Changes

January 2026 — minor update. Revised wording regarding monitoring of HbA1c and prolatin for some atypical antipsychotics. 

Update

Goals

To support primary healthcare professionals to:

• Recognise the features of psychosis or schizophrenia.
• Refer all people with suspected psychosis or schizophrenia for specialist confirmation of the diagnosis.
• Respond appropriately if a person previously diagnosed with psychosis or schizophrenia presents with a relapse of symptoms.
• Provide advice and support to a person with psychosis or schizophrenia, and their families/carers (where appropriate).
• Ensure that a person with psychosis or schizophrenia receives an annual healthcare check.
• Prescribe medications initiated by a specialist and carry out any required monitoring under a shared-care arrangement (if applicable).

Outcome measures

Audit criteria

QOF indicators

Table 1. Indicators related to schizophrenia in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.

QIPP - Options for local implementation

NICE quality standards

Psychosis and schizophrenia in adults

• Adults with a first episode of psychosis start treatment in early intervention in psychosis services within 2 weeks of referral.
• Adults with psychosis or schizophrenia are offered cognitive behavioural therapy for psychosis (CBTp).
• Family members of adults with psychosis or schizophrenia are offered family intervention.
• Adults with schizophrenia who have not responded adequately to treatment with at least two antipsychotic drugs are offered clozapine.
• Adults with psychosis or schizophrenia who wish to find or return to work are offered supported employment programmes.
• Adults with psychosis or schizophrenia have specific comprehensive physical health assessments.
• Adults with psychosis or schizophrenia are offered combined healthy eating and physical activity programmes, and help to stop smoking.
• Carers of adults with psychosis or schizophrenia are offered carer‑focused education and support programmes.

[NICE, 2024a]

 Decision making and mental capacity

• People aged 16 and over who may lack capacity to make decisions are supported with decision making in a way that reflects their individual circumstances and meets their particular needs.
• People aged 16 and over at risk of losing capacity to make decisions, and those with fluctuating capacity, are given the opportunity to discuss advance care planning at each health and social care review.
• People aged 16 and over who are assessed as lacking capacity to make a particular decision at the time that decision needs to be made, have a clear record of the reasons why they lack capacity and the practicable steps taken to support them.
• People aged 16 and over who lack capacity to make a particular decision at the time that decision needs to be made have their wishes, feelings, values and beliefs accounted for in best interests decisions.

[NICE, 2020]

What is it?

• The term psychosis encompasses a number of symptoms associated with significant alternations to a person's perception, thoughts, mood, and behaviour.
• Individuals experiencing psychosis will have a different combination of symptoms, which may include:
  • Positive signs and symptoms, such as:
    • Hallucinations (perceptions in the absence of stimulus). The most common are auditory hallucinations, in which voices are heard and may provide a running commentary on actions, argue with the person, command, or echo the person's thoughts. Hallucinations which are visual, smell, taste, or tactile in nature occur less commonly.
    • Delusions (fixed or falsely-held beliefs) can include delusions of reference (the belief that ordinary events, objects, or the behaviour of others has a meaning specifically for the person, for example, that people on the radio are talking to, or about, them), delusions of control (the belief that the person's thoughts, feelings, or behaviour are being controlled by others. They include thought insertion, thought withdrawal, and thought broadcasting), and delusions of persecution (the belief that other people are plotting against the person).
    • Disorganised behaviour, speech, and/or thoughts (thought disturbance).
  • Negative signs and symptoms, such as:
    • Emotional blunting.
    • Reduced speech.
    • Loss of motivation.
    • Self-neglect.
    • Social withdrawal.
• Schizophrenia is the most common psychotic disorder. The diagnostic criteria for schizophrenia (using the International Classification of Diseases-11 [ICD-11] criteria) require the following symptoms to be present most of the time for 1 month or more:
  • Two of the following features (at least one from the first four):
    • Persistent hallucinations in any form, when accompanied by fleeting or half-formed delusions without clear affective content, or by persistent over-valued ideas (similar to preoccupations), or when occurring every day for weeks or months on end.
    • Disorganised thinking, including thought echo, thought insertion or withdrawal, and thought broadcasting.
    • Delusions of control, influence, or passivity, clearly referred to body or limb movements or specific thoughts, actions, or sensations.
    • Persistent delusions of other kinds that are culturally inappropriate and completely impossible, such as religious or political identity, or superhuman powers and abilities (for example being able to control the weather, or being in communication with aliens from another world).
    • Breaks or interpolations in the train of thought, resulting in incoherence or irrelevant speech, or neologisms (invented words).
    • Catatonic behaviour, such as excitement, posturing, or waxy flexibility; negativism; mutism; and stupor.
    • Negative signs and symptoms, such as marked apathy, reduced speech, and blunting or incongruity of emotional responses, usually resulting in social withdrawal and lowering of social performance; it must be clear that these are not due to depression or to antipsychotic medication.
    • Grossly disorganized behaviour that impedes goal-directed activity (for example, behaviour that appears bizarre or purposeless, unpredictable or inappropriate emotional responses that interfere with the ability to organize behaviour.)
• Schizophrenia is now considered a heterogeneous syndrome along a spectrum of disorders involving psychosis.
• Other psychotic disorders include:
  • Schizoaffective disorder — where symptoms of schizophrenia and a mood disorder (depressed or manic) are equally prominent.
  • Schizophreniform disorder.
  • Brief psychotic disorder.
  • Drug-induced psychosis — substance-induced and usually remits within a month of cessation of use.
  • Persistent delusional disorder — where the most pervasive symptom is delusion.
  • A psychotic syndrome may also accompany other psychiatric conditions such as major depressive disorder and bipolar disorder.

  [Marder, 2019; BMJ Best Practice, 2024a; BMJ Best Practice, 2024b; Tandon, 2024; WHO, 2024]

What causes psychotic disorders?

• The precise cause of psychotic disorders is unknown, but interactions between a number of genetic, social, and environmental risk factors appear to be involved. 
• Psychotic disorders exhibit a clear heritability which twin studies estimate to be around 85%.
  • A 7.5-fold increased risk of psychotic disorders has been demonstrated in people with a parent with schizophrenia. 
• Identified social and environmental risk factors include:
  • Stressful life events (such as bereavement, job loss, eviction, and relationship breakdown) — associated with a 3.2-fold increased risk of psychotic disorders.
  • Childhood adversity (such as abuse, bullying, parental loss or separation) — associated with a 2.8-fold increased risk of psychotic disorders.
  • Family heritage — observational studies in England have shown a 2 to 5-fold increased risk in south-Asian and black populations compared with the white population.
  • Migration (especially from a developing country) — associated with a 3-fold increased risk of schizophrenia. Increased risk also demonstrated in children of migrants (second-generation effect).
  • Urban living — associated with a 2.4-fold increased risk of schizophrenia.
  • Cannabis use — associated with a 40% increased risk of psychotic illness. This risk increases with heavier use, use starting in adolescence, and use of compounds with a high tetrahydrocannabinol content.
  • Other substance use — use of amphetamines, cocaine, ketamine, LSD, or inhaled substances such as toluene and certain types of glue, can cause acute psychosis. Heavy use may also lead to long-term psychotic symptoms that may persist for years after the last exposure.
  • Medication use — high-dose corticosteroid use can precipitate psychosis.
  • Early life factors — such as exposures in utero to medication, maternal stress, nutritional deficiency, and infection; intrauterine growth restriction, birth and postnatal trauma.
  • Parental age — a paternal age of more than 40 years and parental age of less than 20 years have both been associated with an increased risk of schizophrenia.
  • Exposure to the protozoan parasite Toxoplasma gondii — associated with a two-fold increase in risk of schizophrenia.

[Lieberman, 2018; Lewine, 2020; BMJ Best Practice, 2024b; Tandon, 2024]

How common are psychotic disorders?

• The 2014 Adult Psychiatric Morbidity Survey (APMS) found that around 0.5% of people aged 16 years or older in England had received a diagnosis of a psychotic disorder (schizophrenia, schizoaffective disorder, or affective psychosis) in the preceding year.
• The median lifetime risk for schizophrenia is 7.2 per 1000 people.
  • The male-to-female risk ratio is 1.4:1.
  • The global prevalence of schizophrenia is 23.6 million, although the incidence and prevalence of schizophrenia vary depending on ethnicity and geographic location.
    • Studies carried out in different geographical locations worldwide have reported rates of schizophrenia that vary up to 5-fold and overall rates of psychotic disorders that vary up to 15-fold.
    • It is thought that genuine differences in exposure to risk factors contribute to the difference in reported rates from various locations, so an average global prevalence may not be a useful measure.
  • The age of onset peaks around age 20-25 years for males and 25-30 years for females. A smaller second peak of onset occurs in women after the age of 45-50 years.
  • Childhood onset schizophrenia is extremely rare and poorly understood [Driver, 2020].
• Patients with schizophrenia have a higher mortality than the general population due to physical illness (including cardiovascular diseases and cancers), accidents, and suicide.

[APMS, 2014; Jongsma, 2019; BMJ Best Practice, 2024b]

What is the course and prognosis of psychosis?

• Psychosis may be preceded by a prodromal period that can last from a few days to around 18 months.
  • The prodromal period is characterized by cognitive, emotional and behavioural changes which relapse and remit leading to a deterioration in personal functioning and social withdrawal. These may include:
    • Reduced interest in daily activities and problems with sleep, memory, concentration, communication, affect, and motivation.
    • Transient, low-intensity psychotic symptoms — intermittent, self-limiting episodes, typically lasting less than a week, may include hallucinations or unusual thoughts (including new preoccupation with mystical or religious themes and concerns about being under surveillance).
• The prodromal period is often followed by an acute psychotic episode that includes hallucinations, delusions, and behavioural disturbances, often accompanied by agitation and distress.
• After pharmacological, psychological, and other interventions, many people experience regression or resolution of symptoms, although some negative symptoms may remain:
  • A 2021 meta-analysis reported that almost a quarter of people with first-episode psychosis or schizophrenia will develop treatment-resistant schizophrenia (TRS) in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third.
  • It is estimated that four out of every five people show some response to treatment within the first year.
  • One in every five people will have no further psychotic episodes within the next five years.
  • The most common course is an initial improvement of symptoms with ongoing recurrent acute psychotic episodes or relapses over many years.
  • It has been reported that around 15% of people experience persistent psychotic symptoms that are unresponsive to treatment two years after the acute episode. These people may require rehabilitation and support including help with activities of daily living.
• Factors associated with a poor prognosis include: 
  • Longer duration of untreated psychosis.
  • Early or insidious onset of schizophrenia.
  • Male sex.
  • Negative symptoms.
  • Family history of schizophrenia.
  • Poor educational attainment, low socioeconomic status, or social isolation.
  • Significant psychiatric history.
  • Continued substance misuse.

[Siskind, 2022; BMJ Best Practice, 2024b; Tandon, 2024] 

What are the complications?

Complications of psychotic disorders include:

• Premature death — on average, people with schizophrenia die around 15 years earlier than people in the general population, with men tending to die 15.9 years earlier and women 13.6 years earlier. Various factors contribute to this including:
  • Increased risk of suicide — the lifetime risk in a person with schizophrenia is estimated to be about 5% and is highest at the onset of the illness and after each psychotic episode.
    • Risk factors strongly associated with suicide include younger age, male sex, having a higher level of education, prior suicide attempts, a family history of suicide, depression, active hallucinations and delusions, the presence of insight (i.e. recognition that the person's experiences are caused by a mental illness), and comorbid substance misuse.
  • Increased risk of certain physical disorders, including:
    • Cardiovascular disease — studies have shown this to be the cause of approximately 30% of the excess deaths in people with psychotic disorders. This is thought to be caused by a combination of stress, genetic risk, lifestyle issues (for example, smoking, poor diet, lack of exercise), social disadvantage, and use of antipsychotics, which can cause significant weight gain, elevations in lipid levels, and insulin resistance. The most significant antipsychotic-induced weight gain has been reported to occur early in treatment.
    • Type 2 diabetes — also thought to be caused by a combination of lifestyle factors, such as poor diet and lack of exercise, and treatment with antipsychotic drugs. However, research has shown that impaired glucose homeostasis is more commonly present at disease onset in people with schizophrenia and is , therefore, not solely explained by drug treatment. 
    • Smoking-related illness — people with psychotic disorders are more likely to smoke than the general population (approximately 60% of people experiencing their first psychotic episode already smoke, compared to 20% of the general population in the UK), increasing the risk of smoking-related illnesses and, therefore, premature death. 
    • Cancer — studies have shown this to be the cause of approximately 9% of the excess deaths in people with psychotic disorders. Increased risk of early death is thought to be caused by both late recognition and under-treatment. Women with schizophrenia have been found to have a 31% increased risk of developing breast cancer.
    • Infections such as HIV, hepatitis C, and tuberculosis.
• Sexual dysfunction — this is common and heterogeneous. A 2023 systematic review found that the most frequent sexual dysfunction was erectile dysfunction (44% of men), followed by loss of libido (41%), ejaculation dysfunction (39% of men), orgasm dysfunction (28%), and amenorrhea (25% of women).
• Social exclusion — negative symptoms, such as emotional blunting, reduced speech, loss of motivation, self-neglect, and social withdrawal, are often the major cause of social exclusion by impairing the person's ability to learn, work, and maintain relationships.
• Substance misuse — up to one-third of people with schizophrenia misuse drugs, which, as well as posing direct risks to the person's health, may be associated with an increased risk of blood-borne viruses.

[NICE, 2014; Marder, 2019; Chan, 2021; Korchia, 2023; BMJ Best Practice, 2024b]

How do I identify a person at risk of developing a psychotic disorder or experiencing psychosis?

• Suspect frank psychosis in a person with positive symptoms such as hallucinations and delusions, and negative symptoms such as affective flattening (lack of spontaneity or reactivity of mood), avolition (lack of drive), anhedonia (lack of pleasure), attention deficit, or impoverishment of speech and language.
• Be aware that psychosis may be preceded by a prodromal period that can last from a few days to around 18 months. Identifying the prodromal stage offers a critical treatment window to delay or prevent the person's transition to frank psychosis.
  • The prodromal period is characterised by increasing distress and a decline in personal, cognitive and social functioning. Specific symptoms may include:
    • Transient, low-intensity psychotic symptoms — intermittent, self-limiting episodes, typically lasting less than a week. May include hallucinations/unusual perceptual experiences, unusual thoughts (including new preoccupation with mystical or religious themes, concerns about being under surveillance) and may manifest as unusual or uncharacteristic behaviour.
    • Reduced interest in daily activities — may manifest as poor personal hygiene and/or reduced performance at school or work.
    • Problems with mood, sleep, memory, concentration, communication, affect, and motivation.
    • Anxiety, irritability, or depressive features.
    • Incoherent or illogical speech — suggestive of thought disturbance.
  • A positive family history (particularly a first-degree relative with psychosis or schizophrenia) should also raise clinical suspicion in a person exhibiting deterioration in personal and social functioning.
  • Be aware of other risk factors for psychosis and, in particular, consider asking the person about any recent or past stressful or traumatic experiences and whether they have used cannabis.
  • Positive symptoms may not be readily disclosed by the person. It may, therefore, be necessary to directly ask them whether they are experiencing hallucinations ('feeling, seeing, or hearing things that other people cannot') or experiencing delusional thoughts ('feeling that you are being talked about, watched, or given a hard time for no reason, suspecting you are being externally controlled, or having thoughts inserted or removed from your mind, or others being aware of your thoughts').
  • Where symptoms are suggestive of the prodromal period of psychosis, consider conducting a medical assessment to rule-out an alternative underlying cause:
    • Review the person's history to rule out use of prescribed drugs that can cause psychosis, for example, anticonvulsants, high-dose corticosteroids, levodopa and dopamine agonists, or opioids.
    • Carry out a urine drug screen if use of recreational drugs that can cause psychosis, such as amphetamines or cocaine, is suspected.
    • Use clinical judgement to determine whether to screen for HIV and/or syphilis as both infections can cause psychiatric symptoms.
    • Carry out a full blood count if anaemia is a potential cause of negative symptoms.
    • If a neurological condition such as temporal lobe epilepsy or cerebrovascular disease is suspected, see the CKS topics on Epilepsy and Stroke and TIA for further information on diagnosis and management.
• Consider differential diagnoses, including sepsis in people without a prior history of psychotic symptoms, particularly where there are features suggestive of specific infection, such as dysuria or productive cough. For further information, see the CKS topics on Delirium and Sepsis.

What else might it be?

The differential diagnoses of psychotic disorders include:

• Severe affective (mood) disorders associated with psychotic symptoms, including severe depression or bipolar disorder.
  • These conditions are distinguished from schizophrenia by the predominance of affective symptoms that may at times trigger psychosis. In contrast, schizophrenia is dominated by psychotic symptoms that may at times be associated with affective symptoms.
  • For more information, see the CKS topics on Depression and Bipolar disorder.
• Drug-induced psychosis caused by cannabis, corticosteroids, opioids, cocaine, or amphetamines.
• Sepsis — consider in people without a prior history of psychotic symptoms, particularly where there are features suggestive of specific infection, such as dysuria or productive cough. For further information, see the CKS topics on Delirium and Sepsis.
• Another underlying medical condition, such as cerebrovascular disease, cerebral tumours, or temporal lobe epilepsy.
  • For more information, see the CKS topics on Brain and central nervous system cancers - recognition and referral, Epilepsy, and Stroke and TIA.
• Post-traumatic stress disorder (PTSD) may include flashbacks that have a hallucinatory quality and hyper-vigilance that may reach paranoid proportions. PTSD is distinguished from psychotic disorders by the existence of a traumatic event and characteristic features such as reliving or re-enacting the event.
  • For more information, see the CKS topic on Post-traumatic stress disorder.
• Obsessive compulsive disorder (OCD), where strong irrational beliefs are held, but related to specific fears, and for which the person has developed rituals.
  • For more information, see the CKS topic on Obsessive-compulsive disorder.
• Autism spectrum disorder or communication disorders – people with these disorders may display symptoms that resemble a psychotic episode. They may be distinguished from psychotic disorders by their deficits in social interaction with repetitive and restricted behaviours.
  • For more information, see the CKS topic on Autism in adults.

Scenario: Primary care management

From age 18 years onwards.

Scenario: Managing relapse of an established psychotic disorder

From age 18 years onwards.

Scenario: The routine schizophrenia or psychosis review

From age 18 years onwards.

Scenario: Women of childbearing age with psychosis or schizophrenia

From age 18 years onwards.

Available antipsychotics

• Antipsychotics are available as oral preparations or depot injections. They are classified as first-generation antipsychotics (typical) and second-generation antipsychotics (atypical). For more information, see Table 2.
• First-generation antipsychotics are thought to primarily exert their effects by blocking dopamine-2 receptors in the brain, whereas second-generation antipsychotics act on a range of receptors. Antipsychotics have significant effects on acetylcholine, histamine, norepinephrine, and serotonin pathway and can cause extrapyramidal symptoms (EPS) and a wide range of other adverse effects.
• In general, second-generation antipsychotics are associated with fewer EPS than first-generation antipsychotics. However, second-generation antipsychotics are associated with several other important adverse effects, such as weight gain, glucose intolerance, and hyperprolactinaemia.
• There is no first-line antipsychotic drug suitable for all people with psychosis, and (except for clozapine) little meaningful difference in efficacy. Choice, therefore, depends on the person's personal choice, medication history, degree of sedation required, risk of particular adverse effects, and the degree of negative symptoms (second-generation antipsychotics may be more likely to improve negative symptoms).
• Clozapine is generally offered to people who do not respond adequately to two other antipsychotics and is always initiated and monitored in secondary care.
• Individual responses to antipsychotics are variable. Dosage and dosage interval will, therefore, be adjusted specifically according to the person's response. 
  • CKS recommends that people requiring a change in the dose of their antipsychotic should be referred to specialist mental health services, or that specialist advice should be sought.

[NICE, 2014; BNF, 2024]

Table 2. Antipsychotics available to prescribe.

Adverse effects

• Antipsychotics can cause a wide range of adverse effects — the risk varies with the type of antipsychotic (first-generation or second-generation) and the individual drug. CKS recommends that people who may benefit from a dose reduction or switching drugs should be referred to specialist mental health services, or that advice should be sought.
• Adverse effects include [Taylor, 2021; BNF, 2024]:
  • Extrapyramidal symptoms — more common with first-generation antipsychotics. They include:
    • Dystonic reactions (abnormal movements of the face and body), and pseudoparkinsonism (tremor, bradykinesia, and rigidity) — these can be alleviated by antimuscarinic drugs, such as procyclidine (should not be prescribed routinely).
    • Akathisia (motor restlessness) —  can often be relieved by reducing the dose of the antipsychotic.
    • Tardive dyskinesia — late-onset movement disorder that can occur with prolonged use of antipsychotics. It is characterized by rhythmical, involuntary movements, usually lip-smacking and tongue rotating, although it can affect the limbs and trunk. It may be persistent and can sometimes worsen on treatment withdrawal. The drug should be discontinued on appearance of early signs.
  • Weight gain — common with all antipsychotics, but more frequent with second-generation antipsychotics. In general, clozapine and olanzapine have the greatest potential to cause weight gain, followed by chlorpromazine, quetiapine, and risperidone.
  • Dyslipidaemia — phenothiazines (such as chlorpromazine), clozapine, olanzapine, quetiapine, and risperidone all increase lipid levels. Offer dietary advice and consider treatment with a statin according to national guidelines.
  • Hyperprolactinaemia — most antipsychotics can cause hyperprolactinaemia that may lead to galactorrhoea, amenorrhoea, gynaecomastia, hypogonadism, sexual dysfunction, and an increased risk of osteoporosis. Clozapine, olanzapine, quetiapine, and aripiprazole do not increase prolactin above the normal range in standard doses.
  • Sedation — chlorpromazine, clozapine, and promazine cause the highest incidence of sedation. Amisulpride, aripiprazole, sertindole, and sulpiride are associated with a very low incidence of sedation. Performance of skilled tasks (such as driving) may be affected and the effects of alcohol are enhanced. Tolerance to sedation usually develops.
  • Sleep apnoea syndrome — reported in patients using quetiapine. Quetiapine should be used with caution in people receiving concomitant central nervous system depressants and who have a history of, or are at risk for, sleep apnoea, such as those who are overweight/obese or are male [EMC, 2024].
  • Anticholinergic effects (such as dry mouth, blurred vision, urinary retention, constipation, and cutaneous flushing) — chlorpromazine and clozapine have potent anticholinergic effects. Tolerance may develop, but it is very variable, and these adverse effects are often poorly tolerated.
    • Quetiapine should be used with caution in people taking other drugs with anticholinergic effects [EMC, 2024].
  • Postural hypotension — commonly associated with clozapine, chlorpromazine, quetiapine, and risperidone.
  • Hypertension — commonly reported with clozapine but there are also reports with aripiprazole, olanzapine, quetiapine, and risperidone. Hypertension can occur as:
    • A small, steady increase in blood pressure over time (may be associated with weight gain), or
    • An unpredictable, sharp increase in blood pressure on starting a new drug.
  • Reduced seizure threshold — seizures are a recognized adverse effect of antipsychotics (the higher the dose, the greater the risk). Clozapine carries the greatest risk.
  • Impaired glucose tolerance — more common in people with schizophrenia than in the general population, and has been associated with both first-generation and second-generation antipsychotic drugs [MHRA, 2014]. Hyperglycaemia, and sometimes diabetes (including ketoacidosis and coma) can occur in people taking clozapine, olanzapine, risperidone, and quetiapine.
  • Cardiomyopathy, myocarditis, and cutaneous vasculitis – these have been reported with quetiapine, but a causal relationship has not been established. Consider discontinuing treatment if cardiomyopathy or myocarditis are suspected. 
  • QT interval prolongation — the most widely reported cardiac conduction defect caused by antipsychotics and considered to be a class effect [BNF, 2024].
    • Avoid co-prescribing other drugs that are known to prolong the QT interval (for example, tricyclic antidepressants, erythromycin, or antiarrhythmics), and monitor potassium levels at least annually.
    • People taking antipsychotics who experience palpitations or any other symptoms that suggest cardiac disease should undergo electrocardiography.
  • Stroke risk — antipsychotic drugs may be associated with an increased risk of stroke, but the potential additional risk in people with dementia is uncertain [Zivkovic, 2019]. The Committee on Safety of Medicines has advised that [MHRA, 2005]:
    • For acute psychotic conditions in elderly people with dementia, risperidone should be limited to short-term use under specialist advice. Olanzapine is not licensed for acute psychosis.
    • The possibility of cerebrovascular events should be considered carefully before treating people with a history of stroke or transient ischaemic attack risk factors for cerebrovascular disease (for example, hypertension, diabetes, smoking, and atrial fibrillation) should also be considered.
  • Venous thromboembolism (VTE) — antipsychotic use may be associated with an increased risk of VTE [Li, 2024].
    • Data are insufficient to determine any difference in risk between second-generation and first-generation antipsychotics, or between individual drugs.
    • All possible risk factors for VTE should be identified before and during antipsychotic treatment and preventive measures undertaken.
  • Neuroleptic malignant syndrome (NMS) — is a rare but potentially fatal adverse effect of all antipsychotics. Signs and symptoms of NMS include fever, increased sweating, rigidity, confusion, fluctuating consciousness, fluctuating blood pressure, tachycardia, raised creatine kinase, leucocytosis, and raise liver function tests.
  • Pneumonia — recent evidence from observational studies suggest that all antipsychotics are associated with an increased risk of pneumonia. The mechanism by which this occurs is unclear.
  • Neutropenia — stop the suspected drug if neutrophils fall below 1.5 x 109/L and seek urgent advice from a secondary care specialist.
  • Abnormal liver function tests (LFTs) — stop the suspected drug if LFTs suggest hepatitis (transaminases rise to three times normal) or prothrombin time or albumin are abnormal. Seek advice from a secondary care specialist.
  • Photosensitivity — is common with chlorpromazine. Adequate use of sunscreen will prevent sunburn in affected people. Some high-factor sunscreens (sun protection factor 30 or above) are available on prescription. The prescription should be endorsed with ACBS.
  • Skin and subcutaneous tissue disorders — olanzapine has been associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), frequency unknown [EMC, 2023]. Quetiapine has also been reported to cause an extensive rash, exfoliative dermatitis, fever, lymphadenopathy, and eosinophilia. If any of these are reported then treatment should be withdrawn immediately as it may be suggestive of a severe cutaneous severe reaction, such as Stevens-Johnson syndrome [EMC, 2024]. 
  • Diplopia — is an uncommon adverse effect with aripiprazole. 
  • Misuse and abuse — cases of misuse and abuse have been reported with quetiapine. Quetiapine should be prescribed with caution in people who have a history of drug or alcohol abuse.
  • Restless legs syndrome — this is an uncommon adverse effect.

Drug interactions

• The following interactions are common to all antipsychotics:
  • Drugs with a sedative action (such as alcohol, analgesics, tricyclic antidepressants, and sedating antihistamines) will enhance the sedative effects of antipsychotics.
  • Drugs with a hypotensive effect (for example, antihypertensives) will enhance the hypotensive effect of antipsychotics.
  • Drugs that prolong the QT interval, such as antiarrhythmics, macrolides (for example, erythromycin), and tricyclic antidepressants, may have a synergistic effect. Avoid co-prescribing drugs that prolong the QT interval. These drugs are contraindicated with sertindole therapy.
  • Diuretics may cause hypokalaemia, which may increase the risk of arrhythmias; monitor potassium levels in people taking diuretics.
• Azole antifungals
  • Azole antifungals may increase levels of some antipsychotics, for example:
    • Aripiprazole levels are predicted to be increased by itraconazole.
    • Haloperidol levels are increased by 30% or more by itraconazole.
  • If azole antifungals are given concurrently with antipsychotics, monitor for signs of adverse effects of antipsychotics and consider reducing the dose as necessary.
  • The manufacturer of aripiprazole recommends halving the dose of aripiprazole if itraconazole is given concomitantly.
• Carbamazepine
  • Carbamazepine reduces plasma levels of clozapine, haloperidol, and risperidone by half. Carbamazepine also reduces levels of aripiprazole, fluphenazine, olanzapine, quetiapine, and sertindole.
    • Monitor the person's symptoms to ensure that antipsychotics remain effective.
  • Carbamazepine levels are increased by haloperidol, quetiapine, or risperidone.
    • Monitor carbamazepine levels if these drugs are given together.
• Grapefruit juice
  • Advise the person not to drink grapefruit juice if they are taking pimozide. Grapefruit juice increases the levels of pimozide, possibly leading to Torsades de Pointes and potentially fatal arrhythmias.
• Methylphenidate
  
  • Methylphenidate increases the risk of dyskinesias when given with risperidone. Manufacturer advises caution.
• Selective serotonin reuptake inhibitors (SSRIs)
  • SSRIs increase levels of some antipsychotics, for example:
    • Haloperidol levels are increased by 20–30% by fluoxetine and by 20–60% by fluvoxamine.
    • Risperidone levels are increased by fluvoxamine, fluoxetine, and paroxetine.
    • Sertindole levels are increased two- to three-fold by fluoxetine and paroxetine.
    • Clozapine and olanzapine levels are increased by fluoxetine, fluvoxamine, paroxetine, sertraline, and possibly citalopram.
  • Where antipsychotic drug levels are increased, the person should be monitored and the dose adjusted accordingly.
• Smoking cessation
  • Smoking induces the metabolism of olanzapine and clozapine. If the person stops smoking, monitor for increased adverse effects and seek advice about dose adjustment if necessary [MHRA, 2020].

[BNF, 2024; Preston, 2024]

What monitoring is required?

• When antipsychotics are initiated, baseline measurements should be taken in secondary care. People with a psychotic disorder will remain under the responsibility of the secondary care team for the first 12 months, or until their condition has stabilized (whichever is longer).
• Regular monitoring may subsequently be done in primary care on specialist advice or depending on the person's care plan. This may include:
  • Bodyweight, or body mass index (BMI) — weekly for the first 6 weeks, then at 3 months. Thereafter every 12 months, or more often if the person is gaining weight rapidly.
  • Serum electrolytes and urea including creatinine and estimated glomerular filtration rate — every 12 months.
  • Full blood count — every 12 months.
  • Blood lipids — 3 months after starting treatment, then every 12 months.
  • Plasma glucose or HbA1c — 3 months after starting treatment, then every 12 months. Additionally, for clozapine and olanzapine, repeat after the first month of treatment, ideally by oral glucose tolerance test or fasting plasma glucose (HbA1c if fasting not possible). Ask about symptoms of hyperglycaemia (such as polydipsia, polyuria, and increased appetite).
    
    • In some cases both plasma glucose and HbA1c may be monitored.
  • Pulse and blood pressure — during dose titration and at each dose change.
    • Not required for amisulpride, aripiprazole, trifluoperazine, and sulpiride.
  • Electrocardiography (ECG) — after dose changes. Manufacturers also recommend periodic ECG monitoring, with no defined periodicity of this monitoring.
    • Mandatory for haloperidol, pimozide, and sertindole; not required for antipsychotics with no effect, or a low-to-moderate effect on the QT interval and where there are no other risk factors for arrhythmia including drug interactions.
  • Prolactin — 6 months after starting treatment, then every 12 months. Also ask about symptoms of raised prolactin (these include low libido, sexual dysfunction, menstrual abnormalities, gynaecomastia, and galactorrhoea).
    • Not required for aripiprazole, clozapine, quetiapine, or olanzapine (less than 20 mg daily), unless symptoms of hyperprolactinaemia are present.
  • Liver function tests – every 12 months.
  • Creatinine kinase if neuroleptic malignant syndrome is suspected.
  • Monitoring for the emergence of movement disorders.
• Tests which need to be done every 12 months may be carried out at the annual physical review.
• Clozapine
  • People taking clozapine are managed exclusively in secondary care. Clozapine can cause neutropenia or agranulocytosis, and frequent monitoring of the full blood count is required. This is carried out by the clozapine monitoring service.
  • Clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation, which is very common, to very rare intestinal obstruction, faecal impaction, and paralytic ileus. People taking clozapine and their carers should be advised to seek immediate medical advice before taking the next dose of clozapine if constipation develops.
  • Note: following fatal cases involving toxicity of clozapine and other antipsychotic medicines, the MHRA advises that monitoring blood concentration of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and sulpiride may be helpful in certain circumstances, such as patients presenting symptoms suggestive of toxicity, or when concomitant medicines may interact to increase blood concentration of these medicines.

[NICE, 2014; EMC, 2015; EMC, 2018; MHRA, 2020; ABPI, 2021; BNF, 2025]

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of psychosis and schizophrenia.

Search dates

January 2020 - October 2024

Key search terms

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 16th December 2020). These were combined with filters to identify further guidelines and primary care relevant literature in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases. 

S3     S1 OR S2
S2    AB ( schizophreni* or psychosis or psychoses or psychotic* ) OR TI ( schizophreni* or psychosis or psychoses or psychotic* ) 
S1    (MH "Schizophrenia Spectrum and Other Psychotic Disorders+") 

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.