Quetiapine (Seroquel)
SGA • Last reviewed 2025-09-23
General information
Quetiapine is a second-generation antipsychotic approved in the United States for schizophrenia, acute manic or mixed episodes associated with bipolar I disorder (monotherapy or adjunct), bipolar depression, and as adjunctive therapy for major depressive disorder. Immediate-release (IR) tablets were approved in 1997, and an extended-release (XR) formulation followed in 2007 to enable once-daily dosing. The drug is frequently selected when sedation, anxiolysis, or bipolar depressive efficacy is desired, and it is used off label for sleep despite warnings about metabolic and orthostatic adverse effects.
Dosage forms include IR tablets (25, 50, 100, 200, 300, 400 mg) and XR tablets (50, 150, 200, 300, 400 mg). Schizophrenia dosing typically starts at 25 mg twice daily (IR) or 300 mg once daily (XR) with rapid escalation to 300-400 mg/day by day 4 and a usual target range of 300-800 mg/day. Bipolar depression is treated with 300 mg XR nightly given as 50 mg on day 1, 100 mg day 2, 200 mg day 3, and 300 mg day 4; higher doses do not improve outcomes but increase sedation. Dose adjustments are recommended in hepatic impairment and for frail or elderly patients, who should initiate at 25 mg/day with slower titration.
Pharmacodynamically, quetiapine exhibits moderate affinity for dopamine D2 and serotonin 5-HT2A receptors with low transient striatal D2 occupancy (<60%), contributing to low extrapyramidal symptom risk. High-affinity antagonism at histamine H1 and adrenergic alpha1 receptors explains prominent sedation and orthostasis, while antagonism of muscarinic M1 receptors (via the active metabolite) contributes to anticholinergic effects. Norquetiapine, the major active metabolite, is a norepinephrine transporter inhibitor and partial 5-HT1A agonist that is hypothesized to support antidepressant efficacy.
Quetiapine is extensively metabolized by hepatic CYP3A4 to norquetiapine and other inactive metabolites; <1% of a dose is excreted unchanged in urine. IR formulations reach peak plasma concentrations in 1.5 hours and XR tablets in about 6 hours. The terminal half-life of quetiapine is about 6 hours, whereas norquetiapine has a half-life of roughly 12 hours, permitting once-daily XR dosing. Mild-to-moderate hepatic impairment increases exposure up to threefold, warranting lower starting doses; renal impairment has minimal effect because metabolism is hepatic.
Dosing & administration
Schizophrenia (IR): 25 mg twice daily day 1, titrate to 300-400 mg/day by day 4; maintenance 300-800 mg/day divided BID.
Schizophrenia (XR): Start 300 mg once daily, increase to 400-800 mg/day; administer evening meal or without food consistently.
Bipolar depression (XR): 50 mg day 1, 100 mg day 2, 200 mg day 3, 300 mg nightly thereafter.
Bipolar mania: Initiate 50 mg twice daily, reach 400-800 mg/day by day 6; may combine with lithium or divalproex.
Dose considerations by scenario
- Schizophrenia
- Typical maintenance 400-800 mg/day (IR divided BID or XR once daily).
- Bipolar I manic/mixed episode
- Target 400-800 mg/day; combination with lithium/divalproex improves response (monitor sedation).
- Bipolar depression
- 300 mg XR nightly; evidence does not support >300 mg for depressive symptoms.
- Adjunct MDD
- 150-300 mg XR nightly; evaluate benefit versus metabolic and sedation risks.
- Hepatic impairment or elderly
- Start 25 mg/day, increase by 25-50 mg/day to effect; XR not recommended below 50 mg so IR is preferred.
Mechanism of action
Quetiapine acts as an antagonist at 5-HT2A greater than D2 receptors, producing modest mesolimbic D2 occupancy while sparing nigrostriatal pathways. This receptor profile, combined with transient binding kinetics, accounts for low EPS and prolactin elevations relative to some SGAs.
Norquetiapine blocks norepinephrine reuptake and partially agonizes 5-HT1A receptors, which may contribute to anxiolytic and antidepressant properties but also to anticholinergic adverse effects. High H1 affinity accounts for sedation and weight gain, and alpha1 antagonism leads to orthostatic hypotension, particularly during titration.
- Histamine H1 Ki around 1 nM (high sedation potential).
- D2 occupancy under 60 percent at therapeutic doses, limiting EPS.
- Norquetiapine partial 5-HT1A agonism supports antidepressant effect.
Metabolism & pharmacokinetics
Quetiapine undergoes first-pass metabolism via CYP3A4, yielding norquetiapine and other metabolites; inhibitors such as ketoconazole can increase area under the curve fivefold. Food increases XR absorption (especially high-fat meals) and may raise Cmax; consistent administration relative to meals is advised.
Apparent clearance averages 90 L/hour in healthy adults. Because hepatic impairment increases exposure, lower starting doses and slower titration are necessary, while renal impairment has minimal impact. Smoking does not meaningfully alter quetiapine pharmacokinetics, but concomitant CNS depressants can enhance sedation.
- Absolute oral bioavailability
- About 9%
- Tmax
- IR about 1.5 h; XR about 6 h
- Terminal half-life
- Parent about 6 h; norquetiapine about 12 h
- Protein binding
- Around 83%
Drug interactions
Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, HIV protease inhibitors) markedly increase quetiapine exposure; reduce dose to roughly one sixth and monitor for QT prolongation and sedation.
Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. John's wort) reduce plasma concentrations; avoid if possible or increase dose with careful monitoring.
Additive CNS depression occurs with alcohol, benzodiazepines, opioids, and antihistamines; counsel patients about impaired alertness.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP3A4 inhibition | Ketoconazole, itraconazole, clarithromycin, ritonavir | Reduce quetiapine to about 1/6 usual dose; monitor QT interval and sedation. |
| CYP3A4 induction | Carbamazepine, phenytoin, rifampin, St. John's wort | Avoid combination or titrate quetiapine upward with monitoring for efficacy and tolerability. |
| Additive QT prolongation | Class IA/III antiarrhythmics, macrolides | Assess baseline QTc, correct electrolytes, and consider alternatives. |
Monitoring & safety checks
Weight, BMI, waist circumference, fasting lipids and glucose
Baseline, 12 weeks, then annually • High risk of metabolic syndrome and weight gain.
Blood pressure and orthostatic vitals
Baseline, during titration, and each visit • Alpha1 antagonism increases orthostasis risk.
Eye exams
Baseline and every 6 months • Lens changes observed in preclinical studies; label recommends monitoring.
CBC if infection symptoms
As clinically indicated • Rare neutropenia has been reported.
Educate patients about sedation and advise evening dosing; caution against operating machinery until response is known.
Advise gradual position changes and hydration during the first week to mitigate orthostasis.
Discontinuation guidance
If possible taper quetiapine over at least 1-2 weeks to limit insomnia, nausea, and rebound psychosis; reduce more slowly for XR formulations to avoid cholinergic rebound from norquetiapine.
When abrupt discontinuation is necessary (for example severe rash or suspected neuroleptic malignant syndrome), provide supportive care and monitor for relapse; consider temporary benzodiazepines for severe insomnia or agitation.
Special populations
Hepatic impairment: start 25 mg/day and titrate by 25-50 mg/day; consider IR formulation because lowest XR strength is 50 mg.
Renal impairment: no dosage adjustment is required, but monitor for accumulation of inactive metabolites in severe disease.
Geriatric patients: start 25 mg/day, increase slowly; there is increased risk of orthostatic hypotension and falls.
Pregnancy: limited human data; third-trimester exposure has been associated with neonatal EPS or withdrawal; weigh maternal benefit against fetal risk.
Common adverse effects
Very common: somnolence, dizziness, dry mouth, constipation, weight gain.
Metabolic events include dyslipidemia and hyperglycemia; monitor for diabetic ketoacidosis in susceptible patients.
Dose-dependent QT prolongation is generally modest but clinically relevant when combined with other QT-prolonging agents.
References
- SEROQUEL XR (quetiapine) prescribing information — DailyMed / H2-Pharma (2025)
- CANMAT and ISBD 2018 guidelines for the management of patients with bipolar disorder — Bipolar Disorders (2018) DOI: 10.1111/bdi.12647
- The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020) DOI: 10.1176/appi.books.9780890424841Guidelineschizophreniaclinical
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.