Quetiapine

Quetiapine is a second-generation antipsychotic used for schizophrenia, bipolar mania, bipolar depression and, as an add-on, major depression. It is sedating with orthostatic hypotension and metabolic effects, and has a low risk of extrapyramidal symptoms and prolactin elevation. It is frequently misused or used off-label for insomnia, which is not advised.

Classification. Second-generation antipsychotic, dibenzothiazepine.

Mechanism. Antagonism of 5-HT2A and weak dopamine D2 receptors, with strong histamine H1 and alpha-1 blockade. The metabolite norquetiapine inhibits noradrenaline reuptake, which may explain antidepressant effects.

Pharmacokinetics. Well absorbed; food raises levels of the extended-release form. Metabolised by CYP3A4. Half-life about 7 hours for quetiapine and 12 hours for norquetiapine.

Schizophrenia, adults (immediate-release, oral).

• Day 1: 50 mg twice daily; day 2: 100 mg twice daily; day 3: 200 mg twice daily; day 4: 300 mg twice daily.
• Usual 300 to 450 mg daily. Maximum 750 mg daily (800 mg in some labels).

Bipolar mania, adults. Day 1: 100 mg daily in two doses; day 2: 200 mg; day 3: 300 mg; day 4: 400 mg. Increase by up to 200 mg daily to a maximum of 800 mg daily.

Bipolar depression, adults. 50 mg at night on day 1, 100 mg on day 2, 200 mg on day 3, 300 mg on day 4. Usual 300 mg at night; maximum 600 mg daily.

Extended-release (once daily in the evening). Schizophrenia: 300 mg on day 1, 600 mg on day 2; range 400 to 800 mg. Adjunct in major depression: 50 mg on days 1 and 2, then 150 mg; maximum 300 mg daily.

Dose limits. Older adults and liver impairment: start 25 mg daily, increasing by 25 to 50 mg daily. Strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin): reduce to one sixth of the dose. Strong inducers (carbamazepine, phenytoin, rifampicin): may need up to five times the dose. Kidney impairment: no adjustment.

Contraindications. Hypersensitivity; strong CYP3A4 inhibitor use in some labels. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis, and suicidal thinking in under 25 years in depression indications.

Serious adverse effects. Orthostatic hypotension and syncope, QT prolongation, hyperglycaemia and diabetes, dyslipidaemia, neuroleptic malignant syndrome, tardive dyskinesia, neutropenia (rare), seizures, cataract, hypothyroidism, withdrawal symptoms on abrupt stopping.

Common adverse effects. Sedation, dizziness, dry mouth, weight gain, constipation, raised triglycerides and cholesterol, tachycardia.

Interactions. Strong CYP3A4 inhibitors raise levels; carbamazepine, phenytoin and rifampicin lower them. QT-prolonging drugs (macrolides, quinolones, quinine, artemether-lumefantrine, chloroquine, ondansetron) add risk. Alcohol and sedatives add sedation. Antihypertensives add hypotension. Levodopa is antagonised.

Common prescribing errors. Rapid titration causing hypotension; prescribing low doses for insomnia; not adjusting for CYP3A4 inhibitors or inducers; missing metabolic monitoring.

Special groups.

• Pregnancy: use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: low transfer into milk; acceptable with infant monitoring for sedation.
• Children: licensed from 13 years for schizophrenia and 10 years for mania in some regions; specialist use only.
• Older adults: start 25 mg; falls and mortality in dementia.
• Kidney impairment: no adjustment.
• Liver impairment: start 25 mg daily and titrate slowly.

Formulations. Immediate-release tablets 25 mg, 100 mg, 200 mg and 300 mg; extended-release tablets 50 mg to 400 mg. Swallow extended-release tablets whole, in the evening, on an empty stomach or with a light meal.

Baseline. Weight, BMI, waist, blood pressure lying and standing, fasting glucose or HbA1c, lipids, ECG if cardiac risk, lens examination, and a baseline rating of extrapyramidal symptoms.

Monitoring. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Check blood pressure lying and standing after each dose increase. Examine the lens at the start and every 6 to 12 months. Repeat the ECG when a QT-prolonging drug is added; stop or reduce if QTc is over 500 ms.

Stopping. Reduce over 1 to 2 weeks or longer to limit insomnia, nausea and rebound symptoms.

Referral and escalation. Refer to psychiatry for first-episode psychosis, treatment resistance or severe metabolic change. Syncope, seizures or QTc over 500 ms needs emergency care.