quetiapine

General Information

Quetiapine (Seroquel/Seroquel XR) is a second-generation antipsychotic approved for schizophrenia, bipolar I acute mania (monotherapy and adjunct), bipolar depression, and maintenance with lithium or divalproex, with both IR and XR tablets broadly available as generics.

Its mechanism blends rapidly dissociating D2 antagonism with strong 5-HT2A/5-HT2C blockade plus H1 and α1 antagonism, explaining its low EPS risk, antidepressant properties, and characteristic sedation and orthostasis.

Clinicians favor quetiapine for its low EPS liability, antidepressant activity in bipolar disorder, and sedating properties, but metabolic burden, orthostatic hypotension, and potential misuse at low doses necessitate close monitoring.

The contrast view and the Quetiapine evidence feed can help weigh metabolic load, sedation, and prolactin risk, alongside the bipolar disorder hub when planning mood disorder regimens.

CATIE data indicate comparable antipsychotic effectiveness but higher discontinuation for weight gain versus some peers—reinforce metabolic surveillance and lifestyle counselling.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Moderate-affinity dopamine D2 antagonism with rapid dissociation delivers antipsychotic efficacy while keeping striatal occupancy below the EPS threshold.

Serotonin 5-HT2A/5-HT2C blockade plus norquetiapine’s norepinephrine transporter inhibition and 5-HT1A partial agonism underpin antidepressant effects; strong H1 and α1 antagonism drives sedation and orthostasis.

• D2/D3 and 5-HT2A/5-HT2C antagonism.
• Norquetiapine: partial 5-HT1A agonist and norepinephrine transporter inhibitor.
• High histamine H1 and adrenergic α1 antagonism; modest muscarinic activity through norquetiapine.

Metabolism and Pharmacokinetics

• Oral bioavailability ~9%; IR Tmax ~1.5 h, XR ~6 h with up to 50% higher exposure when taken with high-fat meals—advise consistent administration relative to food.
• Approximately 83% protein bound; volume of distribution ~10 L/kg.
• Extensively metabolized by CYP3A4 to multiple metabolites including active norquetiapine; CYP2D6 plays a minor role.
• Half-life ~6–7 h for quetiapine and ~12 h for norquetiapine; <1% of a dose is excreted unchanged in urine.

Dosing and Administration

• Schizophrenia (IR): day 1 25 mg BID, titrate to 300–400 mg/day by day 4; maintenance 300–800 mg/day divided BID.
• Schizophrenia (XR): start 300 mg nightly, increase to 600 mg on day 2; adjust to 400–800 mg once nightly with consistent food timing.
• Bipolar I acute mania: titrate to 400–800 mg/day by day 4 (IR divided or XR nightly); combination with lithium/divalproex improves response but heightens sedation.
• Bipolar depression: XR 50 mg day 1, 100 mg day 2, 200 mg day 3, 300 mg nightly thereafter (150 mg for sensitive or older adults).
• Adjunct MDD: XR 150–300 mg nightly after gradual titration; reassess benefit within 4–8 weeks.
• Hepatic impairment or frail/elderly patients: initiate 25 mg/day (IR) or 50 mg every other day (XR) and titrate by 25–50 mg/day with orthostatic monitoring; retitrate if ≥1 week of doses are missed.
• Maximum recommended dose for schizophrenia or acute mania is 800 mg/day; doses beyond this threshold increase metabolic and sedation burden without clear efficacy gains.

Adverse Effects

Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) markedly increase exposure—avoid or reduce to ≤1/6th of the usual dose with intensive monitoring.
• Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) sharply reduce levels—avoid or select an alternative antipsychotic.
• Lithium or divalproex combinations increase sedation, tremor, and weight gain—monitor closely.
• Additive hypotension occurs with antihypertensives and α1 blockers; check blood pressure during titration.
• Avoid grapefruit products and limit alcohol and other CNS depressants to reduce oversedation.

Other Useful Information

• Schedule metabolic monitoring at baseline, 3 months, 6 months, and annually; escalate sooner if weight gain ≥5% or hyperglycemia emerges.
• Educate patients not to crush or chew XR tablets and to take them consistently with or without food.
• Counsel on morning orthostasis and evening sedation; advise gradual position changes, hydration, and consider bedtime dosing when daytime impairment persists.
• Assess for misuse when prescribing low-dose IR for sleep; reinforce appropriate indications.
• Taper gradually to prevent withdrawal insomnia and relapse; restart titration if therapy lapses for ≥1 week.
• Use the compare view to balance metabolic, prolactin, and sedation profiles when selecting or switching SGAs.
• Coordinate bipolar care plans with the bipolar disorder hub to integrate psychotherapy, lab monitoring, and relapse-prevention strategies.
• Consider baseline and periodic eye exams during long-term therapy to address historical cataract concerns.

References

1. SEROQUEL XR prescribing information — DailyMed (2025)
2. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia — The New England Journal of Medicine (2005)
3. Quetiapine Monotherapy IN Bipolar Depression: Randomized, Double Blind Trial — American Journal of Psychiatry (2010)
4. Continuation of quetiapine versus placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144) — Journal of Clinical Psychiatry (2011)
5. Metabolic AND Endocrine Adverse Effects OF Second Generation Antipsychotics: A Systematic Review — CNS Drugs (2011)
6. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020)Guidelineschizophreniaclinical
7. CANMAT and ISBD 2018 guidelines for the management of patients with bipolar disorder — Bipolar Disorders (2018)