Quetiapine

Indications

• Schizophrenia in adults and adolescents ages 13-17, with both immediate-release and extended-release formulations approved for acute and maintenance use.
• Acute manic or mixed episodes of bipolar I disorder in adults and in children ages 10-17, as monotherapy or as adjunct to lithium or valproate.
• Depressive episodes of bipolar I or II disorder in adults, where quetiapine has the strongest monotherapy evidence base of any antipsychotic.
• Maintenance treatment of bipolar I disorder in adults as adjunct to lithium or divalproex, and extended-release adjunctive treatment of major depressive disorder.
• Off-label uses include generalized anxiety disorder, which has controlled trial support, and low-dose use for insomnia, which is not recommended.

Mechanism of action

• Low-affinity, fast-dissociating D2 antagonist, which explains the very low rate of extrapyramidal symptoms and negligible prolactin elevation.
• Potent 5-HT2A and moderate 5-HT1A partial agonist activity contributes to mood effects and to tolerability in Parkinson disease psychosis.
• The active metabolite norquetiapine inhibits the norepinephrine transporter and blocks 5-HT2C, which underlies antidepressant efficacy.
• High histamine H1 affinity drives profound sedation and appetite stimulation, prominent even at doses of 25-50 mg.
• Alpha-1 blockade causes orthostatic hypotension and dizziness, especially during initial titration and in older adults.

Pharmacokinetics

• Immediate-release absorption is rapid and largely food independent, but extended-release should be taken without food or with a light meal under 300 kcal.
• Extensively metabolized by CYP3A4 to norquetiapine, an active metabolite with a distinct noradrenergic and antidepressant pharmacology.
• Parent half-life is about 6 hours and norquetiapine about 12 hours, so immediate-release usually needs twice-daily dosing.
• Only about 1 percent is excreted unchanged, so renal impairment needs no adjustment while hepatic impairment lowers clearance by about 30 percent.
• The short half-life makes quetiapine unforgiving of missed doses and prone to rebound insomnia and nausea if stopped abruptly.

Dosing

• Schizophrenia with immediate-release: start 25 mg twice daily, titrate to 300-400 mg/day by day 4, usual range 150-750 mg/day, maximum 800 mg/day.
• Extended-release for schizophrenia: start 300 mg once daily in the evening, then adjust within 400-800 mg/day at intervals of at least one day.
• Bipolar depression: 50 mg at bedtime day 1, 100 mg day 2, 200 mg day 3, and 300 mg day 4, which is the target and effective dose.
• Adjunctive extended-release for major depressive disorder: start 50 mg at bedtime, then 150 mg on day 3, with a maximum of 300 mg/day.
• Hepatic impairment: start 25 mg/day and increase by 25-50 mg/day increments; no adjustment is needed for renal impairment or dialysis.
• Taper over one to two weeks when possible, since abrupt discontinuation commonly causes insomnia, nausea, and rebound anxiety.

Adverse effects

• Somnolence occurs in 50 percent or more at higher doses and is the most common reason for discontinuation early in treatment.
• Weight gain and metabolic effects are high, second only to olanzapine and clozapine, with meaningful rises in triglycerides and glucose.
• Orthostatic hypotension, dizziness, dry mouth, and constipation are frequent, largely from alpha-1, histaminergic, and muscarinic effects.
• Extrapyramidal symptoms and prolactin elevation are minimal, which is the main reason quetiapine is used in Parkinson disease and in tardive risk.
• Serious risks include neuroleptic malignant syndrome, modest QT prolongation, cataracts on long-term use, and rare thyroid hormone reduction.

Monitoring

• Weight, BMI, waist circumference, and blood pressure at baseline and each visit early, with fasting glucose or A1c and lipids at 12 weeks then annually.
• The label recommends slit-lamp lens examination at initiation and every 6 months during chronic treatment, based on preclinical cataract findings.
• Check thyroid function periodically, since quetiapine can lower total and free thyroxine in a dose-related fashion.
• Obtain an ECG when combining with other QT-prolonging drugs, in known cardiac disease, or in patients with electrolyte disturbance.
• Screen for sedation-driven falls in older adults and reassess whether nighttime dosing alone can carry the therapeutic load.

Interactions

• Strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, and ritonavir require reducing quetiapine to about one sixth of the usual dose.
• Strong inducers including phenytoin, carbamazepine, and rifampin can cut exposure up to fivefold; increase the dose and reverse on withdrawal.
• Marked additive sedation and respiratory depression risk with opioids, benzodiazepines, and alcohol, a common cause of harm in practice.
• Additive orthostasis with antihypertensives and additive QT effect with methadone, ondansetron, and Class IA or III antiarrhythmics.
• Avoid in patients with known hypersensitivity; caution with anticholinergics given constipation and urinary retention risk.

Special populations

• Third-trimester exposure risks neonatal extrapyramidal signs and withdrawal; quetiapine is among the better-studied antipsychotics in pregnancy.
• Milk levels are low with a relative infant dose typically under 1 percent, so lactation is usually compatible with infant monitoring.
• Approved from age 10 for bipolar mania and 13 for schizophrenia, but adolescents gain substantially more weight than adults at equal doses.
• In older adults clearance falls about 40 percent; start at 25 mg/day and titrate slowly, weighing fall risk against sedation benefit.
• No renal adjustment even on dialysis; in hepatic impairment start low and titrate at half the usual increments.

Clinical pearls

• Low-dose quetiapine for insomnia gives full metabolic risk for a hypnotic effect; use a real hypnotic.
• 300 mg at bedtime is the evidence-based bipolar depression dose, not a dose on the way to higher.
• Its weak, fast-off D2 binding is why it is a first choice in Parkinson disease psychosis.