6.1.1 Schizophrenia

Diagnosis

Schizophrenia combines psychotic symptoms with disturbance of thought, affect, motivation, cognition or behaviour. No single symptom makes the diagnosis.

• First-rank symptoms are thought echo, thought insertion, withdrawal and broadcasting, passivity experiences, and voices giving a running commentary or speaking in the third person. They are useful descriptions but are not specific to schizophrenia.

• ICD-11 needs at least two characteristic symptoms, at least one from the four core groups (persistent delusions, hallucinations, disorganised thinking, or passivity and control experiences), present most of the time for at least one month.

• Prodromal and residual periods do not count towards the ICD-11 month.

• Psychosis confined to a mood episode is classified with that mood disorder. Review the timing of psychotic and mood symptoms, their full requirements and the longitudinal course.

• Bouffée délirante is the French term for a sudden, polymorphous, changeable psychosis in a previously well person that remits fully within weeks to three months.

Schizotypal disorder

• Schizotypal disorder (ICD-11) is an enduring pattern of eccentricity, odd beliefs held with some doubt, odd speech, attenuated perceptual experiences and social discomfort, and it must cause distress or impaired functioning.

• Psychotic-like experiences are optional, and when present they must stay below the threshold for a primary psychotic disorder.

ICD-11 qualifiers

ICD-11 uses symptom qualifiers (positive, negative, depressive, manic, psychomotor, cognitive) and course qualifiers (episode pattern and remission status). The former paranoid, hebephrenic, catatonic, residual and simple subtypes are not current diagnoses.

Catatonia is assessed separately and, when its requirements are met, recorded alongside the associated mental disorder or medical cause.

Catatonic signs

• The traditional cluster of catatonic schizophrenia was catalepsy, mannerisms, posturing and mutism.

• Fink and Taylor used the wider catatonia syndrome to argue that catatonia is not specific to schizophrenia.

Differential diagnosis

• Persistent hallucinations, fixed delusions or formal thought disorder point to schizophrenia rather than paranoid personality disorder.

• Body dysmorphic disorder, even the delusional form with absent insight, is treated with a serotonin reuptake inhibitor, which has controlled trial support, rather than an antipsychotic.

• Toxicology, infection testing, EEG or imaging are added when the onset, neurological signs or cognitive change suggest them.

• Substance use disorders affect about 40 to 50% of patients over a lifetime in some samples.

• A shared religious or cultural belief is not automatically a symptom.

Epidemiology

• The male excess in incidence is confined to early adult life, because women have a second incidence peak in midlife, so later first onsets are more often female.

• Expressed emotion differs by sex: families of men are more often high in expressed emotion, and that climate harms men more than women.

Genetic risk

• Genetic loading is the largest single risk factor: a first-degree relative confers roughly ninefold to tenfold risk and an identical twin forty-fold or more, against about twofold or less for environmental exposures.

• Risk comes from many common variants and some rare variants of larger effect, such as the 22q11.2 deletion.

• Parents carry a lower risk than siblings or children.

• Monozygotic concordance of about 50% shows that genes raise liability without determining it; the child of two affected parents comes close to it.

• These are historical estimates, not precise predictions for an individual.

Environmental and social risk

An affected relative signals inherited liability, whereas prenatal infection, maternal undernutrition, urban upbringing and obstetric complications are environmental exposures.

• The social (selection) drift hypothesis explains the link with low social class by early-onset illness causing downward social mobility, not poverty causing the illness.

Ethnicity: the AESOP study

• AESOP found raised incidence of schizophrenia and other psychoses in Black Caribbean and Black African people in England compared with White British people, highest in African-Caribbean people at roughly ninefold.

• Black Caribbean and Black African patients were the groups most often admitted compulsorily during first-episode psychosis.

• Diagnostic bias alone does not explain the excess, and lower incidence where ethnic density is greater supports a role for social context.

Causal models

• The neurodevelopmental model rests on prenatal adversity, obstetric complications and early developmental differences; abnormal adolescent synaptic pruning involving complement pathways such as C4 is one proposed mechanism.

• The dopamine model grew from the efficacy of D2 antagonists and psychosis caused by dopamine agonists; raised presynaptic striatal dopamine synthesis is the replicated finding.

• The regional version links mesolimbic dopamine excess to positive symptoms and cortical deficit to negative and cognitive symptoms, though the evidence is stronger for striatal change.

• Aberrant salience is inappropriate significance attached to neutral events, which the person may explain with delusional beliefs.

• NMDA receptor hypofunction is supported by ketamine and phencyclidine, which reproduce positive, negative and cognitive features.

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Clinical features

• Lack of insight is the most prevalent feature, found in about 97% of patients in the WHO International Pilot Study of Schizophrenia, against roughly 50 to 75% for individual symptoms.

• Interepisode cognitive deficits fall mainly in executive function and working memory (an effortful prefrontal function), while orientation, naming, crystallised knowledge and procedural learning are relatively spared.

• During active psychosis, selective attention is biased towards symptom-related material, such as threat in persecutory delusions.

• Primary negative symptoms must be told from secondary ones caused by depression, sedation, parkinsonism, continuing psychosis or an unstimulating environment.

• On the PANSS (Positive and Negative Syndrome Scale), hostility is a positive subscale item, whereas some florid-sounding items sit in the general psychopathology or negative subscales.

Sleep and imaging

• Shortened REM latency is the most replicated polysomnographic change: REM arrives early without an overall rise in REM, while slow-wave and other NREM measures fall.

• Structural imaging shows enlarged lateral and third ventricles, a raised ventricle-to-brain ratio and widespread grey and white matter reduction.

• Reversed asymmetry of the planum temporale is characteristic; the planum normally is larger on the left and lies on the upper surface of the superior temporal gyrus.

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The at-risk mental state

• A prodrome is often recognised only in retrospect, and most people identified as clinically high risk never develop psychosis.

• NICE advises individual cognitive behavioural therapy (CBT), with or without family intervention, to reduce the risk of transition.

• Sexual dysfunction is already present in antipsychotic-naive people in the at-risk state, so it is not solely a medication effect.

Course and outcome

• Most people recover from the first acute phase and over half reach a moderately good global outcome, yet about three-quarters have recurrent relapse with continuing disability.

• Lally and colleagues (2017) found remission in about 58% over a mean 5.5 years and recovery in about 38% over a mean 7.2 years, with rates levelling off after two years.

• That plateau shows psychosis is not progressively deteriorating.

• About 30% have treatment-resistant illness, with symptoms persisting despite adequate trials of two different antipsychotics.

• The "rule of thirds" oversimplifies a variable course, and sustained symptomatic and functional recovery is rarer than symptom remission alone.

• Personal recovery means building a valued life, and it can happen despite continuing symptoms.

Prognostic factors

• Insidious onset is the most consistent predictor of a long duration of untreated psychosis, because gradual onset delays recognition and help-seeking.

• A long duration of untreated psychosis predicts worse symptomatic and social outcome, and the effect persists at long-term follow-up.

• Early improvement within the first two weeks of an antipsychotic is the strongest predictor of response at the end of an acute trial; little early change makes later response to that drug unlikely.

Relapse, adherence and suicide

• Non-adherence to antipsychotics is the strongest and most consistent predictor of relapse, raising the risk about fivefold in the first years after a first episode.

• Non-adherence is also the leading single factor raising the risk of hospitalisation in severe mental illness, ahead of male sex, younger age and comorbidity.

• About a quarter of patients are partially or fully non-adherent at 7 to 10 days, about half by one year and about three-quarters by two years.

• The Drug Attitude Inventory and the Medication Adherence Rating Scale assess adherence and attitudes to medication in psychosis.

• High expressed emotion in relatives (critical comments, hostility, emotional over-involvement) roughly doubles relapse, more so with long daily contact.

• Limiting face-to-face contact with a high expressed emotion relative to under about 35 hours a week is protective.

• Relapses may follow an individual warning pattern and can occur despite adherence.

• Depression during or after a first psychotic episode is the strongest predictor of later suicidal behaviour, and its effect lasts for years.

Mortality and physical health

• People with schizophrenia die earlier, mostly from physical disease: the all-cause standardised mortality ratio is about 2 to 3, and 10 to 20 years of life are lost.

• Cardiovascular disease, not suicide, is the largest single contributor to the excess deaths.

• Smoking, the metabolic effects of medication and unequal access to healthcare all contribute.

• About 40% of CATIE participants met criteria for metabolic syndrome at entry.

Physical monitoring on antipsychotics

Before any antipsychotic, NICE asks for weight, waist, pulse, blood pressure, glucose or HbA1c, lipids, prolactin and movement findings, with an ECG when indicated.

• Postural (orthostatic) hypotension is a fall in systolic pressure of 20 mmHg or more, or diastolic pressure of 10 mmHg or more, on standing from lying.

Psychosocial treatment

• Engagement rests on calm surroundings, continuity, clear choices and consent-based carer involvement, with the antipsychotic chosen jointly from previous response, adverse effects and preference.

• Family intervention, including psycho-education for family and patient, has the most consistent evidence for reducing relapse and readmission.

• NICE recommends family intervention for families in close contact, lasting three months to a year with at least ten planned sessions.

• CBT for psychosis, supported employment, housing and physical healthcare are offered alongside medication.

Antipsychotic treatment

Trials, doses and review

• NICE asks for 4 to 6 weeks at the optimum dose before judging whether a new antipsychotic has worked.

• Antipsychotic-naive first-episode patients respond to low to moderate doses, and higher doses add adverse effects without proportionate benefit.

• After one inadequate trial, check substance use, optimise the dose, then switch to another single agent.

• Regular combined prescribing is reserved for brief overlap during a switch and for augmenting clozapine after an optimised trial.

• Pseudo-resistance is excluded first by checking the diagnosis, adherence, dose, duration, drug interactions and substance use.

• A persisting first-rank symptom is the response being measured, not a confound.

• Antipsychotics are continued for at least 1 to 2 years after recovery, because NICE advises that relapse risk is high if they stop within that period.

• Aggression driven by active psychosis is best reduced by treating the psychosis with an antipsychotic.

• Quetiapine suits routine use, whereas clozapine is restricted to treatment-resistant illness.

• High-dose prescribing means a daily dose above 100% of that drug's own BNF maximum, so each regimen is judged against its own ceiling.

Long-acting injectables

• A long-acting injectable is the maintenance choice when an effective, tolerated oral drug fails only through non-adherence, shown by persisting symptoms with missed doses.

• For a given antipsychotic, tardive dyskinesia is no more common with the injectable form than the oral form.

Comparative trials

• CUtLASS 1 found no disadvantage from first-generation drugs against non-clozapine second-generation drugs on quality of life at one year.

• CATIE phase 1 compared olanzapine, perphenazine, quetiapine, risperidone and ziprasidone; clozapine entered only in the phase 2 efficacy pathway.

• CATIE used perphenazine, a medium-potency drug, as its only first-generation arm, rather than haloperidol with its extrapyramidal burden.

• Patients stayed on olanzapine longest before stopping for any reason (all-cause persistence).

• Olanzapine had fewer discontinuations for extrapyramidal effects than perphenazine but more for weight and metabolic change, and newer drugs showed no class-wide advantage.

Negative symptoms, cognition and depression

• Most antipsychotics help only secondary negative symptoms, and first-generation drugs offer little for primary ones.

• For primary negative symptoms, cariprazine (which beat risperidone head to head), low-dose amisulpride, clozapine and olanzapine have supportive evidence.

• European Psychiatric Association (2021) guidance combines a switch from a first- to a second-generation drug, an antidepressant add-on, social skills training, cognitive remediation, and rehabilitation such as supported employment and housing.

• D-serine, which enhances NMDA receptor function through the glycine co-agonist site, has been trialled as an add-on for negative symptoms.

• Mirtazapine added to clozapine has trial evidence for improving anhedonia and negative symptoms.

• No drug has conclusive evidence for cognitive impairment (BAP 2020), so the best strategy is the lowest effective antipsychotic dose.

• Cognitive remediation therapy trains attention, working memory and planning directly, and suits functional decline driven by cognitive deficits once positive symptoms are controlled.

• CBT for psychosis suits voices that persist despite a therapeutic clozapine level, working on beliefs about the voice and on coping.

• A depressive episode after psychosis remits is treated as depression, usually with a selective serotonin reuptake inhibitor (SSRI) first.

Adverse effects of antipsychotics

Metabolic effects

• Olanzapine carries the greatest risk of weight gain, hyperglycaemia, dyslipidaemia and insulin resistance after clozapine, so it is avoided when diabetes risk must stay low.

• Aripiprazole, amisulpride, lurasidone and haloperidol carry the lowest risk of weight gain and worsened glycaemic control.

• Dibenzodiazepine-type drugs (clozapine, olanzapine) carry the highest dyslipidaemia risk through high H1, 5-HT2C and M3 affinity.

• Quetiapine and low-potency first-generation drugs also raise lipids substantially, risperidone is intermediate and aripiprazole is close to lipid-neutral.

• Weight gain is multifactorial: hypothalamic 5-HT2C blockade weakens satiety alongside H1 blockade, and gain tracks those affinities, not D2 affinity.

• A single dose of olanzapine raises meal-related ghrelin in rats, one proposed contributor to impaired satiation.

• Metformin is the preferred add-on once lifestyle measures fail, with the best randomised and meta-analytic evidence and the strongest results with clozapine and olanzapine.

• Quetiapine lowers thyroxine, sometimes raises thyroid-stimulating hormone and may cause hypothyroidism, so thyroid function is tested at baseline and yearly.

• Olanzapine commonly causes transient, asymptomatic rises in ALT and AST.

Prolactin and sexual effects

• Hyperprolactinaemia follows potent, sustained D2 blockade at the pituitary and tuberoinfundibular pathway, causing sexual, menstrual and breast effects; serum prolactin confirms it.

• Prolactin peaks during sleep, so a sample drawn on waking can be spuriously high, and stress also raises it.

• The substituted benzamides, risperidone and potent first-generation drugs raise prolactin strongly, and gynaecomastia and sexual dysfunction follow risperidone.

• Amisulpride crosses the blood-brain barrier poorly, leaving pituitary D2 receptors heavily blocked.

• Aripiprazole, a partial D2 agonist, lowers or does not raise prolactin, and adding low dose to a working prolactin-raising drug lowers prolactin without a switch.

• Aripiprazole is the preferred switch from a risperidone-family drug, because any sustained full D2 antagonist keeps prolactin raised.

• Quetiapine spares prolactin through loose, brief D2 binding and is the choice when aripiprazole cannot be used.

• A prolactin-sparing drug is preferred when bone density is already low, because hyperprolactinaemia adds to osteoporosis risk.

• Five or more years of prolactin-raising antipsychotic use is associated with higher breast cancer risk in women with schizophrenia, whereas prolactin-sparing use is not.

• Strong prolactin-raisers are best avoided after breast cancer, given prolactin's proliferative action.

• A markedly raised prolactin that fails to fall after a switch suggests an endogenous cause, so pituitary MRI follows while the effective antipsychotic continues.

QTc and the heart

• QT prolongation arises from blockade of cardiac potassium channels (the hERG-encoded rapid delayed rectifier current), which delays ventricular repolarisation.

• Thioridazine was withdrawn in the UK for dose-related QTc prolongation and torsade de pointes; pimozide, haloperidol and amisulpride remain available with ECG requirements.

• Aripiprazole is the usual switch when an antipsychotic has prolonged the QTc or the baseline ECG is abnormal.

• Electrolyte disturbance is a genuine risk factor for QTc prolongation, and female sex, not male, carries the higher risk.

• Hypokalaemia lengthens the QT (in practice QU) interval, with ST depression, flat or inverted T waves and prominent U waves.

• Macrolide antibiotics prolong the QTc directly by hERG blockade, whereas other classes do so only indirectly by lowering potassium or magnesium.

• Postural hypotension depends on alpha-1 blockade, so the substituted benzamides (amisulpride, sulpiride) carry the lowest risk, and quetiapine and clozapine carry a high one.

• Priapism is a rare alpha-1 effect, most linked with low-potency drugs such as chlorpromazine.

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Movement disorders

• Extrapyramidal risk follows the strength of nigrostriatal D2 blockade, so high-potency first-generation drugs carry the most and partial agonists, benzamides and loosely binding second-generation drugs carry less.

• High-potency drugs such as haloperidol and fluphenazine carry the greatest tardive dyskinesia risk and have weak antimuscarinic, antihistaminic and alpha-1 effects.

• Drug-induced parkinsonism differs from idiopathic Parkinson's disease by symmetrical, bilateral onset, with rigidity and bradykinesia dominating over tremor, and it lacks clasp-knife spasticity or cerebellar signs.

• The Simpson-Angus Scale rates gait, limb and neck rigidity, glabellar tap, tremor and salivation.

• The Barnes Akathisia Rating Scale scores observed restlessness, the patient's awareness of it, distress and a global rating.

• The Abnormal Involuntary Movement Scale rates movements in seven body areas, with further global items.

• The Liverpool University Neuroleptic Side Effect Rating Scale is self-completed, with 51 items: 41 genuine side effects and 10 red herrings, where a high red herring score suggests over-reporting.

• Acute dystonia is most likely in young men, antipsychotic-naive patients and those on high-potency drugs, and less likely in women and older people.

• In akathisia, anticholinergics rarely help unless parkinsonism coexists.

• Tardive dyskinesia arises from nigrostriatal D2 receptor supersensitivity after chronic blockade.

• Because of that supersensitivity, raising the dose masks tardive dyskinesia temporarily, and lowering it can worsen the movements at first.

• Clozapine has the best evidence and lowest risk once tardive dyskinesia has developed, because its striatal D2 occupancy is weak and loosely bound.

• Tetrabenazine is the only medicine with a UK licence for persistent, disabling tardive dyskinesia.

Neuroleptic malignant syndrome

• Dehydration and rapid dose escalation raise the risk, both through abrupt central dopamine blockade.

• Neuroleptic malignant syndrome is a clinical emergency with fever, rigidity, altered mental state and autonomic instability after dopamine blockade; presentation can be incomplete.

• Treatment starts by stopping the antipsychotic and giving supportive care and a benzodiazepine.

• Bromocriptine is added in moderately severe cases, with dantrolene kept for severe or rapidly progressing ones.

Choosing a drug by comorbidity

• In epilepsy, olanzapine and quetiapine carry moderate seizure risk, chlorpromazine is in the highest group and clozapine is highest overall.

• Aripiprazole causes little sedation, little weight gain and no prolactin rise, though patients must be warned about akathisia.

Treatment resistance and clozapine

• Clozapine is indicated after two adequate sequential antipsychotic trials, at least one a non-clozapine second-generation drug, and it should not be delayed once indicated.

• Only clozapine has evidence of benefit once resistance is confirmed, and about half (40 to 60%) of resistant patients respond to an adequate trial.

• Clozapine has the strongest evidence for reducing suicidal behaviour, from the randomised InterSePT trial against olanzapine, and it may reduce overall mortality.

• Clozapine has the strongest evidence for reducing persistent hostility, aggression and violence, partly independently of its antipsychotic action.

When clozapine gives only a partial response

• The preferred augmentation after an optimised trial is a second antipsychotic that does not compound clozapine's adverse effects, such as aripiprazole or amisulpride.

• Aripiprazole added to clozapine can reduce weight gain and dyslipidaemia and may modestly help negative symptoms, whereas amisulpride suits residual positive symptoms.

• Allopurinol, a xanthine oxidase inhibitor that raises adenosine, has randomised add-on evidence when clozapine fails.

• The Maudsley Guidelines list mostly an antipsychotic alone at high dose or combined with another (such as olanzapine with amisulpride), but not pairs with additive QT risk.

Haematology and blood monitoring

• A baseline neutrophil count is the clozapine-specific test that gates dispensing through the monitoring service; ECG, metabolic, liver and endocrine checks are general baselines.

• Baseline neutrophil variation is interpreted through the service's pathway rather than automatically excluding treatment.

• UK monitoring is weekly for 18 weeks, fortnightly from week 19 to one year, then four-weekly for the whole of treatment.

• Agranulocytosis is a fall in neutrophils, the cell line on which thresholds are set, whereas leukopenia is a total white cell count below the reference range.

• Neutropenia, agranulocytosis and pancytopenia each have their own defining cut-off.

• Clozapine causes agranulocytosis in just under 1% of patients and neutropenia in about 3%, with the risk highest early in treatment.

• Under routine monitoring, the risk of dying from agranulocytosis is about 1 in 10,000.

• Asian ethnicity roughly doubles agranulocytosis risk and older age raises it, whereas young age and Black African ancestry predict neutropenia rather than agranulocytosis.

• Fever or signs of infection call for an urgent full blood count with differential.

• Lithium raises the neutrophil and total white cell count, so a responder with a low count can stay on clozapine.

• Carbamazepine is not given with clozapine, because it adds its own agranulocytosis risk and lowers clozapine levels by enzyme induction.

Agranulocytosis is idiosyncratic and unrelated to dose or plasma level, whereas seizures, hypersalivation, orthostatic hypotension and sedation rise with dose, level or titration speed.

Plasma levels and interactions

• The target plasma range is about 350 to 600 micrograms per litre, and seizure risk rises above it, particularly over 1 mg/L.

• CYP1A2 is the main enzyme clearing clozapine, so a strong CYP1A2 inhibitor raises the level and causes dose-related toxicity.

• Inhibitors call for a lower dose: fluvoxamine (via CYP1A2) raises levels most of the SSRIs, with seizure risk, and fluoxetine acts via CYP2D6.

• Inducers lower clozapine levels: tobacco smoke, omeprazole and phenytoin.

• Smoking status is the dominant influence on levels: smokers need higher doses, and stopping smoking removes the induction, so clozapine and olanzapine doses and levels need review.

• Women have higher levels than men at the same dose through lower clearance, so they often need lower doses.

• At steady state in a trough sample, clozapine runs a little above norclozapine, a mean ratio of about 1.3.

• The ratio falls after recent missed doses, because clozapine falls faster, and rises with early sampling, CYP1A2 inhibition, loss of smoking induction and inflammation.

• Lithium with clozapine raises the risk of neuroleptic malignant syndrome, a pharmacodynamic interaction.

Seizures

• Clozapine lowers the seizure threshold more than any other routine antipsychotic, dose-dependently, and its seizures are most often generalised tonic-clonic.

• Uncontrolled epilepsy is a licensed contraindication to starting clozapine.

• Lamotrigine, valproate, topiramate and gabapentin are all acceptable anticonvulsant prophylaxis, and none is uniquely preferred.

• Valproate is called the anticonvulsant of choice because it does not induce clozapine metabolism, unlike carbamazepine and phenytoin.

• Anticonvulsant choice also weighs reproductive risk and interactions.

Myocarditis and cardiovascular effects

• Myocarditis is a risk distinctive to clozapine, usually within the first two months and most often in the first weeks of titration; cardiomyopathy may occur later.

• It presents non-specifically with fever, a flu-like prodrome, persistent resting tachycardia, breathlessness and ECG change, and only a minority have chest pain.

• Troponin is the first test, and raised CRP with normal neutrophils and no infective source points to myocarditis.

• Suspected myocarditis means stopping clozapine at once and arranging urgent cardiology assessment.

• Persistent benign sinus tachycardia, once myocarditis is excluded by normal troponin, CRP and echocardiogram, can be slowed with a cardioselective beta-blocker such as bisoprolol.

• Clozapine is the antipsychotic most associated with raised blood pressure, usually early and often with tachycardia, probably through sympathetic activation.

Other adverse effects

• Ordinary constipation is only a caution, and it is treated promptly with an osmotic laxative such as macrogol, often with senna, or senna with docusate.

• Bulk-forming laxatives such as ispaghula need normal motility, so they do not suit clozapine constipation.

• Hypersalivation is proposed to arise from M4 muscarinic agonism with alpha-2 adrenoceptor blockade.

• Glycopyrronium bromide stays outside the central nervous system, whereas hyoscine worsens cognition in older patients.

• Clozapine can precipitate or worsen obsessive-compulsive symptoms.