Clozapine

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia and reduces suicidality in schizophrenia. Its use is restricted by mandatory neutrophil monitoring because of agranulocytosis, and by myocarditis, seizures, severe constipation, sialorrhoea, and many interactions. It is initiated and supervised by specialists.

Classification. Second-generation antipsychotic, dibenzodiazepine.

Mechanism. Weak dopamine D2 antagonism with strong 5-HT2A, muscarinic M1, histamine H1 and alpha-1 blockade; the active metabolite norclozapine acts at M1 receptors.

Pharmacokinetics. Well absorbed, unaffected by food. Metabolised mainly by CYP1A2, with CYP3A4 and CYP2D6. Half-life about 12 hours. Smoking induces CYP1A2 and lowers levels by about 50%. A trough level over about 350 micrograms/L is linked to response; levels over 1000 micrograms/L raise seizure risk.

All regimens are oral with no loading dose.

Treatment-resistant schizophrenia, adults (after failure of two adequate antipsychotic courses).

• Day 1: 12.5 mg once or twice daily; day 2: 25 to 50 mg.
• Titration: increase by 25 to 50 mg daily as tolerated to 300 to 450 mg daily by the end of 2 weeks, then by up to 100 mg once or twice weekly.
• Usual 200 to 450 mg daily in divided doses, with the larger dose at night. Maximum 900 mg daily.
• Duration: long term; stop only on specialist advice.

Restarting after missed doses. If 48 hours or more have been missed, restart at 12.5 mg once or twice daily and retitrate.

Dose limits. Older adults: start 12.5 mg once daily and titrate by 25 mg daily. Kidney or liver impairment: start 12.5 mg and titrate cautiously; avoid in severe disease. Fluvoxamine, ciprofloxacin and oral contraceptives raise levels; reduce the dose. Stopping smoking raises levels by about 50% within a week: reduce the dose by about one third and measure a level.

Neutrophil monitoring (required). Baseline absolute neutrophil count (ANC) 1500 cells/µL or more (1000 cells/µL or more for benign ethnic neutropenia). Weekly for the first 6 months (18 weeks in some regions), every 2 weeks until 12 months, then monthly. Response to a fall in ANC: mild neutropenia 1000 to 1499 cells/µL, continue and test 3 times weekly until 1500 or more; moderate 500 to 999, interrupt and test daily until over 1000, then 3 times weekly; severe under 500, stop and test daily with specialist haematology advice.

Contraindications. Previous clozapine-induced agranulocytosis or severe neutropenia, bone marrow disorders, uncontrolled epilepsy, paralytic ileus, severe cardiac disease including myocarditis and cardiomyopathy, alcoholic or toxic psychosis, circulatory collapse, severe kidney or liver disease, concurrent drugs that cause marrow suppression (including carbamazepine), hypersensitivity.

Serious adverse effects. Severe neutropenia and agranulocytosis, myocarditis and cardiomyopathy (highest risk in the first 4 weeks), seizures (dose-related, rising over 600 mg daily), constipation progressing to ileus or bowel obstruction, orthostatic hypotension and collapse, QT prolongation, metabolic syndrome, neuroleptic malignant syndrome, pulmonary embolism, pneumonia from aspiration of saliva.

Common adverse effects. Sialorrhoea (especially at night), sedation, tachycardia, constipation, weight gain, dizziness, nocturnal enuresis, fever in the first weeks.

Interactions. Carbamazepine is avoided. Fluvoxamine, ciprofloxacin and oral contraceptives raise levels; smoking, rifampicin, phenytoin and omeprazole lower them. Benzodiazepines can cause collapse in the titration phase. Anticholinergics add constipation. Other marrow-suppressing drugs (co-trimoxazole, chloramphenicol, methotrexate, zidovudine) increase neutropenia risk. Lithium and valproate may increase neurotoxicity or seizures.

Common prescribing errors. Titrating too fast; restarting at the old dose after a gap of 48 hours or more; failing to adjust for a change in smoking; missing constipation; not measuring ANC on schedule.

Special groups.

• Pregnancy: use only if benefit outweighs risk; gestational diabetes and neonatal sedation are reported; monitor neutrophils.
• Breastfeeding: avoid because of the risk of agranulocytosis in the infant.
• Children: not advised in under 16 years.
• Older adults: start 12.5 mg; high risk of hypotension, anticholinergic effects and constipation.
• Kidney and liver impairment: start 12.5 mg and titrate cautiously; avoid in severe disease.
• Regional: benign ethnic neutropenia (Duffy-null phenotype) is common in people of African ancestry and lowers the usual ANC; use the benign ethnic neutropenia thresholds and do not withhold clozapine on a low baseline ANC alone.

Formulations. Tablets 25 mg and 100 mg; oral suspension 50 mg/mL in some regions. Give with or without food.

Baseline. ANC, full blood count, ECG, troponin and C-reactive protein, weight, BMI, waist, blood pressure lying and standing, fasting glucose or HbA1c, lipids, liver and kidney function, smoking status, bowel history.

Monitoring. ANC weekly for the first 6 months (18 weeks in some regions), every 2 weeks until 12 months, then monthly; stop for ANC under 500 cells/µL. Troponin and C-reactive protein weekly for the first 4 weeks; stop and review if troponin is over twice the upper limit of normal or C-reactive protein is over 100 mg/L. Temperature, pulse and blood pressure daily during the first 2 weeks.

Ask about constipation at every review; give a regular laxative and stop clozapine for severe constipation or ileus. Weight, waist, fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Trough level 12 hours after the dose when response is poor, after smoking changes, or when an interacting drug is started.

Stopping. Reduce over 1 to 2 weeks with monitoring for cholinergic rebound and relapse; stop immediately only for severe neutropenia or myocarditis.

Referral and escalation. Prescribing is restricted to psychiatry. Fever, sore throat or infection, chest pain, breathlessness, tachycardia over 120 beats/minute, seizures, severe constipation or abdominal pain needs same-day assessment with an urgent full blood count.