Schizophrenia is characterised by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganised speech and behaviour, flattened affectivity (reduced emotional displays), cognitive deficits (impaired reasoning and problem-solving abilities) and occupational and social malfunctioning

The cause of schizophrenia is unknown, but there is strong evidence of a genetic and environmental component

Symptoms usually begin in adolescence or early adulthood.

One or more symptomatic episodes must persist for ≥ 6 months before the diagnosis is made.

Treatment consists of drug therapy, cognitive therapy and psychosocial rehabilitation.

Early diagnosis and early treatment improve long-term functioning.

Psychosis involves symptoms such as delusions, hallucinations, disorganised thought and language, and bizarre and inappropriate motor behaviour (including catatonia) that indicate loss of contact with reality.

The worldwide prevalence of schizophrenia is about 1%.

The rate is comparable between men and women and relatively constant across cultures.

Urban environment, poverty, childhood trauma, neglect and prenatal infections are risk factors and there is a genetic predisposition (1).

The condition begins in late adolescence and lasts a lifetime, typically with poor psychosocial function.

The average age of onset is in the first part of the second decade in women and slightly earlier in men; about 40% of males have their first episode before the age of 20.

Onset during childhood is rare; it may also occur in early adolescence or during old age (in which case it is sometimes called paraphrenia).

General reference

Schizophrenia Working Group of the Psychiatric Genomics Consortium: Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421-427, 2014. doi: 10.1038/nature13595.

Aetiology of schizophrenia

Although its specific cause is unknown, schizophrenia has a biological basis, as demonstrated by the following evidence

• Alterations in brain structure (e.g., increased volume of the brain ventricles, thinning of the cortex, decreased anterior hippocampus and other brain regions)
• Changes in neurochemistry, in particular altered activity in dopamine markers and glutamate transmissions
• Recently demonstrated genetic risk factors (1)

Some experts argue that schizophrenia occurs more frequently in individuals with neurodevelopmental vulnerabilities and that the onset, remission and recurrence of symptoms are the result of interactions between these permanent vulnerabilities and environmental stressors.

Neurodevelopmental vulnerabilities

Although schizophrenia rarely occurs in early childhood, childhood factors influence the onset of the illness in adulthood.

These factors include

• Genetic predisposition
• Intrauterine, birth or postnatal complications
• viral infections of the central nervous system
• Childhood trauma and neglect

Although many people with schizophrenia do not have a positive family history of the disorder, it is believed that genetic factors are strongly implicated.

Individuals with a first-degree relative with schizophrenia have a risk of developing the disorder of approximately 10-12%, compared to a 1% risk in the general population.

Monozygotic twins have a concordance of about 45%.

Maternal nutritional deficiencies and exposure to influenza during the 2nd trimester of pregnancy, birth weight < 2500 g, Rh incompatibility in a 2nd pregnancy and hypoxia increase the risk.

Neurobiological and neuropsychiatric tests indicate that schizophrenic patients show abnormalities of pursuit eye movements, cognitive and attention impairment and somato-sensory suppression deficits more frequently than the general population.

These signs also occur among first-degree relatives of individuals with schizophrenia, and indeed in patients with many other psychotic disorders, and may represent an inherited component of vulnerability.

The commonality of these findings among psychotic disorders suggests that our conventional diagnostic categories do not reflect the biological distinctions underlying psychosis (1).

Environmental stressors that trigger the onset of schizophrenia

Environmental stressors may trigger the onset or recurrence of psychotic symptoms in vulnerable individuals.

Stressors may be primarily pharmacological (e.g., substance use, especially marijuana) or social (e.g., job loss or impoverishment, moving away from home to study at university, end of a romantic relationship, joining the armed forces).

There is emerging evidence that environmental events may initiate epigenetic changes that could influence gene transcription and disease onset.

Protective factors that may mitigate the impact of stress on symptom formation or exacerbation include strong psychosocial support, well-developed coping skills, and antipsychotic medication.

References on aetiology

Schizophrenia Working Group of the Psychiatric Genomics Consortium: Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421-427, 2014. doi: 10.1038/nature13595.

Symptomatology of schizophrenia

Schizophrenia is a chronic illness that can progress through several stages, although the duration and characteristics of the stages may vary.

Patients with schizophrenia tend to have experienced psychotic symptoms for an average period of 12-24 months before seeking medical help, but the disorder is now more often recognised earlier in its course.

Symptoms of schizophrenia commonly impair the performance of complex and difficult cognitive and motor functions; therefore, symptoms often interfere markedly with work, social relationships and self-care.

The most frequent consequences are unemployment, isolation, deterioration of relationships and a decline in quality of life.

Stages in schizophrenia

In the prodromal phase, individuals may show no symptoms or may manifest impaired social skills, mild cognitive disorganisation or perceptual impairment, decreased ability to experience pleasure (anhedonia) and other general coping deficits.

These traits may be mild and only recognised retrospectively or they may be more evident, with impairment of social, school and occupational functioning.

In the advanced prodromal phase, subclinical symptoms may emerge, manifesting withdrawal or isolation, irritability, suspiciousness, unusual thoughts, distorted perceptions, and disorganisation (1).

The onset of schizophrenia (delusions and hallucinations) may be acute (within days or weeks) or slow and insidious (several years).

In the early phase of psychosis, symptoms are active and often worse.

In the middle phase, symptomatic periods may be episodic (with clearly identifiable exacerbations and remissions) or continuous; functional deficits tend to worsen.

In the late phase of illness, the disease pattern may become stable but there is considerable variability; disability may stabilise, worsen or even decline.

Symptom categories in schizophrenia

Generally, symptoms are classified as

• Positive: a distortion of normal functions
• Negative: a decrease or loss of normal functions and affectivity
• Disorganised: disturbances in thinking and bizarre behaviour
• Cognitive: deficits in information processing and problem solving

Patients may experience symptoms in one or more categories.

Positive symptoms can be further classified as

• Delusions
• Hallucinations

Delusions are erroneous beliefs that are maintained despite clear contradictory evidence.

There are several types of delusions:

• Persecutory delusions: patients believe they are being harassed, followed, cheated or spied on.
• Reference delusions: Patients are convinced that passages from books, newspapers, song lyrics or other environmental stimuli are directed at them.
• Delusions of theft or thought graft: patients believe that others can read their minds, that their thoughts are being transmitted to others, or that thoughts and impulses are being imposed on them by external forces.

Delusions in schizophrenia tend to be bizarre, i.e., implausible and not derived from common life experiences (e.g., believing that someone has removed their internal organs without leaving a scar).

Hallucinations are sensory perceptions that are not perceived by anyone else.

They may be auditory, visual, olfactory, gustatory or tactile, but auditory hallucinations are by far the most common.

Patients may hear voices commenting on their behaviour, conversing with each other or making critical and hurtful comments.

Delusions and hallucinations can be extremely irritating for patients.

Negative symptoms (deficits) include

• Affective flattening: the patient’s face appears motionless, with little eye contact and lack of expression.
• Poor speech: the patient speaks little and gives brief answers to questions, which creates the impression of inner emptiness.
• Anhedonia: there is a lack of interest in activities and an increase in aphinalistic activities.
• Asociality: there is a lack of interest in human relationships.

Negative symptoms often lead to low motivation and a reduction in intentionality and goals.

Disorganised symptoms, which can be considered a special type of positive symptoms, include

• Thought disorders
• Bizarre behaviour

Thinking is disorganised when there is incoherent and untargeted speech that slips from one topic to another.

Speech can range from mild disorganisation to incoherence and incomprehensibility.

Bizarre behaviour may include childlike stupidity, agitation and inappropriate appearance, hygiene or conduct.

Catatonia is extreme bizarre behaviour, which may involve maintaining a rigid posture and resisting efforts to be moved or engaging in aphinalistic, stimulus-independent motor activity.

Cognitive deficits include impairment of the following:

• Attention
• Processing speed
• Working or declarative memory
• Abstract thinking
• Problem solving
• Understanding social interactions

The patient’s thinking may be rigid and his or her ability to solve problems, understand the views of others and learn from experience may be impaired.

The severity of cognitive impairment is a major determinant of overall disability.

Subtypes of schizophrenia

Some experts classify schizophrenia into deficit and nondeficit subtypes, based on the presence and severity of negative symptoms such as affective withdrawal, lack of motivation, and decreased planning.

Patients with the deficit subtype have prevalent negative symptoms that cannot be explained by other factors (e.g., depression, anxiety, uninspiring environment, adverse effects of medication).

Those with the non-deficit subtype may present with delusions, hallucinations and thought disorders, but are relatively free of negative symptoms.

The previously identified subtypes of schizophrenia (paranoid, disorganised, catatonic, residual, undifferentiated) have not proved valid and reliable and are no longer used.

Suicide

Approximately 5-6% of patients with schizophrenia commit suicide and approximately 20% attempt suicide; many more have significant suicidal ideation.

Suicide is the leading cause of premature death among schizophrenics and partly explains why the disorder reduces life expectancy by an average of 10 years.

The risk may be particularly high for young people with schizophrenia and substance abuse disorders.

The risk is also increased in patients who have depressive symptoms or feelings of hopelessness, who are unemployed, or who have just had a psychotic episode or been discharged from hospital.

Patients with late onset and good premorbid functioning, the patients with the best prognosis of remission, are also those with the highest risk of suicide.

Because these patients retain the capacity to experience suffering and distress, they may be more likely to act out of the despair that arises from a realistic recognition of the effects of their disorder.

Violence

Schizophrenia is a modest risk factor for violent behaviour.

Threats of violence and aggressive outbursts are far more frequent than seriously dangerous behaviour.

In fact, people with schizophrenia are less violent overall than people without schizophrenia.

The patients most likely to resort to violence are those with substance use disorders, those with persecutory delusions or prevailing hallucinations and those who do not take their prescribed medication.

Very rarely, a severely depressed, isolated, paranoid person will attack or kill the person he or she perceives as the sole source of his or her difficulties (e.g., an authority figure, celebrity, spouse).

Symptom references

Tsuang MT, Van Os J, Tandon R, et al: Attenuated psychosis syndrome in DSM-5. Schizophr Res 150(1):31-35, 2013. doi: 10.1016/j.schres.2013.05.004.

Diagnosis of schizophrenia

• Clinical criteria (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5])
• It is a combination of history, symptoms and signs

The earlier the diagnosis is made and treated, the better the outcome.

There are no definitive tests for schizophrenia.

Diagnosis is based on a comprehensive assessment of the anamnesis, symptoms and signs.

Information obtained from collateral sources, such as family members, friends, teachers and colleagues, is often important.

According to the DSM-5, the diagnosis of schizophrenia requires both of the following conditions:

• ≥ 2 characteristic symptoms (delusions, hallucinations, disorganised speech, disorganised behaviour, negative symptoms) over a significant period of at least 6 months (symptoms must include at least one of the first 3)
• Prodromal or attenuated signs of illness with decreased social, occupational or self-care functioning manifested over a period of 6 months, including at least 1 month of active symptoms

Differential diagnosis

Psychosis due to other disorders or substance use disorders must be excluded by history and clinical investigation including laboratory tests and a neuroimaging study.

Although some patients with schizophrenia have structural brain abnormalities on radiological examination, these abnormalities are not specific enough to be of diagnostic value.

Other mental disorders with similar symptoms include some clinical pictures that can be correlated with schizophrenia:

• Brief psychotic disorder
• Delusional disorder
• schizoaffective disorder
• schizotypal personality disorder

In addition, mood disorders can cause psychosis in some individuals.

Neuropsychological tests, brain imaging, electroencephalography and other tests of brain function (e.g., eye tracking) do not help to distinguish between the main psychotic disorders.

However, initial research (1) suggests that the results of such tests can be used to group patients into 3 different biotypes of psychosis that do not correspond to current clinical diagnostic categories.

Some personality disorders (especially schizotypal disorder) cause symptoms similar to those of schizophrenia, although they are usually milder and do not involve psychosis.

Diagnosis reference

Clementz BA, Sweeney JA, Hamm JP, et al: Identification of distinct psychosis biotypes using brain-based biomarkers. Am J Psychiatry 173(4): 373-384, 2016.

Prognosis of schizophrenia

Studies derived from the RAISE (Recovery After an Initial Schizophrenia Episode) initiative have shown that the earlier and more aggressively treatment is initiated, the better the outcome (1).

In the first 5 years after symptom onset, functioning may deteriorate and social and work skills may fail, with progressive neglect of self-care.

Negative symptoms may become more severe and cognitive functioning may deteriorate.

From then on, disability levels tend to stabilise.

Some evidence suggests that the severity of the disease may decrease in later life, particularly in women.

In patients with severe negative symptoms and cognitive dysfunction, spontaneous movement disorders may occur, even when antipsychotics are not taken.

Schizophrenia may be associated with other mental disorders.

If it is associated with significant obsessive-compulsive symptoms, the prognosis is particularly poor; if it is associated with symptoms of borderline personality disorder, the prognosis is better.

About 80% of people with schizophrenia experience one or more episodes of major depression at some point in their lives.

For the first year after diagnosis, the prognosis is closely linked to adherence to prescribed psychopharmacological therapy and avoidance of recreational drugs.

Overall, one third of patients achieve significant and lasting improvement; one third show some improvement but with intermittent relapses and residual disability; and one third remain severely and permanently incapacitated.

Only about 15% of all patients return fully to their pre-morbid levels of functioning.

Factors associated with a favourable prognosis include

• Good premorbid functioning (e.g. good student, good work history)
• Late onset and/or sudden onset
• Positive family history of mood disorders other than schizophrenia
• Minimal cognitive deficits
• Few negative symptoms
• Shorter duration of untreated psychosis

Factors associated with a poor prognosis include

• Young age of onset
• Poor premorbid functioning
• Positive family history of schizophrenia
• Many negative symptoms
• Longer duration of untreated psychosis

Men have a poorer prognosis than women; women respond better to treatment with antipsychotic drugs.

Substance use is a significant problem in many people with schizophrenia.

There is evidence that the use of marijuana and other hallucinogens is highly disruptive to patients with schizophrenia and should be strongly discouraged and aggressively treated if present.

Substance use comorbidity is a significant predictor of poor outcome and can lead to poor medication adherence, repeated relapses, frequent hospitalisation, deterioration of functioning and loss of social support, and even homelessness.

Prognosis references

RAISE: Recovery After an Initial Schizophrenia Episode-A Research Project of the National Institute of Mental Health (NIMH)

Treatment of schizophrenia

• Antipsychotic medication
• Rehabilitation, including cognitive remediation, social and support services
• Psychotherapy, oriented towards resilience training

The time between the onset of psychotic symptoms and initial treatment is related to the speed of response to initial treatment and the quality of response to treatment.

When treated early, patients respond more rapidly and completely.

Without continuous use of antipsychotics after an initial episode, 70 to 80% of patients have a subsequent episode within 12 months.

Continuous use of antipsychotics can reduce the relapse rate at 1 year to about 30% or less with long-acting drugs.

Drug treatment is continued for at least 1-2 years after a first episode.

If patients have been ill for longer, it is administered for many years.

Early diagnosis and multimodal treatment have transformed the care of patients with psychotic disorders such as schizophrenia.

Coordination of specialist care, including resilience training, personal and family therapy, management of cognitive dysfunction and supported employment, is an important contribution to psychosocial recovery.

General objectives for the treatment of schizophrenia are to

• Reducing the severity of psychotic symptoms
• Preserve psychosocial function
• Preventing recurrence of symptomatic episodes and associated functional impairment
• Reduce the use of recreational substances

The main components of treatment are antipsychotic medication, rehabilitation through social support services and psychotherapy.

Since schizophrenia is a long-term, recurrent disorder, teaching patients self-management techniques is a significant overall goal. Providing information about the disorder (psychoeducation) to parents of younger patients may reduce the relapse rate (1,2). (See also the American Psychiatric Association’s Practice Guideline for the Treatment of Patients With Schizophrenia, 2nd Edition).

Antipsychotic drugs are divided into conventional antipsychotics and 2nd generation antipsychotics based on their affinity and receptor activity to the specific neurotransmitter.

Second-generation antipsychotics offer some advantages both in terms of discretely greater efficacy (although recent evidence casts doubt on the advantage of second-generation antipsychotics as a class) and in reducing the likelihood of developing an involuntary movement disorder and related adverse effects.

However, the risk of developing a metabolic syndrome (excess abdominal fat, insulin resistance, dyslipidaemia and hypertension) is greater with 2nd generation antipsychotics than with conventional ones.

Several antipsychotics in both classes can cause long QT syndrome and ultimately increase the risk of fatal arrhythmias; these drugs include thioridazine, haloperidol, olanzapine, risperidone, and ziprasidone.

Rehabilitation and social support services

Psychosocial skills training and vocational rehabilitation programmes help many patients to work, shop and take care of themselves; maintain a home; have interpersonal relationships; and work with mental health professionals.

Supported employment, in which patients are placed in a competitive work situation and provided with an on-site mentor to help them adjust to work, can be particularly useful.

Over time, the work mentor serves only as a support for problem solving or communication with other employees.

Support services enable many patients with schizophrenia to remain in the community.

Although most patients can live independently, some require supervised housing, where a staff member is present to ensure medication adherence.

The programmes provide a graduated level of supervision in different residential facilities, ranging from 24-hour support to periodic home visits.

These programmes help to promote patient autonomy while providing sufficient care to minimise the possibility of relapse and the need for hospitalisation.

Intensive community treatment programmes provide services in the patient’s home or other residential facilities and are based on a high staff-to-patient ratio; treatment teams directly provide all or almost all of the necessary care services.

In the event of severe relapses, hospitalisation or crisis management in an alternative setting to hospital may be necessary, and compulsory hospitalisation may be required if the patient poses a danger to himself or others.

Despite improvements in rehabilitation and support services in the community, a small percentage of patients, particularly those with severe cognitive deficits and those who are poorly responsive to drug therapy, require long-term institutionalisation or other supportive care.

Cognitive remediation therapy is helpful in some patients.

This therapy is designed to improve neurocognitive function (e.g., attention, working memory, executive functions) and to help patients learn or relearn how to perform tasks.

This therapy can lead to the patient feeling better.

Psychotherapy

The aim of psychotherapy in schizophrenia is to develop a collaborative relationship between patients, family members and the doctor, so that patients can learn to understand and manage their illness, take their medication as prescribed and manage stress more effectively.

Although individual psychotherapy combined with drug therapy is the common approach, few empirical guidelines are available.

The most effective psychotherapy is probably that which begins by identifying the patient’s basic needs with respect to social services, provides support and information about the nature of the illness, promotes adaptive activities, and is based on empathy and a deep dynamic understanding of schizophrenia.

Many patients need empathic psychological support to adapt to what is often a chronic illness, which can substantially limit functioning.

In addition to individual psychotherapy, there has been a significant development of cognitive-behavioural therapy for schizophrenia.

For example, this therapy, done in a group or individual setting, can focus on ways to decrease delusional thoughts.

For patients living in families, family psycho-educational interventions can reduce the rate of relapse.

Support groups and family associations, such as the National Alliance on Mental Illness, are often helpful to families.

General treatment references

Correll CU, Rubio JM, Inczedy-Farkas G, et al: Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia. JAMA Psychiatry 74 (7):675-684, 2017. doi: 10.1001/jamapsychiatry.2017.0624.

Wang SM, Han C, Lee SJ: Investigational dopamine antagonists for the treatment of schizophrenia. Expert Opin Investig Drugs 26(6):687-698, 2017. doi: 10.1080/13543784.2017.1323870.

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Source:

MSD