no reliable markers for the later development of the disorder. There is tentative though inconclusive evidence for the effectiveness of early intervention to prevent schizophrenia in the prodrome phase. 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. Cognitive behavioural therapy (CBT) may reduce the risk of psychosis in those at high risk after a year and is recommended in this group, by the National Institute for Health and Care Excellence (NICE). Another preventive measure is to avoid drugs that have been associated with development of the disorder, including cannabis, cocaine, and amphetamines.

Antipsychotics are prescribed following a first-episode psychosis, and following remission a preventive maintenance use is 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.

Management

The primary treatment of schizophrenia is the use of antipsychotic medications, often in combination with psychosocial interventions and social supports. Community support services including drop-in centres, visits by members of a community mental health team, supported employment, and support groups are common. The time between the onset of psychotic symptoms to being given treatment – the duration of untreated psychosis (DUP) is associated with a poorer outcome in both the short term and the long term.

Voluntary or involuntary admittance 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. This process was known as deinstitutionalisation, 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. There will still remain a few people who do not improve enough to be discharged. In those countries that lack the necessary supportive and social services long-term hospital stays are more usual.

Medication

The first-line treatment for schizophrenia is an antipsychotic. The first-generation antipsychotics, now called typical antipsychotics, are dopamine antagonists that block D2 receptors, and affect the neurotransmission of dopamine. 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. They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications. There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people. 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.

Tobacco smoking increases the metabolism of some antipsychotics, by strongly activating CYP1A2, the enzyme that breaks them down, and a significant difference is found in these levels between smokers and non-smokers. It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%. 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. The altering effects are due to compounds in tobacco smoke and not to nicotine; the use of nicotine replacement therapy therefore has the equivalent effect of stopping smoking and monitoring would still be needed.

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

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. A new first-in-class antipsychotic that targets multiple neurotransmitter systems called lumateperone (ITI-007), was trialled and approved by the FDA in December 2019 for the treatment of schizophrenia in adults. 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 and positive 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 a fast heart rate.

Side Effects

Typical antipsychotics are associated with a higher rate of movement disorders including akathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic 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. Another less rare condition of tardive dyskinesia can 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.

Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring. Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfully re-challenged (restarted) with clozapine.

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy. 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 a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.

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. Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction. Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies. Unwanted side effects cause people to stop treatment, resulting in relapses.

Treatment Resistant Schizophrenia

About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning. 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), and clozapine will be offered. Clozapine is of benefit to around half of this group although it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people. Between 12-20% will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia. ECT may be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit. 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.

TRS is often accompanied by a low quality of life, and greater social dysfunction. 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. About 16% 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. This finding also supports the involvement of dopamine in the development of schizophrenia. Studies suggest that TRS may be a more heritable form.

TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies. This variation is seen to possibly indicate an underlying neurobiology such as dopamine super-sensitivity (DSS), glutamate or serotonin dysfunction, inflammation and oxidative stress. Studies have found that dopamine super-sensitivity is found in up to 70% of those with TRS. The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes. 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. 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. In those with ultra treatment resistance the decrease in grey matter volume was larger.

A link has been made between the gut microbiota and the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These include liver enzyme genes that control the availability of a drug to brain targets, and genes responsible for the structure and function of these targets. In the colon the bacteria encode a hundred times more genes than exist in the human genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the portal circulation. This small fraction is then subject to the metabolic action of 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 that parenteral administration of 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.

Psychosocial Interventions

A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy, group therapy, cognitive remediation therapy, CBT, and metacognitive training. Skills training, and help with substance use, and weight management – often needed as a side effect of an antipsychotic, are also offered. 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. In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended. The aim is to reduce the number of relapses and stays in hospital.

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. 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.

Some studies have shown little evidence for the effectiveness of CBT in either reducing symptoms or preventing relapse. 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. 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. Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK. This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example. Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.

Other

Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life. 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. However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity. Supervised sessions are recommended. In the UK healthy eating advice is offered alongside exercise programmes.

An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those of folate, and vitamin D are linked to the risk factors for the development of schizophrenia and for early death including heart disease. 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. The use of supplemental folate is recommended. A zinc deficiency has also been noted. Vitamin B12 is 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. It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics.

Violence

Most people with schizophrenia are not aggressive, and are more likely to be victims of violence rather than perpetrators. However, though the risk of violence in schizophrenia is small the association is consistent, and there are minor subgroups where the risk is high. This risk is usually associated with a comorbid disorder such as a substance use disorder – in particular alcohol, or with antisocial personality disorder. Substance abuse is strongly linked, and other risk factors are linked to deficits in cognition and social cognition including facial perception and insight that are in part included in theory of mind impairments. Poor cognitive functioning, decision-making, and facial perception may contribute to making a wrong judgement of a situation that could result in an inappropriate response such as violence. These associated risk factors are also present in antisocial personality disorder which when present as a comorbid disorder greatly increases the risk of violence.

A review in 2012 showed that schizophrenia was responsible for 6% of homicides in Western countries. Another wider review put the homicide figure at between 5-20%. There was found to be a greater risk of homicide during first episode psychosis that accounted for 38.5% of homicides. The association between schizophrenia and violence is complex. Homicide is linked with young age, male sex, a history of violence, and a stressful event in the preceding year. Clinical risk factors are severe untreated psychotic symptoms – untreated due to either not taking medication or to the condition being treatment resistant. A comorbid substance use disorder or an antisocial personality disorder increases the risk for homicidal behaviour by 8-fold, in contrast to the 2-fold risk in those without the comorbid disorders. Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region. What role schizophrenia has on violence independent of substance misuse is controversial, but certain aspects of individual histories or mental states may be factors.

Hostility is anger felt and directed at a person or group and has related dimensions of impulsiveness and aggression. When this impulsive-aggression is evident in schizophrenia neuroimaging has suggested the malfunctioning of a neural circuit that modulates hostile thoughts and behaviours that are linked with negative emotions in social interactions. This circuit includes the amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula, and hippocampus. Hostility has been reported during acute psychosis, and following hospital discharge. There is a known association between low cholesterol levels, and impulsivity, and violence. A review finds that people with schizophrenia, and lower cholesterol levels are four times more likely to instigate violent acts. This association is also linked to the increased number of suicides in schizophrenia. It is suggested that cholesterol levels could serve as a biomarker for violent and suicidal tendencies.

A review found that just under 10% of those with schizophrenia showed violent behaviour compared to 1.6% of the general population. An excessive risk of violence is associated with drugs or alcohol and increases the risk by as much as 4-fold. Violence often leads to imprisonment. Clozapine is an effective medication that can be used in penal settings such as prisons. However, a condition of benign ethnic neutropenia in many African-Americans excludes them from the use of clozapine the most effective medication. Cognitive deficits are recognised as playing an important part in the origin and maintenance of aggression, and cognitive remediation therapy may therefore help to prevent the risk of violence in schizophrenia.

Prognosis

Schizophrenia has great human and economic costs. It results in a decreased life expectancy of 20 years. This is primarily because of its association with obesity, poor diet, a sedentary lifestyle, and smoking, with an increased rate of suicide playing a lesser role. Side effects of antipsychotics may also increase the risk. These differences in life expectancy increased between the 1970s and 1990s. An Australian study puts the rate of early death at 25 years, and views the main cause to be related to heart disease.

Several studies indicate that almost 40% of those with schizophrenia die from complications of cardiovascular disease including heart attacks, and sudden cardiac death which is seen to be increasingly associated. An underlying factor of sudden cardiac death may be Brugada syndrome (BrS) – BrS mutations that overlap with those linked with schizophrenia are the calcium channel mutations. BrS may also be drug-induced from certain antipsychotics and antidepressants. Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia. 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%. 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.

Schizophrenia is a major cause of disability. In 2016 it was classed as the 12th most disabling condition. Approximately 75% of people with schizophrenia have ongoing disability with relapses and 16.7 million people globally are deemed to have moderate or severe disability from the condition. Some people do recover completely and others function well in society. Most people with schizophrenia live independently with community support. About 85% are unemployed. In people with a first episode of psychosis in schizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%. Males are affected more often than females, and have a worse outcome. Outcomes for schizophrenia appear better in the developing than the developed world. These conclusions have been questioned. Social problems, such as long-term unemployment, poverty, homelessness, exploitation, stigmatisation and victimisation are common consequences, and lead to social exclusion.

There is a higher than average suicide rate associated with schizophrenia estimated at around 5% to 6%, most often occurring in the period following onset or first hospital admission. Several times more (20 to 40%) attempt suicide at least once. There are a variety of risk factors, including male gender, depression, a high IQ, heavy smoking, and substance abuse. Repeated relapse is linked to an increased risk of suicidal behaviour. The use of clozapine can reduce the risk of suicide and aggression.

A strong association between schizophrenia and tobacco smoking has been shown in worldwide studies. Smoking 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. Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content. Some propose that this is in an effort to improve symptoms. Among people with schizophrenia use of cannabis is also common.

Society and Culture

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. 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. A similar change was made in South Korea in 2012 to attunement disorder. A professor of psychiatry, Jim van Os, has proposed changing the English term to psychosis spectrum syndrome. In 2013 with the reviewed DSM-5, the DSM-5 committee was in favour of giving a new name to schizophrenia but they referred this to WHO.

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. 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.

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 Memorial Prize in Economic Sciences. 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 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 a film with the title Three Christs was released in 2020. Such religious delusions are a fairly common feature in psychoses including schizophrenia.

Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence. Such sensationalist reporting stigmatizes schizophrenia more than any other mental illness. In the UK guidelines are given for the reporting of different conditions. Its campaigns have shown a reduction in negative reporting.

Research Directions

Research into schizophrenia has made use of a number of animal models in particular rats, that have shown to be useful in evaluating the different aspects of its development and pathology. Effects of early intervention is an active area of research, importantly focusing on the early detection of at-risk individuals and the development of risk calculators. Methods for large-scale population screening are also included.

Various agents have been explored for possible effectiveness in treating negative symptoms, for which antipsychotics have been of little benefit. 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.

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

Another active area of research is the study of a variety of potential biomarkers that 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 as C-reactive protein are useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. However, other inflammatory cytokines are found to be elevated in first episode psychosis and acute relapse that are normalised after treatment with antipsychotics, and these may be considered as state markers. Deficits in sleep spindles in schizophrenia may serve as a marker of an impaired thalamocortical circuit, and a mechanism for memory impairment. MicroRNAs are highly influential in early neuronal development, and their disruption is implicated in several CNS disorders; circulating microRNAs (cimiRNAs) are found in body fluids such as blood and cerebrospinal fluid, and changes in their levels are seen to relate to changes in microRNA levels in specific regions of brain tissue. These studies suggest that cimiRNAs have the potential to be early and accurate biomarkers in a number of disorders including schizophrenia.

The use of choline as a supplement during pregnancy may have effect in the prevention of the later development of schizophrenia, and is an area of research.

In 2020, over 3,000 clinical trials into drugs, symptom assessment tools, and treatments related to schizophrenia were listed with some recruiting, and some newly completed.

Sybil (2007)

Introduction

Sybil is a 2007 American made-for-television drama film directed by Joseph Sargent, and written by John Pielmeier, based on the 1973 book Sybil by Flora Rheta Schreiber, which fictionalised the story of Shirley Ardell Mason, who was diagnosed with multiple personality disorder (more commonly known then as “split personality”, now called dissociative identity disorder).

This is the second adaptation of the book, following the Emmy Award-winning 1976 mini-series Sybil that was broadcast by NBC.

Outline

Troubled Columbia University art student and later student teacher Sybil Dorsett is referred to psychiatrist Cornelia Wilbur by Dr. Atcheson, a colleague who believes that the young woman is suffering from female hysteria. As her treatment progresses, Sybil confesses that she frequently experiences blackouts and cannot account for large blocks of time. Wilbur helps her recall a childhood in which she suffered physical, emotional, and sexual abuse at the hands of her disturbed mother Hattie.

Eventually, 16 identities varying in age and personal traits begin to emerge. Chief among them is Victoria, a French woman who explains to Dr. Wilbur how she shepherds the many parts of Sybil’s whole. Frustrating the therapist are objections raised by her associates, who suspect she has influenced her patient into creating her other selves, and Sybil’s father, who refuses to admit his late wife was anything other than a loving mother.

Although she had promised never to hypnotize Sybil, later into the treatment, Dr. Wilbur takes her patient to her home by a lake and hypnotizes her into having all 16 personalities be the same age as she and become just aspects of Sybil. By nightfall, Sybil claims she feels different, and emotionally declares her hatred toward her mother.

The last part of the movie tells of the history of Shirley Mason, the real woman who was known by the pseudonym of Sybil Dorsett.

Cast

  • Jessica Lange ….. Dr. Cornelia Wilbur.
  • Tammy Blanchard ….. Sybil Dorsett.
  • Eddie Ruiz ….. Dr. Ladysman.
  • JoBeth Williams … Hattie Dorsett.

Trivia

  • The university scenes were filmed at Dalhousie University in Nova Scotia.
  • In January 2006, The Hollywood Reporter announced CBS had greenlit the project, but it was shelved after completion.
  • The film was released in Italy, New Zealand, the Dominican Republic, Brazil, Norway, and Hungary before finally being broadcast in the US by CBS on 07 June 2008.

Production & Filming Details

  • Director(s): Joseph Sargent.
  • Producer(s):
    • Andrea Lapins … associate producer.
    • Michael Mahoney … producer.
    • Norman Stephens … executive producer.
    • Mark Wolper … executive producer.
  • Writer(s): John Pielmeier.
  • Music: Charles Bernstein.
  • Cinematography: Donald M. Morgan.
  • Editor(s): Michael Brown (as Mike Brown).
  • Production:
    • Norman Stephens Productions.
    • Warner Bros. Television.
    • Wolper Organisation.
  • Distributor(s): CBS (original airing, US).
  • Release Date: 28 May 2007 (Italy).
  • Running Time: 89 minutes.
  • Rating: Unknown.
  • Country: US.
  • Language: English.

Video Link

Sybil (1976)

Introduction

Sybil is a 1976 two-part, ​3 1⁄4-hour American television film starring Sally Field and Joanne Woodward.

It is based on the book of the same name, and was broadcast on NBC on 14-15 November 1976.

Refer to On This Day … 25 January for information Shirley Ardell Mason, whom Sybil is based on (2007 film version).

Outline

After suffering a small breakdown in front of her students (and then being forced to hear a neighbour play Chopin’s Étude in A Minor, “Winter Wind”, incessantly), Sybil Dorsett is given a neurological examination by Dr. Cornelia Wilbur, a psychiatrist. She admits to having blackouts and fears that are getting worse. Dr. Wilbur theorises that the incidents are a kind of hysteria, all related to a deeper problem. She asks Sybil to return at a later date for more counselling. Sybil says she will have to ask her father.

Sybil’s father, Willard Dorsett, and her stepmother, Freida, are in New York on a visit. Sybil meets them at a cafeteria for lunch. She explains to her father that the problems she used to have as a young girl have returned and that she wants to see a psychiatrist, Dr. Wilbur. Sybil’s parents make it clear to Sybil that they disapprove of psychiatrists and psychiatry, saying how evil and controlling psychiatrists are. Sybil becomes upset and dissociates into Peggy, who becomes enraged and breaks a glass. Peggy angrily storms out of the cafeteria. Later that evening, Dr. Wilbur receives a late night call from someone who identifies herself as Vickie and says Sybil is about to jump out a hotel window. Dr. Wilbur rescues Sybil, who denies knowing Vickie. Suddenly, Sybil becomes hysterical and begins speaking like a young girl. This girl introduces herself as Peggy, and Wilbur realises that Sybil is suffering from dissociative identity disorder, previously known as multiple personality disorder.

Vickie introduces herself to Wilbur at the next session. Vickie, who knows everything about the other personalities, tells Wilbur about some of them, including Marcia, who is suicidal, and Vanessa, who plays the piano although Sybil has not played in years and swears she forgot how to play piano.

Over the weeks, each of the personalities introduce themselves to Wilbur. At the same time, the personality Vanessa falls in love with a charming neighbour named Richard.

Wilbur finally explains to Sybil about the other personalities. As proof, Wilbur plays the session’s tape to allow Sybil to hear their voices, but when a voice that sounds like Sybil’s mother Hattie speaks, an infant personality named Ruthie emerges. Wilbur is unable to communicate with the pre-verbal child and must wait until Sybil returns.

Life becomes more chaotic for Sybil as the other personalities grow stronger. The personalities make Dr. Wilbur a Christmas card, but Sybil made everything purple, a colour that frightens Peggy. Dr. Wilbur hypnotises Vickie and asks about the purple. Vickie relates a memory of a time Sybil’s mother locked young Sybil in the wheat bin in the barn. Thinking she was smothering, Sybil used her purple crayon to scratch on the inside of the bin so someone would know she had been there.

Vanessa invites Richard and his son Matthew to have Christmas dinner, after which Richard spends the night in Sybil’s apartment. Sybil has a nightmare and awakens as Marcia, who tries to throw herself off the roof. Richard rescues her and calls Wilbur. Soon afterwards, Richard moves away, crushing both Sybil and Vanessa. Once again confronted with her diagnosis, Sybil attempts to convince Wilbur that she has in fact been faking all of the other personalities the entire time and denies that multiple personalities exist within her.

Wilbur goes in search of Sybil’s father, who mentions that Sybil’s mother Hattie was diagnosed with paranoid schizophrenia, but denies that she ever abused Sybil. Wilbur also seeks out Sybil’s paediatrician. The doctor gives Wilbur a frightening account of extensive internal scarring he found while treating Sybil for a bladder problem. Finally, Wilbur visits the old Dorsett house, where she discovers the green kitchen Sybil’s selves have described many times. She also finds the purple crayon scratches inside the wheat bin. She takes them back to New York City to prove all the memories really happened.

Dr. Wilbur takes Sybil for a drive, during which Peggy reveals the horrific physical abuse she suffered at her mother’s hands. After Peggy exhausts herself, Sybil emerges, remembering everything that Peggy has just said. Finally, she is able to express her rage against her mother.

Dr. Wilbur hypnotises Sybil to introduce her to the other personalities. Sybil, who has always been frightened of Peggy, meets her at last and is surprised that she is only a young girl. Sybil embraces a weeping Peggy. A voiceover from Dr. Wilbur explains that after this incident, Sybil recovered her memories and went on to live a full and happy life as an academic.

The “big chair” featured in the film in which the Sybil character felt comfortable provided the name for Tears for Fears hit album Songs From The Big Chair.

Cast

  • Joanne Woodward as Dr. Cornelia Wilbur.
  • Sally Field as Sybil Dorsett.
  • Brad Davis as Richard, Sybil’s neighbour boyfriend.
  • Martine Bartlett as Hattie Dorsett, Sybil’s mother.
  • Penelope Allen as Miss Penny.
  • Jane Hoffman as Frieda Dorsett.
  • Charles Lane as Dr. Quinoness.
  • Jessamine Milner as Grandma Dorsett.
  • William Prince as Willard Dorsett.
  • Camila Ashland as Cam.
  • Tommy Crebbs as Matthew.
  • Gina Petrushka as Dr. Lazarus.
  • Harold Pruett as Danny.
  • Natasha Ryan as Child Sybil.
  • Paul Tulley as Dr. Castle.
  • Anne Beesley as The Selves.
  • Virginia Campbell as The Selves.
  • Missy Karn as The Selves.
  • Tasha Lee as The Selves.
  • Cathy Lynn Lesko as The Selves.
  • Rachel Longaker as The Selves.
  • Jennifer McAllister as The Selves.
  • Kerry Muir as The Selves.
  • Karen Obediear as The Selves.
  • Tony Sherman as The Selves.
  • Danny Stevenson as The Selves.
  • Gordon Jump as Tractor farmer.
  • Lionel Pina as Tommy.

The Alters

  • Peggy: A nine-year-old girl who believes she is still in the small town in which Sybil grew up. Peggy holds the rage Sybil felt at her mother’s abuse and frequently expresses her anger through temper tantrums and breaking glass. Like many of the selves, she enjoys drawing and painting. She fears hands, dishtowels, music, and the colours green and purple, all triggers to specific instances of abuse.
  • Vicky: A very sophisticated and mature eighteen-year-old girl who is aware of all the other personalities and knows everything the others do, though Sybil does not. Vicky speaks French and claims to have grown up in Paris with many brothers and sisters and loving parents. The dominant personality and the only personality to undergo hypnosis.
  • Vanessa: A young, vibrant, red-haired girl about twelve years old, she is outgoing and full of “joie de vivre”. Falls in love with Richard and helps Sybil build a relationship with him, until he moves away.
  • Marcia: A young girl obsessed with thoughts of death and suicide, who tries to kill herself (and thus Sybil) on several occasions. Dresses in black.
  • Ruthie: A preverbal infant. When Sybil is extremely frightened, she regresses into Ruthie and cannot move or speak.
  • Mary: Named for and strongly resembles Sybil’s grandmother. When Sybil’s grandmother (the only person Sybil felt loved her) died, Sybil was so bereft that she created Mary as an internalised version of Grandma. Mary speaks in the voice of an old woman and frequently behaves as one.
  • Nancy: A product of Sybil’s father’s religious fanaticism, Nancy fears the end of the world and God’s punishment.
  • Clara: Around 8-9 years old. Very religious; critical and resentful of Sybil.
  • Helen: Around 13-14 years old. Timid and afraid, but determined “to be somebody”.
  • Marjorie: Around 10-11 years old. Serene and quick to laugh, enjoys parties and travel.
  • Sybil Ann: Around 5-6 years old. Pale, timid, and extremely lethargic; the defeated Sybil.
  • Mike: A brash young boy who likes to build and do carpentry. He builds bookshelves and a partition wall for Sybil’s apartment, frightening her badly when she doesn’t know how they got there. He and Sid both believe that they will grow penes and be able “to give a girl a baby” when they are older.
  • Sid: Younger and a little more taciturn than Mike, he also enjoys building things, as well as sports. Identifies strongly with Sybil’s father and wants to be like him when he grows up.

Production

Sally Field stars in the title role, with Joanne Woodward playing the part of Sybil’s psychiatrist, Cornelia B. Wilbur. Woodward herself had starred in The Three Faces of Eve, in which she portrayed a woman with three personalities, winning the Academy Award for Best Actress for the role. Based on the book Sybil by Flora Rheta Schreiber, the movie dramatises the life of a shy young graduate student, Sybil Dorsett (in real life, Shirley Ardell Mason), suffering from dissociative identity disorder as a result of the psychological trauma she suffered as a child. With the help of her psychiatrist, Sybil gradually recalls the severe child abuse that led to the development of 16 different personalities. Field’s portrayal of Sybil won much critical acclaim, as well as an Emmy Award.

Edited and Unedited Versions

The film, originally 198 minutes long, was initially shown over the course of two nights on NBC in 1976. Due to high public interest, the VHS version of Sybil was released in the 1980s, with one version running 122 minutes and another, extended version running 132 minutes. Several key scenes, including Sybil’s final climactic “introduction” to her other personalities, are missing in both versions. The film is shown frequently on television, often with scenes restored or deleted to adjust for time constraints and the varying sensitivity of viewers. The DVD includes the full 198-minute version originally displayed on the NBC broadcast.

A 128-minute edit of the film was shown in cinemas in Australia, opening in January 1978.

Production & Filming Details

  • Director(s): Daniel Petrie.
  • Producer(s): Philip Capice, Peter Dunne, and Jacqueline Babbin.
  • Writer(s): Stewart Stern.
  • Music: Leonard Rosenman.
  • Cinematography: Mario Tosi.
  • Editor(s): Michael S. McLean and Rita Roland.
  • Production: Lorimar Productions.
  • Distributor(s):
  • Release Date: 14-15 November 1976.
  • Running Time: 198 minutes (original version), 133 minutes (theatrical), and 187 minutes (DVD).
  • Rating: Unknown.
  • Country: US.
  • Language: English.

Video Link

On This Day … 25 January

People (Births)

  • 1923 – Shirley Ardell Mason, American psychiatric patient (d. 1998).

Shirley Ardell Mason

Shirley Ardell Mason (25 January 1923 to 26 February 1998) was an American art teacher who was reputed to have dissociative identity disorder (previously known as multiple personality disorder).

Her life was purportedly described, with adaptations to protect her anonymity, in 1973 in the book Sybil, subtitled The True Story of a Woman Possessed by 16 Separate Personalities. Two films of the same name were made, one released in 1976 and the other in 2007. Both the book and the films used the name Sybil Isabel Dorsett to protect Mason’s identity, though the 2007 remake stated Mason’s name at its conclusion.

Mason’s diagnosis and treatment under Cornelia B. Wilbur have been criticised, with allegations that Wilbur manipulated or possibly misdiagnosed Mason.

Biography

Mason was born and raised in Dodge Centre, Minnesota, the only surviving child of Walter Wingfield Mason (a carpenter and architect) and Martha Alice “Mattie” Atkinson. In regard to Mason’s mother: “…many people in Dodge Centre say Mattie” – “Hattie” in the book – “was bizarre,” according to Bettie Borst Christensen, who grew up across the street. “She had a witch-like laugh….She didn’t laugh much, but when she did, it was like a screech.” Christensen remembers Mason’s mother walking around after dark, looking in the neighbours’ windows. At one point, Martha Mason was reportedly diagnosed with schizophrenia.

Mason graduated from Dodge Centre High School in 1941 and became an art student at Mankato State College, now Minnesota State University, Mankato. In the early 1950s, Mason was a substitute teacher and a student at Columbia University. She had long suffered from blackouts and emotional breakdowns, and finally entered psychotherapy with Cornelia B. Wilbur, a Freudian psychiatrist. Their sessions together are the basis of the book. From 1970-1971, she taught art at Rio Grande College in Rio Grande, Ohio (now the University of Rio Grande).

Some people in Mason’s home town, reading the book, recognised Mason as Sybil. By that time, Mason had severed nearly all ties with her past and was living in West Virginia. She later moved to Lexington, Kentucky, where she lived near Wilbur. She taught art classes at a community college and ran an art gallery out of her home for many years.

Wilbur diagnosed Mason with breast cancer in 1990, and she declined treatment; it later went into remission. The following year, Wilbur developed Parkinson’s disease, and Mason moved into Wilbur’s house to take care of her until Wilbur’s death in 1992. Mason was a devout Seventh-day Adventist. When her breast cancer returned Mason gave away her books and paintings to friends. She left the rest of her estate to a Seventh-day Adventist TV minister. Mason died on 26 February 1998.

Over one hundred paintings were found locked in a closet in Mason’s Lexington home when it was being emptied after her estate sale. These paintings, often referred to as the “Hidden Paintings”, span the years 1943, eleven years before starting psychotherapy with Dr. Wilbur, to 1965, the year of her successful integration. Several of the paintings were signed by Shirley. However, many remained unsigned, and include examples of some of the artwork presumably created by, and signed by the alternate personalities.

Sybil

Flora Rheta Schreiber’s non-fiction book Sybil: The True Story of a Woman Possessed by 16 Separate Personalities told a version of Mason’s story with names and details changed to protect her anonymity. The book, whose veracity was challenged (e.g. Sybil Exposed by Debbie Nathan), stated that Mason had multiple personalities as a result of severe child sexual abuse at the hands of her mother, who, Wilbur believed, had schizophrenia.

The book was made into a highly acclaimed TV movie starring Sally Field and Joanne Woodward, in 1976. The TV movie was remade in 2007 with Tammy Blanchard and Jessica Lange.

Controversy

Mason’s diagnosis had been challenged. Psychiatrist Herbert Spiegel saw Mason for several sessions while Wilbur was on vacation and felt that Wilbur was manipulating Mason into behaving as though she had multiple personalities when she did not. Spiegel suspected Wilbur of having publicised Mason’s case for financial gain. According to Spiegel, Wilbur’s client was a hysteric but did not show signs of multiple personalities; in fact, he later stated that Mason denied to him that she was “multiple” but claimed that Wilbur wanted her to exhibit other personalities. Spiegel confronted Wilbur, who responded that the publisher would not publish the book unless it was what she said it was.

Spiegel revealed that he possessed audio tapes in which Wilbur tells Mason about some of the other personalities she has already seen in prior sessions. Spiegel believes these tapes are the “smoking gun” proving that Wilbur induced her client to believe she was multiple. Spiegel made these claims 24 years later, after Schreiber, Wilbur and Mason had all died and he was finally asked about the topic.

In August 1998, psychologist Robert Rieber of John Jay College of Criminal Justice stated that the tapes belonged to him and that Wilbur had given them to him decades earlier. He cited the tapes to challenge Mason’s diagnosis. Rieber had never interviewed or treated Mason but asserted that she was an “extremely suggestible hysteric.” He claimed Wilbur had manipulated Mason in order to secure a book deal.

In a review of Rieber’s book, psychiatrist Mark Lawrence asserts that Rieber repeatedly distorted the evidence and left out a number of important facts about Mason’s case to advance his case against the validity of the diagnosis.

Debbie Nathan’s Sybil Exposed draws upon an archive of Schreiber’s papers stored at John Jay College of Criminal Justice and other first-hand sources. Nathan claims that Wilbur, Mason, and Schreiber knowingly perpetrated a fraud and describes the purported manipulation of Wilbur by Mason and vice versa and that the case created an “industry” of repressed memory. Nathan hypothesizes that Mason’s physical and sensory issues may have been due to untreated pernicious anaemia, the symptoms of which were mistaken at the time for psychogenic issues. She notes that after Mason was treated with calf’s-liver supplements for chronic blood disorders as a child and young woman, her psychological symptoms likewise went into remission for years at a time, and that Wilbur herself noted that “Sybil” suffered from pernicious anaemia later in life. Nathan’s writing and her research methods have been publicly criticised by Mason’s family and by Dr. Patrick Suraci, who was personally acquainted with Shirley Mason.

In addition, Suraci claims that Spiegel behaved unethically in withholding tapes which supposedly proved Wilbur had induced Mason to believe she had multiple personalities. Spiegel also claimed to have made films of himself hypnotising Mason, supposedly proving that Wilbur had “implanted false memories” in her mind, but when Suraci asked to see the films Spiegel said he had lost them. Although Wilbur’s papers were destroyed, copies and excerpts within Flora Rheta Schreiber’s papers at the Lloyd Sealy Library of John Jay College were unsealed in 1998.

In 2013, Nancy Preston published After Sybil, a personal memoir which includes facsimile reproductions of Mason’s personal letters to her, along with colour plates of her paintings. According to Preston, Mason taught art at Ohio’s Rio Grande College, where Preston was a student. The two became close friends and corresponded until a few days before Mason’s death. In the letters, Mason claimed that she had had multiple personalities.

Schizophrenia & Smoking Traits

Research Paper Title

Colocalisation of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits.

Background

Epidemiological data suggest that smoking may be a risk factor for schizophrenia (SCZ), but more evidence is needed. Two regions coding nicotinic acetylcholine receptor (nAchR) subunits, atCHRNA2 and the CHRNA5/A3/B4 cluster, were associated with SCZ in genome-wide association studies (GWAS). Additionally, a signal at CHRNA4 is near significance. CHRNA2 was also associated with cannabis use disorder (CUD). These regions were also associated with smoking behaviours. If tobacco is a risk factor, the GWAS signals at smoking behaviours and SCZ have to be due to the same causal variants, i.e. they have to colocalise, although colocalisation does not necessarily imply causality. Here, we present colocalisation analysis at these loci between SCZ and smoking behaviours.

Methods

The Bayesian approach implemented in coloc was used to check for posterior probability of colocalisation versus independent signals at the three loci with some evidence of association with SCZ and smoking behaviours, using GWAS summary statistics. Colocalisation was also assessed for positive control traits and CUD. Three different sensibility analyses were used to confirm the results. A visualisation tool, LocusCompare, was used to facilitate interpretation of the coloc results.

Results

Evidence for colocalisation of GWAS signals between SCZ and smoking behaviours was found for CHRNA2. Evidence for independent causal variants was found for the other two loci. CUD GWAS signal at CHRNA2 colocalises with SCZ and smoking behaviours.

Conclusions

Overall, the results indicate that the association between some nAchR subunit genes and SCZ cannot be solely explained by their effect on smoking behaviours.

Reference

Al-Soufi, L. & Costas, J. (2021) Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits. Drug and Alcohol Dependence. doi: 10.1016/j.drugalcdep.2021.108517. Online ahead of print.

What is Capgras Delusion?

Introduction

Capgras delusion is a psychiatric disorder in which a person holds a delusion that a friend, spouse, parent, or other close family member (or pet) has been replaced by an identical impostor. It is named after Joseph Capgras (1873-1950), a French psychiatrist.

The Capgras delusion is classified as a delusional misidentification syndrome, a class of delusional beliefs that involves the misidentification of people, places, or objects. It can occur in acute, transient, or chronic forms. Cases in which patients hold the belief that time has been “warped” or “substituted” have also been reported.

The delusion most commonly occurs in individuals diagnosed with paranoid schizophrenia but has also been seen in brain injury, dementia with Lewy bodies, and other dementia. It presents often in individuals with a neurodegenerative disease, particularly at an older age. It has also been reported as occurring in association with diabetes, hypothyroidism, and migraine attacks. In one isolated case, the Capgras delusion was temporarily induced in a healthy subject by the drug ketamine. It occurs more frequently in females, with a female to male ratio of approximately 3 to 2.

Signs and Symptoms

The following two case reports are examples of the Capgras delusion in a psychiatric setting:

Example 01

Mrs. D, a 74-year-old married housewife, recently discharged from a local hospital after her first psychiatric admission, presented to our facility for a second opinion. At the time of her admission earlier in the year, she had received the diagnosis of atypical psychosis because of her belief that her husband had been replaced by another unrelated man. She refused to sleep with the impostor, locked her bedroom and door at night, asked her son for a gun, and finally fought with the police when attempts were made to hospitalise her. At times she believed her husband was her long deceased father. She easily recognised other family members and would misidentify her husband only.

Example 02

Diane was a 28-year-old single woman who was seen for an evaluation at a day hospital program in preparation for discharge from a psychiatric hospital. This was her third psychiatric admission in the past five years. Always shy and reclusive, Diane first became psychotic at age 23. Following an examination by her physician, she began to worry that the doctor had damaged her internally and that she might never be able to become pregnant. The patient’s condition improved with neuroleptic treatment but deteriorated after discharge because she refused medication. When she was admitted eight months later, she presented with delusions that a man was making exact copies of people—”screens”—and that there were two screens of her, one evil and one good. The diagnosis was schizophrenia with Capgras delusion. She was disheveled and had a bald spot on her scalp from self-mutilation.

Example 03

The following case is an instance of the Capgras delusion resulting from a neurodegenerative disease:

Fred, a 59-year-old man with a high school qualification, was referred for neurological and neuropsychological evaluation because of cognitive and behavioural disturbances. He had worked as the head of a small unit devoted to energy research until a few months before. His past medical and psychiatric history was uneventful. […] Fred’s wife reported that about 15 months from onset he began to see her as a “double” (her words). The first episode occurred one day when, after coming home, Fred asked her where Wilma was. On her surprised answer that she was right there, he firmly denied that she was his wife Wilma, whom he “knew very well as his sons’ mother”, and went on plainly commenting that Wilma had probably gone out and would come back later. […] Fred presented progressive cognitive deterioration characterised both by severity and fast decline. Apart from [Capgras disorder], his neuropsychological presentation was hallmarked by language disturbances suggestive of frontal-executive dysfunction. His cognitive impairment ended up in a severe, all-encompassing frontal syndrome.

Causes

It is generally agreed that the Capgras delusion has a complex and organic basis caused by structural damage to organs and can be better understood by examining neuroanatomical damage associated with the syndrome.

In one of the first papers to consider the cerebral basis of the Capgras delusion, Alexander, Stuss and Benson pointed out in 1979 that the disorder might be related to a combination of frontal lobe damage causing problems with familiarity and right hemisphere damage causing problems with visual recognition.

Further clues to the possible causes of the Capgras delusion were suggested by the study of brain-injured patients who had developed prosopagnosia. In this condition, patients are unable to recognise faces consciously, despite being able to recognise other types of visual objects. However, a 1984 study by Bauer showed that even though conscious face recognition was impaired, patients with the condition showed autonomic arousal (measured by a galvanic skin response measure) to familiar faces, suggesting that there are two pathways to face recognition – one conscious and one unconscious.

In a 1990 paper published in the British Journal of Psychiatry, psychologists Hadyn Ellis and Andy Young hypothesized that patients with Capgras delusion may have a “mirror image” or double dissociation of prosopagnosia, in that their conscious ability to recognise faces was intact, but they might have damage to the system that produces the automatic emotional arousal to familiar faces. This might lead to the experience of recognising someone while feeling something was not “quite right” about them. In 1997, Ellis and his colleagues published a study of five patients with Capgras delusion (all diagnosed with schizophrenia) and confirmed that although they could consciously recognise the faces, they did not show the normal automatic emotional arousal response. The same low level of autonomic response was shown in the presence of strangers. Young (2008) has theorised that this means that patients with the disease experience a “loss” of familiarity, not a “lack” of it. Further evidence for this explanation comes from other studies measuring galvanic skin responses (GSR) to faces. A patient with Capgras delusion showed reduced GSRs to faces in spite of normal face recognition. This theory for the causes of Capgras delusion was summarised in Trends in Cognitive Sciences in 2001.

William Hirstein and Vilayanur S. Ramachandran reported similar findings in a paper published on a single case of a patient with Capgras delusion after brain injury. Ramachandran portrayed this case in his book Phantoms in the Brain[24] and gave a talk about it at TED 2007. Since the patient was capable of feeling emotions and recognising faces but could not feel emotions when recognising familiar faces, Ramachandran hypothesizes that the origin of Capgras syndrome is a disconnection between the temporal cortex, where faces are usually recognised, and the limbic system, involved in emotions. More specifically, he emphasizes the disconnection between the amygdala and the inferotemporal cortex.

In 2010, Hirstein revised this theory to explain why a person with Capgras syndrome would have the particular reaction of not recognizing a familiar person. Hirstein explained the theory as follows:

My current hypothesis on Capgras, which is a more specific version of the earlier position I took in the 1997 article with V. S. Ramachandran. According to my current approach, we represent the people we know well with hybrid representations containing two parts. One part represents them externally: how they look, sound, etc. The other part represents them internally: their personalities, beliefs, characteristic emotions, preferences, etc. Capgras syndrome occurs when the internal portion of the representation is damaged or inaccessible. This produces the impression of someone who looks right on the outside, but seems different on the inside, i.e., an impostor. This gives a much more specific explanation that fits well with what the patients actually say. It corrects a problem with the earlier hypothesis in that there are many possible responses to the lack of an emotion upon seeing someone.

Furthermore, Ramachandran suggests a relationship between the Capgras syndrome and a more general difficulty in linking successive episodic memories because of the crucial role emotion plays in creating memories. Since the patient could not put together memories and feelings, he believed objects in a photograph were new on every viewing, even though they normally should have evoked feelings (e.g. a person close to him, a familiar object, or even himself). Others like Merrin and Silberfarb (1976) have also proposed links between the Capgras syndrome and deficits in aspects of memory. They suggest that an important and familiar person (the usual subject of the delusion) has many layers of visual, auditory, tactile, and experiential memories associated with them, so the Capgras delusion can be understood as a failure of object constancy at a high perceptual level.

Most likely, more than just an impairment of the automatic emotional arousal response is necessary to form the Capgras delusion, as the same pattern has been reported in patients showing no signs of delusions. Ellis suggested that a second factor explains why this unusual experience is transformed into a delusional belief; this second factor is thought to be an impairment in reasoning, although no definitive impairment has been found to explain all cases. Many have argued for the inclusion of the role of patient phenomenology in explanatory models of the Capgras syndrome in order to better understand the mechanisms that enable the creation and maintenance of delusional beliefs.

Capgras syndrome has also been linked to reduplicative paramnesia, another delusional misidentification syndrome in which a person believes a location has been duplicated or relocated. Since these two syndromes are highly associated, it has been proposed that they affect similar areas of the brain and therefore have similar neurological implications. Reduplicative paramnesia is understood to affect the frontal lobe, and thus it is believed that Capgras syndrome is also associated with the frontal lobe. Even if the damage is not directly to the frontal lobe, an interruption of signals between other lobes and the frontal lobe could result in Capgras syndrome.

Diagnosis

Because it is a rare and poorly understood condition, there is no definitive way to diagnose the Capgras delusion. Diagnosis is primarily made on a psychiatric evaluation of the patient, who is most likely brought to a psychiatrist’s attention by a family member or friend believed to be an imposter by the person under the delusion.

Treatment

Treatment has not been well studied and so there is no evidence-based approach. Treatment is generally therapy, often with support of antipsychotic medication.

Brief History

Capgras syndrome is named after Joseph Capgras, a French psychiatrist who first described the disorder in 1923 in his paper co-authored by Jean Reboul-Lachaux, on the case of a French woman, “Madame Macabre,” who complained that corresponding “doubles” had taken the places of her husband and other people she knew. Capgras and Reboul-Lachaux first called the syndrome “l’illusion des sosies”, which can be translated literally as “the illusion of look-alikes.”

The syndrome was initially considered a purely psychiatric disorder, the delusion of a double seen as symptomatic of schizophrenia, and purely a female disorder (though this is now known not to be the case) often noted as a symptom of hysteria. Most of the proposed explanations initially following that of Capgras and Reboul-Lachaux were psychoanalytical in nature. It was not until the 1980s that attention was turned to the usually co-existing organic brain lesions originally thought to be essentially unrelated or accidental. Today, the Capgras syndrome is understood as a neurological disorder, in which the delusion primarily results from organic brain lesions or degeneration.

In Popular Culture

In the Memoirs Found in a Bathtub novel by the Polish writer Stanisław Lem, first published in 1961, the narrator inhabits a paranoid dystopia where nothing is as it seems, chaos seems to rule all events, and everyone is deeply suspicious of everyone. In the end, it is revealed that the world is filled by phantom body doubles.

A central character in Richard Powers’s 2006 novel The Echo Maker suffers from Capgras Delusion subsequent to traumatic brain injury.

The protagonist in the movie Synecdoche, New York, who is named Caden Cotard (played by Philip Seymour Hoffman), goes to see his ex-wife at her apartment, and, as he enters the building, one of the resident call boxes is taped with the name “Capgras”. He is then misidentified as his ex-wife’s cleaning lady, Ellen Bascomb, as he tries to enter the apartment, and, later in the film, he actually comes to play the role of Ellen Bascomb in his own play. Throughout the film, Cotard enlists actor-doubles to play actors, and, as the film progresses, the actor-doubles are in turn then given actors-doubles.

In “Dorado Falls,” an episode from the seventh season of the television series Criminal Minds, a Navy SEAL develops Capgras delusion as the result of an automobile accident. His experience with classified military missions causes him to become extremely paranoid, and he begins killing the people he sees on a regular basis, believing them to have been replaced by duplicates who are plotting against him.

Does Lack of a Consistent Definition Hinder Treatment for Clozapine-Resistant Schizophrenia Patients?

Research Paper Title

Characteristics and definitions of ultra-treatment-resistant schizophrenia – A systematic review and meta-analysis.

Background

The aim of this systematic review and meta-analysis was to characterise ultra-treatment-resistant Schizophrenia also known as clozapine-resistant schizophrenia (CRS) patients across clozapine combination and augmentation trials through demographic and clinical baseline data. Furthermore, the researchers investigated the variability and consistency in CRS definitions between studies.

Methods

Systematic searches of articles indexed in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and PsycINFO were conducted in March 2020. 1541 randomised and non-randomised clinical trials investigating pharmacological and non-pharmacological clozapine add-on strategies were screened and a total of 71 studies were included. The primary outcome was the overall symptom score at baseline, measured with Positive and Negative Syndrome Scale (PANSS) total or Brief Psychiatric Rating Scale (BPRS) total scores.

Results

Data from 2731 patients were extracted. Patients were overall moderately ill with a mean PANSS total score at baseline of 79.16 (±7.52), a mean duration of illness of 14.64 (±4.14) years with a mean clozapine dose of 436.94 (±87.47) mg/day. Illness severity data were relatively homogenous among patients independently of the augmentation strategy involved, although stark geographical differences were found. Overall, studies showed a large heterogeneity of CRS definitions and insufficient guidelines implementation.

Conclusions

This first meta-analysis characterising CRS patients and comparing CRS definitions revealed a lack of consistent implementation of a CRS definition from guidelines into clinical trials, compromising the replicability of the results and their applicability in clinical practice. The researchers offer a new score modelled on a best practice definition to help future trials increase their reliability.

Reference

Campana, M., Falkai, P., Siskind, D., Hasan, A. & Wagner, E. (2021) Characteristics and definitions of ultra-treatment-resistant schizophrenia – A systematic review and meta-analysis. Schizophrenia Research. 228, pp.218-226. doi: 10.1016/j.schres.2020.12.002. Online ahead of print.

What is Psychosis?

Introduction

Psychosis is an abnormal condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations. Other symptoms may include incoherent speech and behaviour that is inappropriate for the situation. There may also be sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities. Psychosis can have serious outcomes.

Psychosis has many different causes. These include mental illness, such as schizophrenia or bipolar disorder, sleep deprivation, some medical conditions, certain medications, and drugs such as alcohol or cannabis. One type, known as postpartum psychosis, can occur after giving birth. The neurotransmitter dopamine is believed to play a role. Acute psychosis is considered primary if it results from a psychiatric condition and secondary if it is caused by a medical condition. The diagnosis of a mental illness requires excluding other potential causes. Testing may be done to check for central nervous system diseases, toxins, or other health problems as a cause.

Treatment may include antipsychotic medication, counselling, and social support. Early treatment appears to improve outcomes. Medications appear to have a moderate effect. Outcomes depend on the underlying cause. In the United States about 3% of people develop psychosis at some point in their lives. The condition has been described since at least the 4th century BC by Hippocrates and possibly as early as 1500 BC in the Egyptian Ebers Papyrus.

Signs and Symptoms

Hallucinations

A hallucination is defined as sensory perception in the absence of external stimuli. Hallucinations are different from illusions and perceptual distortions, which are the misperception of external stimuli. Hallucinations may occur in any of the senses and take on almost any form. They may consist of simple sensations (such as lights, colours, sounds, tastes, or smells) or more detailed experiences (such as seeing and interacting with animals and people, hearing voices, and having complex tactile sensations). Hallucinations are generally characterised as being vivid and uncontrollable. Auditory hallucinations, particularly experiences of hearing voices, are the most common and often prominent feature of psychosis.

Up to 15% of the general population may experience auditory hallucinations (though not all are due to psychosis). The prevalence of auditory hallucinations in patients with schizophrenia is generally put around 70%, but may go as high as 98%. Reported prevalence in bipolar disorder ranges between 11% and 68%. During the early 20th century, auditory hallucinations were second to visual hallucinations in frequency, but they are now the most common manifestation of schizophrenia, although rates vary between cultures and regions. Auditory hallucinations are most commonly intelligible voices. When voices are present, the average number has been estimated at three. Content, like frequency, differs significantly, especially across cultures and demographics. People who experience auditory hallucinations can frequently identify the loudness, location of origin, and may settle on identities for voices. Western cultures are associated with auditory experiences concerning religious content, frequently related to sin. Hallucinations may command a person to do something potentially dangerous when combined with delusions.

Extracampine hallucinations are perceptions outside the sensory apparatus for example a sound is perceived through the knee, or a visual extracampine hallucination is seeing by sensing that somebody is near to you, that is not there.

Visual hallucinations occur in roughly a third of people with schizophrenia, although rates as high as 55% are reported. The prevalence in bipolar disorder is around 15%. Content frequently involves animate objects, although perceptual abnormalities such as changes in lighting, shading, streaks, or lines may be seen. Visual abnormalities may conflict with proprioceptive information, and visions may include experiences such as the ground tilting. Lilliputian hallucinations are less common in schizophrenia, and occur more frequently in various types of encephalopathy such as peduncular hallucinosis.

A visceral hallucination, also called a cenesthetic hallucination, is characterised by visceral sensations in the absence of stimuli. Cenesthetic hallucinations may include sensations of burning, or re-arrangement of internal organs.

Delusions

Psychosis may involve delusional beliefs. A delusion is commonly defined as an unrelenting sense of certainty maintained despite strong contradictory evidence. Delusions are context- and culture-dependent: a belief which inhibits critical functioning and is widely considered delusional in one population may be common (and even adaptive) in another, or in the same population at a later time. Since normative views may themselves contradict available evidence, a belief need not contravene cultural standards in order to be considered delusional.

Prevalence in schizophrenia is generally considered at least 90%, and around 50% in bipolar disorder.

The DSM-5 characterises certain delusions as “bizarre” if they are clearly implausible, or are incompatible with the surrounding cultural context. The concept of bizarre delusions has many criticisms, the most prominent being judging its presence is not highly reliable even among trained individuals.

A delusion may involve diverse thematic content. The most common type is a persecutory delusion, in which a person believes that some entity is attempting to harm them. Others include delusions of reference (the belief that some element of one’s experience represents a deliberate and specific act by or message from some other entity), delusions of grandeur (the belief that one possesses special power or influence beyond one’s actual limits), thought broadcasting (the belief that one’s thoughts are audible) and thought insertion (the belief that one’s thoughts are not one’s own).

The subject matter of delusions seems to reflect the current culture in a particular time and location. For example in the US, during the early 1900s syphilis was a common topic, during the second world war Germany, during the cold war communists, and in recent years technology has been a focus. Some psychologists, such as those who practice the Open Dialogue method believe that the content of psychosis represent an underlying thought process that may, in part, be responsible for psychosis, though the accepted medical position is that psychosis is due to a brain disorder.

Historically, Karl Jaspers classified psychotic delusions into primary and secondary types. Primary delusions are defined as arising suddenly and not being comprehensible in terms of normal mental processes, whereas secondary delusions are typically understood as being influenced by the person’s background or current situation (e.g. ethnicity; also religious, superstitious, or political beliefs).

Disorganisation

Disorganisation is split into disorganised speech or thinking, and grossly disorganised motor behaviour. Disorganised speech or thinking, also called formal thought disorder, is disorganisation of thinking that is inferred from speech. Characteristics of disorganised speech include rapidly switching topics, called derailment or loose association; switching to topics that are unrelated, called tangential thinking; incomprehensible speech, called word salad or incoherence. Disorganised motor behaviour includes repetitive, odd, or sometimes purposeless movement. Disorganised motor behaviour rarely includes catatonia, and although it was a historically prominent symptom, it is rarely seen today. Whether this is due to historically used treatments or the lack thereof is unknown.

Catatonia describes a profoundly agitated state in which the experience of reality is generally considered impaired. There are two primary manifestations of catatonic behaviour. The classic presentation is a person who does not move or interact with the world in any way while awake. This type of catatonia presents with waxy flexibility. Waxy flexibility is when someone physically moves part of a catatonic person’s body and the person stays in the position even if it is bizarre and otherwise non-functional (such as moving a person’s arm straight up in the air and the arm staying there).

The other type of catatonia is more of an outward presentation of the profoundly agitated state described above. It involves excessive and purposeless motor behaviour, as well as extreme mental preoccupation that prevents an intact experience of reality. An example is someone walking very fast in circles to the exclusion of anything else with a level of mental preoccupation (meaning not focused on anything relevant to the situation) that was not typical of the person prior to the symptom onset. In both types of catatonia there is generally no reaction to anything that happens outside of them. It is important to distinguish catatonic agitation from severe bipolar mania, although someone could have both.

Negative Symptoms

Negative symptoms include reduced emotional expression, decreased motivation, and reduced spontaneous speech. Afflicted individuals lack interest and spontaneity, and have the inability to feel pleasure.

Psychosis in Adolescents

Psychosis is rare in adolescents. Young people who have psychosis may have trouble connecting with the world around them and may experience hallucinations and/or delusions. Adolescents with psychosis may also have cognitive deficits that may make it harder for the youth to socialise and work. Potential impairments include the speed of mental processing, ability to focus without getting distracted (attention span), and problems with their verbal memory.

Causes

The symptoms of psychosis may be caused by serious psychiatric disorders such as schizophrenia, a number of medical illnesses, and trauma. Psychosis may also be temporary or transient, and be caused by medications or substance abuse (substance-induced psychosis).

Normal States

Brief hallucinations are not uncommon in those without any psychiatric disease. Causes or triggers include:

  • Falling asleep and waking: hypnagogic and hypnopompic hallucinations, which are entirely normal.
  • Bereavement, in which hallucinations of a deceased loved one are common.
  • Severe sleep deprivation.
  • Stress.

Trauma

Traumatic life events have been linked with an elevated risk in developing psychotic symptoms. Childhood trauma has specifically been shown to be a predictor of adolescent and adult psychosis. Approximately 65% of individuals with psychotic symptoms have experienced childhood trauma (e.g. physical or sexual abuse, physical or emotional neglect). Increased individual vulnerability toward psychosis may interact with traumatic experiences promoting an onset of future psychotic symptoms, particularly during sensitive developmental periods. Importantly, the relationship between traumatic life events and psychotic symptoms appears to be dose-dependent in which multiple traumatic life events accumulate, compounding symptom expression and severity. This suggests trauma prevention and early intervention may be an important target for decreasing the incidence of psychotic disorders and ameliorating its effects.

Psychiatric Disorder

From a diagnostic standpoint, organic disorders were believed to be caused by physical illness affecting the brain (that is, psychiatric disorders secondary to other conditions) while functional disorders were considered disorders of the functioning of the mind in the absence of physical disorders (that is, primary psychological or psychiatric disorders). Subtle physical abnormalities have been found in illnesses traditionally considered functional, such as schizophrenia. The DSM-IV-TR avoids the functional/organic distinction, and instead lists traditional psychotic illnesses, psychosis due to general medical conditions, and substance-induced psychosis.

Primary psychiatric causes of psychosis include the following:

  • Schizophrenia and schizophreniform disorder.
  • Affective (mood) disorders, including major depression, and severe depression or mania in bipolar disorder (manic depression).
    • People experiencing a psychotic episode in the context of depression may experience persecutory or self-blaming delusions or hallucinations, while people experiencing a psychotic episode in the context of mania may form grandiose delusions.
  • Schizoaffective disorder, involving symptoms of both schizophrenia and mood disorders.
  • Brief psychotic disorder, or acute/transient psychotic disorder.
  • Delusional disorder (persistent delusional disorder).
  • Chronic hallucinatory psychosis.

Psychotic symptoms may also be seen in:

  • Schizotypal personality disorder.
  • Certain personality disorders at times of stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder).
  • Major depressive disorder in its severe form, although it is possible and more likely to have severe depression without psychosis.
  • Bipolar disorder in the manic and mixed episodes of bipolar I disorder and depressive episodes of both bipolar I and bipolar II; however, it is possible to experience such states without psychotic symptoms.
  • Posttraumatic stress disorder.
  • Induced delusional disorder.
  • Sometimes in obsessive compulsive disorder.
  • Juvenile‐onset affective disorder.
  • Dissociative disorders, due to many overlapping symptoms, careful differential diagnosis includes especially dissociative identity disorder.

Stress is known to contribute to and trigger psychotic states. A history of psychologically traumatic events, and the recent experience of a stressful event, can both contribute to the development of psychosis. Short-lived psychosis triggered by stress is known as brief reactive psychosis, and patients may spontaneously recover normal functioning within two weeks. In some rare cases, individuals may remain in a state of full-blown psychosis for many years, or perhaps have attenuated psychotic symptoms (such as low intensity hallucinations) present at most times.

Neuroticism is an independent predictor of the development of psychosis.

Subtypes

Subtypes of psychosis include:

  • Menstrual psychosis, including circa-mensual (approximately monthly) periodicity, in rhythm with the menstrual cycle.
  • Postpartum psychosis, occurring shortly after giving birth.
  • Monothematic delusions.
  • Myxedematous psychosis.
  • Stimulant psychosis.
  • Tardive psychosis.
  • Shared psychosis.

Cycloid Psychosis

Cycloid psychosis is a psychosis that progresses from normal to full-blown, usually between a few hours to days, not related to drug intake or brain injury. The cycloid psychosis has a long history in European psychiatry diagnosis. The term “cycloid psychosis” was first used by Karl Kleist in 1926. Despite the significant clinical relevance, this diagnosis is neglected both in literature and in nosology. The cycloid psychosis has attracted much interest in the international literature of the past 50 years, but the number of scientific studies have greatly decreased over the past 15 years, possibly partly explained by the misconception that the diagnosis has been incorporated in current diagnostic classification systems. The cycloid psychosis is therefore only partially described in the diagnostic classification systems used. Cycloid psychosis is nevertheless its own specific disease that is distinct from both the manic-depressive disorder, and from schizophrenia, and this despite the fact that the cycloid psychosis can include both bipolar (basic mood shifts) as well as schizophrenic symptoms. The disease is an acute, usually self-limiting, functionally psychotic state, with a very diverse clinical picture that almost consistently is characterized by the existence of some degree of confusion or distressing perplexity, but above all, of the multifaceted and diverse expressions the disease takes. The main features of the disease is thus that the onset is acute, contains the multifaceted picture of symptoms and typically reverses to a normal state and that the long-term prognosis is good. In addition, diagnostic criteria include at least four of the following symptoms:

  • Confusion.
  • Mood-incongruent delusions.
  • Hallucinations.
  • Pan-anxiety, a severe anxiety not bound to particular situations or circumstances.
  • Happiness or ecstasy of high degree.
  • Motility disturbances of akinetic or hyperkinetic type.
  • Concern with death.
  • Mood swings to some degree, but less than what is needed for diagnosis of an affective disorder.

Cycloid psychosis occurs in people of generally 15-50 years of age.

Medical Conditions

A very large number of medical conditions can cause psychosis, sometimes called secondary psychosis. Examples include:

  • Disorders causing delirium (toxic psychosis), in which consciousness is disturbed.
  • Neurodevelopmental disorders and chromosomal abnormalities, including velocardiofacial syndrome.
  • Neurodegenerative disorders, such as Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease.
  • Focal neurological disease, such as stroke, brain tumours, multiple sclerosis, and some forms of epilepsy.
  • Malignancy (typically via masses in the brain, paraneoplastic syndromes).
  • Infectious and post-infectious syndromes, including infections causing delirium, viral encephalitis, HIV/AIDS, malaria, syphilis.
  • Endocrine disease, such as hypothyroidism, hyperthyroidism, Cushing’s syndrome, hypoparathyroidism and hyperparathyroidism; sex hormones also affect psychotic symptoms and sometimes giving birth can provoke psychosis, termed postpartum psychosis.
  • Inborn errors of metabolism, such as Succinic semialdehyde dehydrogenase deficiency, porphyria and metachromatic leukodystrophy.
  • Nutritional deficiency, such as vitamin B12 deficiency.
  • Other acquired metabolic disorders, including electrolyte disturbances such as hypocalcaemia, hypernatremia, hyponatremia, hypokalaemia, hypomagnesemia, hypermagnesemia, hypercalcemia, and hypophosphatemia, but also hypoglycaemia, hypoxia, and failure of the liver or kidneys.
  • Autoimmune and related disorders, such as systemic lupus erythematosus (lupus, SLE), sarcoidosis, Hashimoto’s encephalopathy, anti-NMDA-receptor encephalitis, and non-celiac gluten sensitivity.
  • Poisoning, by therapeutic drugs (see below), recreational drugs (see below), and a range of plants, fungi, metals, organic compounds, and a few animal toxins.
  • Sleep disorders, such as in narcolepsy (in which REM sleep intrudes into wakefulness).
  • Parasitic diseases, such as neurocysticercosis.

Psychoactive Drugs

Various psychoactive substances (both legal and illegal) have been implicated in causing, exacerbating, or precipitating psychotic states or disorders in users, with varying levels of evidence. This may be upon intoxication for a more prolonged period after use, or upon withdrawal. Individuals who have a substance induced psychosis tend to have a greater awareness of their psychosis and tend to have higher levels of suicidal thinking compared to individuals who have a primary psychotic illness. Drugs commonly alleged to induce psychotic symptoms include alcohol, cannabis, cocaine, amphetamines, cathinones, psychedelic drugs (such as LSD and psilocybin), κ-opioid receptor agonists (such as enadoline and salvinorin A) and NMDA receptor antagonists (such as phencyclidine and ketamine). Caffeine may worsen symptoms in those with schizophrenia and cause psychosis at very high doses in people without the condition. Cannabis and other illicit recreational drugs are often associated with psychosis in adolescents and cannabis use before 15 years old may increase the risk of psychosis later in life as an adult.

Alcohol

Approximately three percent of people who are suffering from alcoholism experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to the long-term effects of alcohol consumption resulting in distortions to neuronal membranes, gene expression, as well as thiamine deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as causing psychosocial impairments.

Cannabis

According to some studies, the more often cannabis is used the more likely a person is to develop a psychotic illness, with frequent use being correlated with twice the risk of psychosis and schizophrenia. While cannabis use is accepted as a contributory cause of schizophrenia by some, it remains controversial, with pre-existing vulnerability to psychosis emerging as the key factor that influences the link between cannabis use and psychosis. Some studies indicate that the effects of two active compounds in cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposite effects with respect to psychosis. While THC can induce psychotic symptoms in healthy individuals, CBD may reduce the symptoms caused by cannabis.

Cannabis use has increased dramatically over the past few decades whereas the rate of psychosis has not increased. Together, these findings suggest that cannabis use may hasten the onset of psychosis in those who may already be predisposed to psychosis. High-potency cannabis use indeed seems to accelerate the onset of psychosis in predisposed patients. A 2012 study concluded that cannabis plays an important role in the development of psychosis in vulnerable individuals, and that cannabis use in early adolescence should be discouraged.

Methamphetamine

Methamphetamine induces a psychosis in 26-46% of heavy users. Some of these people develop a long-lasting psychosis that can persist for longer than six months. Those who have had a short-lived psychosis from methamphetamine can have a relapse of the methamphetamine psychosis years later after a stressful event such as severe insomnia or a period of heavy alcohol abuse despite not relapsing back to methamphetamine. Individuals who have a long history of methamphetamine abuse and who have experienced psychosis in the past from methamphetamine abuse are highly likely to re-experience methamphetamine psychosis if drug use is recommenced. Methamphetamine-induced psychosis is likely gated by genetic vulnerability, which can produce long-term changes in brain neurochemistry following repetitive use.

Medication

Administration, or sometimes withdrawal, of a large number of medications may provoke psychotic symptoms. Drugs that can induce psychosis experimentally or in a significant proportion of people include amphetamine and other sympathomimetics, dopamine agonists, ketamine, corticosteroids (often with mood changes in addition), and some anticonvulsants such as vigabatrin. Stimulants that may cause this include lisdexamfetamine.

Medication may induce psychological side effects, including depersonalisation, derealisation and psychotic symptoms like hallucinations as well as mood disturbances.

Pathophysiology

Neuroimaging

The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called pneumoencephalography (a painful and now obsolete procedure where cerebrospinal fluid is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an X-ray picture).

Both first episode psychosis, and high risk status is associated with reductions in grey matter volume (GMV). First episode psychotic and high risk populations are associated with similar but distinct abnormalities in GMV. Reductions in the right middle temporal gyrus, right superior temporal gyrus (STG), right parahippocampus, right hippocampus, right middle frontal gyrus, and left anterior cingulate cortex (ACC) are observed in high risk populations. Reductions in first episode psychosis span a region from the right STG to the right insula, left insula, and cerebellum, and are more severe in the right ACC, right STG, insula and cerebellum.

Another meta analysis reported bilateral reductions in insula, operculum, STG, medial frontal cortex, and ACC, but also reported increased GMV in the right lingual gyrus and left precentral gyrus. The Kraepelinian dichotomy is made questionable by grey matter abnormalities in bipolar and schizophrenia; schizophrenia is distinguishable from bipolar in that regions of grey matter reduction are generally larger in magnitude, although adjusting for gender differences reduces the difference to the left dorsomedial prefrontal cortex, and right dorsolateral prefrontal cortex.

During attentional tasks, first episode psychosis is associated with hypoactivation in the right middle frontal gyrus, a region generally described as encompassing the dorsolateral prefrontal cortex (dlPFC). In congruence with studies on grey matter volume, hypoactivity in the right insula, and right inferior parietal lobe is also reported. During cognitive tasks, hypoactivities in the right insula, dACC, and the left precuneus, as well as reduced deactivations in the right basal ganglia, right thalamus, right inferior frontal and left precentral gyri are observed. These results are highly consistent and replicable possibly except the abnormalities of the right inferior frontal gyrus. Decreased grey matter volume in conjunction with bilateral hypoactivity is observed in anterior insula, dorsal medial frontal cortex, and dorsal ACC. Decreased grey matter volume and bilateral hyperactivity is reported in posterior insula, ventral medial frontal cortex, and ventral ACC.

Hallucinations

Studies during acute experiences of hallucinations demonstrate increased activity in primary or secondary sensory cortices. As auditory hallucinations are most common in psychosis, most robust evidence exists for increased activity in the left middle temporal gyrus, left superior temporal gyrus, and left inferior frontal gyrus (i.e. Broca’s area). Activity in the ventral striatum, hippocampus, and ACC are related to the lucidity of hallucinations, and indicate that activation or involvement of emotional circuitry are key to the impact of abnormal activity in sensory cortices. Together, these findings indicate abnormal processing of internally generated sensory experiences, coupled with abnormal emotional processing, results in hallucinations. One proposed model involves a failure of feedforward networks from sensory cortices to the inferior frontal cortex, which normally cancel out sensory cortex activity during internally generated speech. The resulting disruption in expected and perceived speech is thought to produce lucid hallucinatory experiences.

Delusions

The two-factor model of delusions posits that dysfunction in both belief formation systems and belief evaluation systems are necessary for delusions. Dysfunction in evaluations systems localised to the right lateral prefrontal cortex, regardless of delusion content, is supported by neuroimaging studies and is congruent with its role in conflict monitoring in healthy persons. Abnormal activation and reduced volume is seen in people with delusions, as well as in disorders associated with delusions such as frontotemporal dementia, psychosis and Lewy body dementia. Furthermore, lesions to this region are associated with “jumping to conclusions”, damage to this region is associated with post-stroke delusions, and hypometabolism this region associated with caudate strokes presenting with delusions.

The aberrant salience model suggests that delusions are a result of people assigning excessive importance to irrelevant stimuli. In support of this hypothesis, regions normally associated with the salience network demonstrate reduced grey matter in people with delusions, and the neurotransmitter dopamine, which is widely implicated in salience processing, is also widely implicated in psychotic disorders.

Specific regions have been associated with specific types of delusions. The volume of the hippocampus and parahippocampus is related to paranoid delusions in Alzheimer’s disease, and has been reported to be abnormal post mortem in one person with delusions. Capgras delusions have been associated with occipito-temporal damage, and may be related to failure to elicit normal emotions or memories in response to faces.

Negative Symptoms

Psychosis is associated with ventral striatal hypoactivity during reward anticipation and feedback. Hypoactivity in the left ventral striatum is correlated with the severity of negative symptoms. While anhedonia is a commonly reported symptom in psychosis, hedonic experiences are actually intact in most people with schizophrenia. The impairment that may present itself as anhedonia probably actually lies in the inability to identify goals, and to identify and engage in the behaviours necessary to achieve goals. Studies support a deficiency in the neural representation of goals and goal directed behaviour by demonstrating that receipt (not anticipation) of reward is associated with a robust response in the ventral striatum; reinforcement learning is intact when contingencies about stimulus-reward are implicit, but not when they require explicit neural processing; reward prediction errors (during functional neuroimaging studies), particularly positive PEs are abnormal. A positive prediction error response occurs when there is an increased activation in a brain region, typically the striatum, in response to unexpected rewards. A negative prediction error response occurs when there is a decreased activation in a region when predicted rewards do not occur. ACC response, taken as an indicator of effort allocation, does not increase with reward or reward probability increase, and is associated with negative symptoms; deficits in dlPFC activity and failure to improve performance on cognitive tasks when offered monetary incentives are present; and dopamine mediated functions are abnormal.

Neurobiology

Psychosis has been traditionally linked to the overactivity of the neurotransmitter dopamine. In particular to its effect in the mesolimbic pathway. The two major sources of evidence given to support this theory are that dopamine receptor D2 blocking drugs (i.e., antipsychotics) tend to reduce the intensity of psychotic symptoms, and that drugs that accentuate dopamine release, or inhibit its reuptake (such as amphetamines and cocaine) can trigger psychosis in some people (see stimulant psychosis).

NMDA receptor dysfunction has been proposed as a mechanism in psychosis. This theory is reinforced by the fact that dissociative NMDA receptor antagonists such as ketamine, PCP and dextromethorphan (at large overdoses) induce a psychotic state. The symptoms of dissociative intoxication are also considered to mirror the symptoms of schizophrenia, including negative symptoms. NMDA receptor antagonism, in addition to producing symptoms reminiscent of psychosis, mimics the neurophysiological aspects, such as reduction in the amplitude of P50, P300, and MMN evoked potentials. Hierarchical Bayesian neurocomputational models of sensory feedback, in agreement with neuroimaging literature, link NMDA receptor hypofunction to delusional or hallucinatory symptoms via proposing a failure of NMDA mediated top down predictions to adequately cancel out enhanced bottom up AMPA mediated predictions errors. Excessive prediction errors in response to stimuli that would normally not produce such a response is thought to root from conferring excessive salience to otherwise mundane events. Dysfunction higher up in the hierarchy, where representation is more abstract, could result in delusions. The common finding of reduced GAD67 expression in psychotic disorders may explain enhanced AMPA mediated signalling, caused by reduced GABAergic inhibition.

The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses adenylate cyclase activity, the D1 receptor increases it. If D2-blocking drugs are administered, the blocked dopamine spills over to the D1 receptors. The increased adenylate cyclase activity affects genetic expression in the nerve cell, which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis. Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the ‘dopamine hypothesis’ may be oversimplified. Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis and Zoldan et al. reported moderately successful use of ondansetron, a 5-HT3 receptor antagonist, in the treatment of levodopa psychosis in Parkinson’s disease patients.

A review found an association between a first-episode of psychosis and prediabetes.

Prolonged or high dose use of psychostimulants can alter normal functioning, making it similar to the manic phase of bipolar disorder. NMDA antagonists replicate some of the so-called “negative” symptoms like thought disorder in subanesthetic doses (doses insufficient to induce anesthesia), and catatonia in high doses). Psychostimulants, especially in one already prone to psychotic thinking, can cause some “positive” symptoms, such as delusional beliefs, particularly those persecutory in nature.

Diagnosis

To make a diagnosis of a mental illness in someone with psychosis other potential causes must be excluded. An initial assessment includes a comprehensive history and physical examination by a health care provider. Tests may be done to exclude substance use, medication, toxins, surgical complications, or other medical illnesses. A person with psychosis is referred to as psychotic.

Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors, including medical illnesses. Excluding medical illnesses associated with psychosis is performed by using blood tests to measure:

  • Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism.
  • Basic electrolytes and serum calcium to rule out a metabolic disturbance.
  • Full blood count including ESR to rule out a systemic infection or chronic disease.
  • Serology to exclude syphilis or HIV infection.
  • Other investigations include:
    • EEG to exclude epilepsy; and
    • MRI or CT scan of the head to exclude brain lesions.

Because psychosis may be precipitated or exacerbated by common classes of medications, medication-induced psychosis should be ruled out, particularly for first-episode psychosis. Both substance- and medication-induced psychosis can be excluded to a high level of certainty, using toxicology screening.

Because some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests, a psychotic individual’s family, partner, or friends should be asked whether the patient is currently taking any dietary supplements.

Common mistakes made when diagnosing people who are psychotic include:

  • Not properly excluding delirium.
  • Not appreciating medical abnormalities (e.g., vital signs).
  • Not obtaining a medical history and family history.
  • Indiscriminate screening without an organizing framework.
  • Missing a toxic psychosis by not screening for substances and medications.
  • Not asking their family or others about dietary supplements.
  • Premature diagnostic closure.
  • Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder.

Only after relevant and known causes of psychosis are excluded, a mental health clinician may make a psychiatric differential diagnosis using a person’s family history, incorporating information from the person with psychosis, and information from family, friends, or significant others.

Types of psychosis in psychiatric disorders may be established by formal rating scales. The Brief Psychiatric Rating Scale (BPRS) assesses the level of 18 symptom constructs of psychosis such as hostility, suspicion, hallucination, and grandiosity. It is based on the clinician’s interview with the patient and observations of the patient’s behaviour over the previous 2-3 days. The patient’s family can also answer questions on the behaviour report. During the initial assessment and the follow-up, both positive and negative symptoms of psychosis can be assessed using the 30 item Positive and Negative Symptom Scale (PANSS).

The DSM-5 characterizes disorders as psychotic or on the schizophrenia spectrum if they involve hallucinations, delusions, disorganised thinking, grossly disorganised motor behaviour, or negative symptoms. The DSM-5 does not include psychosis as a definition in the glossary, although it defines “psychotic features”, as well as “psychoticism” with respect to personality disorder. The ICD-10 has no specific definition of psychosis.

Factor analysis of symptoms generally regarded as psychosis frequently yields a five factor solution, albeit five factors that are distinct from the five domains defined by the DSM-5 to encompass psychotic or schizophrenia spectrum disorders. The five factors are frequently labelled as hallucinations, delusions, disorganisation, excitement, and emotional distress. The DSM-5 emphasizes a psychotic spectrum, wherein the low end is characterised by schizoid personality disorder, and the high end is characterised by schizophrenia.

Prevention

The evidence for the effectiveness of early interventions to prevent psychosis appeared inconclusive. But psychosis caused by drugs can be prevented. Whilst early intervention in those with a psychotic episode might improve short-term outcomes, little benefit was seen from these measures after five years. However, there is evidence that cognitive behavioural therapy (CBT) may reduce the risk of becoming psychotic in those at high risk, and in 2014 the UK National Institute for Health and Care Excellence (NICE) recommended preventive CBT for people at risk of psychosis.

Treatment

The treatment of psychosis depends on the specific diagnosis (such as schizophrenia, bipolar disorder or substance intoxication). The first-line treatment for many psychotic disorders is antipsychotic medication, which can reduce the positive symptoms of psychosis in about 7 to 14 days. For youth or adolescents, treatment options include medications, psychological interventions, and social interventions.

Medication

The choice of which antipsychotic to use is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Tentative evidence supports that amisulpride, olanzapine, risperidone and clozapine may be more effective for positive symptoms but result in more side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages. 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. Clozapine is an effective treatment for those who respond poorly to other drugs (“treatment-resistant” or “refractory” schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.

Most people on antipsychotics get side effects. People on typical antipsychotics tend to have a higher rate of extrapyramidal side effects while some atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome; this is most pronounced with olanzapine, while risperidone and quetiapine are also associated with weight gain. Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.

Counselling

Psychological treatments such as acceptance and commitment therapy (ACT) are possibly useful in the treatment of psychosis, helping people to focus more on what they can do in terms of valued life directions despite challenging symptomology.

There are psychological interventions that seek to treat the symptoms of psychosis. In a 2019 review, nine classes of psychosocial interventions were identified: need adapted treatment, open dialogue, psychoanalysis/psychodynamic psychotherapy, major role therapy, soteria, psychosocial outpatient and inpatient treatment, milieu therapy, and CBT. This paper concluded that when on minimal or no medication “the overall evidence supporting the effectiveness of these interventions is generally weak”.

Early Intervention

Refer to early intervention in psychosis.

Early intervention in psychosis is based on the observation that identifying and treating someone in the early stages of a psychosis can improve their longer term outcome. This approach advocates the use of an intensive multi-disciplinary approach during what is known as the critical period, where intervention is the most effective, and prevents the long-term morbidity associated with chronic psychotic illness.

Brief History

Etymology

The word psychosis was introduced to the psychiatric literature in 1841 by Karl Friedrich Canstatt in his work Handbuch der Medizinischen Klinik. He used it as a shorthand for ‘psychic neurosis’. At that time neurosis meant any disease of the nervous system, and Canstatt was thus referring to what was considered a psychological manifestation of brain disease. Ernst von Feuchtersleben is also widely credited as introducing the term in 1845, as an alternative to insanity and mania.

The term stems from Modern Latin psychosis, “a giving soul or life to, animating, quickening” and that from Ancient Greek ψυχή (psyche), “soul” and the suffix -ωσις (-osis), in this case “abnormal condition”.

In its adjective form “psychotic”, references to psychosis can be found in both clinical and non-clinical discussions. However, in a non-clinical context, “psychotic” is generally used as a synonym for “insane”.

Classification

The word was also used to distinguish a condition considered a disorder of the mind, as opposed to neurosis, which was considered a disorder of the nervous system. The psychoses thus became the modern equivalent of the old notion of madness, and hence there was much debate on whether there was only one (unitary) or many forms of the new disease. One type of broad usage would later be narrowed down by Koch in 1891 to the ‘psychopathic inferiorities’ – later renamed abnormal personalities by Schneider.

The division of the major psychoses into manic depressive illness (now called bipolar disorder) and dementia praecox (now called schizophrenia) was made by Emil Kraepelin, who attempted to create a synthesis of the various mental disorders identified by 19th-century psychiatrists, by grouping diseases together based on classification of common symptoms. Kraepelin used the term ‘manic depressive insanity’ to describe the whole spectrum of mood disorders, in a far wider sense than it is usually used today.

In Kraepelin’s classification this would include ‘unipolar’ clinical depression, as well as bipolar disorder and other mood disorders such as cyclothymia. These are characterised by problems with mood control and the psychotic episodes appear associated with disturbances in mood, and patients often have periods of normal functioning between psychotic episodes even without medication. Schizophrenia is characterised by psychotic episodes that appear unrelated to disturbances in mood, and most non-medicated patients show signs of disturbance between psychotic episodes.

Treatment

Early civilisations considered madness a supernaturally inflicted phenomenon. Archaeologists have unearthed skulls with clearly visible drillings, some datable back to 5000 BC suggesting that trepanning was a common treatment for psychosis in ancient times. Written record of supernatural causes and resultant treatments can be traced back to the New Testament. Mark 5:8-13 describes a man displaying what would today be described as psychotic symptoms. Christ cured this “demonic madness” by casting out the demons and hurling them into a herd of swine. Exorcism is still utilised in some religious circles as a treatment for psychosis presumed to be demonic possession. A research study of out-patients in psychiatric clinics found that 30% of religious patients attributed the cause of their psychotic symptoms to evil spirits. Many of these patients underwent exorcistic healing rituals that, though largely regarded as positive experiences by the patients, had no effect on symptomology. Results did, however, show a significant worsening of psychotic symptoms associated with exclusion of medical treatment for coercive forms of exorcism.

The medical teachings of the fourth-century philosopher and physician Hippocrates of Cos proposed a natural, rather than supernatural, cause of human illness. In Hippocrates’ work, the Hippocratic corpus, a holistic explanation for health and disease was developed to include madness and other “diseases of the mind.” Hippocrates writes:

Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears. Through it, in particular, we think, see, hear, and distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant…. It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness, and acts that are contrary to habit.

Hippocrates espoused a theory of humouralism wherein disease is resultant of a shifting balance in bodily fluids including blood, phlegm, black bile, and yellow bile. According to humouralism, each fluid or “humour” has temperamental or behavioural correlates. In the case of psychosis, symptoms are thought to be caused by an excess of both blood and yellow bile. Thus, the proposed surgical intervention for psychotic or manic behaviour was bloodletting.

18th-century physician, educator, and widely considered “founder of American psychiatry”, Benjamin Rush, also prescribed bloodletting as a first-line treatment for psychosis. Although not a proponent of humouralism, Rush believed that active purging and bloodletting were efficacious corrections for disruptions in the circulatory system, a complication he believed was the primary cause of “insanity”. Although Rush’s treatment modalities are now considered antiquated and brutish, his contributions to psychiatry, namely the biological underpinnings of psychiatric phenomenon including psychosis, have been invaluable to the field. In honour of such contributions, Benjamin Rush’s image is in the official seal of the American Psychiatric Association.

Early 20th-century treatments for severe and persisting psychosis were characterized by an emphasis on shocking the nervous system. Such therapies include insulin shock therapy, cardiazol shock therapy, and electroconvulsive therapy. Despite considerable risk, shock therapy was considered highly efficacious in the treatment of psychosis including schizophrenia. The acceptance of high-risk treatments led to more invasive medical interventions including psychosurgery.

In 1888, Swiss psychiatrist Gottlieb Burckhardt performed the first medically sanctioned psychosurgery in which the cerebral cortex was excised. Although some patients showed improvement of symptoms and became more subdued, one patient died and several developed aphasia or seizure disorders. Burckhardt would go on to publish his clinical outcomes in a scholarly paper. This procedure was met with criticism from the medical community and his academic and surgical endeavours were largely ignored. In the late 1930s, Egas Moniz conceived the leucotomy (AKA prefrontal lobotomy) in which the fibres connecting the frontal lobes to the rest of the brain were severed. Moniz’s primary inspiration stemmed from a demonstration by neuroscientists John Fulton and Carlyle’s 1935 experiment in which two chimpanzees were given leucotomies and pre- and post-surgical behaviour was compared. Prior to the leucotomy, the chimps engaged in typical behaviour including throwing faeces and fighting. After the procedure, both chimps were pacified and less violent. During the Q&A, Moniz asked if such a procedure could be extended to human subjects, a question that Fulton admitted was quite startling. Moniz would go on to extend the controversial practice to humans suffering from various psychotic disorders, an endeavour for which he received a Nobel Prize in 1949. Between the late 1930s and early 1970s, the leucotomy was a widely accepted practice, often performed in non-sterile environments such as small outpatient clinics and patient homes. Psychosurgery remained standard practice until the discovery of antipsychotic pharmacology in the 1950s.

The first clinical trial of antipsychotics (also commonly known as neuroleptics) for the treatment of psychosis took place in 1952. Chlorpromazine (brand name: Thorazine) passed clinical trials and became the first antipsychotic medication approved for the treatment of both acute and chronic psychosis. Although the mechanism of action was not discovered until 1963, the administration of chlorpromazine marked the advent of the dopamine antagonist, or first generation antipsychotic. While clinical trials showed a high response rate for both acute psychosis and disorders with psychotic features, the side effects were particularly harsh, which included high rates of often irreversible Parkinsonian symptoms such as tardive dyskinesia. With the advent of atypical antipsychotics (also known as second generation antipsychotics) came a dopamine antagonist with a comparable response rate but a far different, though still extensive, side-effect profile that included a lower risk of Parkinsonian symptoms but a higher risk of cardiovascular disease. Atypical antipsychotics remain the first-line treatment for psychosis associated with various psychiatric and neurological disorders including schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia, and some autism spectrum disorders.

Dopamine is now one of the primary neurotransmitters implicated in psychotic symptomology. Blocking dopamine receptors (namely, the dopamine D2 receptors) and decreasing dopaminergic activity continues to be an effective but highly unrefined effect of antipsychotics, which are commonly used to treat psychosis. Recent pharmacological research suggests that the decrease in dopaminergic activity does not eradicate psychotic delusions or hallucinations, but rather attenuates the reward mechanisms involved in the development of delusional thinking; that is, connecting or finding meaningful relationships between unrelated stimuli or ideas. The author of this research paper acknowledges the importance of future investigation:

The model presented here is based on incomplete knowledge related to dopamine, schizophrenia, and antipsychotics – and as such will need to evolve as more is known about these. Shitij Kapur, From dopamine to salience to psychosis – linking biology, pharmacology and phenomenology of psychosis.

Freud’s former student Wilhelm Reich explored independent insights into the physical effects of neurotic and traumatic upbringing, and published his holistic psychoanalytic treatment with a schizophrenic. With his incorporation of breathwork and insight with the patient, a young woman, she achieved sufficient self-management skills to end the therapy.

Lacan extended Freud’s ideas to create a psychoanalytic model of psychosis based upon the concept of ” foreclosure”, the rejection of the symbolic concept of the father.

Society

Psychiatrist David Healy has criticised pharmaceutical companies for promoting simplified biological theories of mental illness that seem to imply the primacy of pharmaceutical treatments while ignoring social and developmental factors that are known important influences in the aetiology of psychosis.

Research

Further research in the form of randomised controlled trials is needed to determine the effectiveness of treatment approaches for helping adolescents with psychosis.