Quetiapine

1. Drug Name

• Generic Name: Quetiapine

• Brand Names: Seroquel, Seroquel XR, and others.

2. Drug Classification

• Class: Antipsychotic Agent

• Subclass: Atypical Antipsychotic (Second-Generation Antipsychotic)

3. Mechanism of Action

Quetiapine is an atypical (second-generation) antipsychotic that works by modulating several neurotransmitter systems in the brain. Its primary action involves dopamine D2 receptor antagonism and serotonin 5-HT2A receptor antagonism. The pharmacological effects are as follows:

• Dopamine D2 Antagonism: Quetiapine binds to and blocks the D2 receptors in the mesolimbic and mesocortical regions of the brain, which helps in alleviating psychotic symptoms like delusions and hallucinations.

• Serotonin 5-HT2A Antagonism: The drug also antagonizes serotonin 5-HT2A receptors, which is thought to reduce negative symptoms (e.g., social withdrawal, lack of motivation) and contribute to fewer extrapyramidal symptoms (EPS) than older antipsychotics.

• Alpha-1 Adrenergic Receptor Blockade: This contributes to its sedative effects and can lead to orthostatic hypotension.

• Histamine H1 Receptor Antagonism: This accounts for its sedative and sleep-promoting properties, making quetiapine effective for patients with both psychotic disorders and insomnia.

Quetiapine’s pharmacodynamic profile is thought to be responsible for its broader therapeutic range, addressing not only psychosis but also mood stabilization in bipolar disorder and major depressive disorder (as adjunct therapy).

4. Pharmacokinetics

• Absorption: Quetiapine is well absorbed following oral administration, with bioavailability of approximately 9% due to first-pass metabolism in the liver. The XR formulation offers a slower release and thus more stable plasma levels over time.

• Distribution: Quetiapine is widely distributed, with a volume of distribution (Vd) of around 17 L/kg. It is highly protein-bound (83-91%) in plasma.

• Metabolism: The drug is extensively metabolized in the liver primarily by CYP3A4, producing both active and inactive metabolites. This metabolism can be influenced by inducers (e.g., carbamazepine) or inhibitors (e.g., ketoconazole) of CYP3A4, which may necessitate dose adjustments.

• Excretion: The half-life of quetiapine is approximately 6 hours for the immediate-release formulation and 7 hours for the extended-release formulation. It is predominantly excreted in the urine (about 73%) as metabolites, with a small amount excreted in the feces.

• Special Considerations: In elderly patients or those with hepatic impairment, the metabolism of quetiapine may be slower, necessitating lower starting doses. Renal impairment does not significantly affect quetiapine clearance.

5. Indications

• Primary Indications:

  • Schizophrenia: Quetiapine is used to treat both the acute and maintenance phases of schizophrenia, helping to manage both positive (e.g., hallucinations) and negative symptoms (e.g., anhedonia).

  • Bipolar Disorder: It is approved for the treatment of both manic and depressive episodes in bipolar disorder and is often used for long-term maintenance.

  • Major Depressive Disorder (Adjunctive Therapy): Quetiapine XR is used as an adjunct to antidepressants in the treatment of major depressive disorder (MDD), particularly in patients who do not respond to monotherapy.

• Off-label Uses:

  • Generalized Anxiety Disorder (GAD): Quetiapine may be used off-label for the management of GAD, particularly in refractory cases.

  • Insomnia: Due to its sedative effects, quetiapine may be used off-label for short-term management of insomnia, though its use is controversial in this setting due to the potential for side effects.

6. Dosage and Administration

• Adult Dosing:

  • Schizophrenia (Immediate-Release): The typical starting dose is 25 mg twice daily, with gradual titration to a target dose of 300-400 mg/day after 1–2 weeks.

  • Schizophrenia (Extended-Release): The starting dose is usually 300 mg once daily, titrated up to 400–800 mg/day depending on response and tolerance.

  • Bipolar Disorder (Acute Mania): Start with 50 mg twice daily, gradually increasing to a total dose of 400–800 mg/day.

  • Bipolar Disorder (Depression, Adjunct): Start at 50 mg once daily (XR form), with titration to 150 mg/day as tolerated.

  • Major Depressive Disorder (Adjunctive Therapy): Begin with 50 mg once daily, increasing as necessary to 150 mg/day.

• Pediatric Dosing: Quetiapine is typically used in adolescents (13–17 years) for schizophrenia and bipolar disorder with starting doses and maximum doses adjusted based on weight and clinical response.

• Renal and Hepatic Impairment: In patients with hepatic impairment, dose reduction and gradual titration are recommended. In those with renal impairment, no significant adjustments are required.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to quetiapine or any component of the formulation.

  • Severe hepatic impairment: Use with caution or avoid in patients with cirrhosis or acute liver failure.

• Relative Contraindications:

  • Cardiovascular Disease: Use cautiously in patients with a history of orthostatic hypotension, QT prolongation, or heart failure.

  • Severe Renal Impairment: Although renal dysfunction does not significantly affect its pharmacokinetics, it should still be used with caution in this population.

  • Elderly Patients: The elderly are more susceptible to sedation, orthostatic hypotension, and metabolic side effects like weight gain and dyslipidemia.

8. Warnings and Precautions

• Metabolic Effects: Quetiapine may cause weight gain, hyperglycemia, and dyslipidemia. Long-term use increases the risk of metabolic syndrome and type 2 diabetes, requiring regular monitoring of weight, blood glucose, and lipids.

• Extrapyramidal Symptoms (EPS): While quetiapine has a lower risk of EPS compared to typical antipsychotics, it can still cause dystonia, akathisia, and tardive dyskinesia with long-term use.

• Neuroleptic Malignant Syndrome (NMS): Rare but serious, NMS is characterized by hyperthermia, muscle rigidity, and autonomic dysregulation. Immediate discontinuation of quetiapine is required.

• QT Interval Prolongation: Quetiapine can prolong the QT interval, leading to an increased risk of arrhythmias. It should be used with caution in patients with a history of arrhythmias or electrolyte imbalances.

• Orthostatic Hypotension: Quetiapine can cause significant hypotension, especially at the start of treatment. Caution is advised in elderly patients or those taking antihypertensive medications.

• Suicidal Thoughts: Antipsychotics, including quetiapine, carry a warning for increased risk of suicidal thoughts and behavior, particularly in adolescents and young adults.

9. Adverse Effects

• Common Adverse Effects:

  • Sedation or drowsiness, particularly at higher doses or in the initial stages of treatment.

  • Weight gain and increased appetite.

  • Dizziness and orthostatic hypotension.

  • Dry mouth and constipation due to anticholinergic effects.

• Less Common but Clinically Significant:

  • Extrapyramidal Symptoms (EPS): Includes symptoms like tremors, rigidity, and akathisia.

  • Metabolic Syndrome: Includes hyperglycemia, dyslipidemia, and hypertension.

  • QT Prolongation: May increase the risk of arrhythmias, especially if combined with other drugs that prolong the QT interval.

• Serious Adverse Effects:

  • Neuroleptic Malignant Syndrome (NMS): A rare, life-threatening condition with symptoms like fever, muscle rigidity, and autonomic instability.

  • Agranulocytosis or blood dyscrasias (rare, but serious).

  • Severe hypersensitivity reactions, including angioedema and rash.

10. Drug Interactions

• Major Drug Interactions:

  • CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): These can significantly increase quetiapine’s plasma concentration, requiring dose adjustments.

  • CYP3A4 Inducers (e.g., carbamazepine, phenytoin): These can reduce quetiapine’s plasma concentration, necessitating higher doses.

  • Other CNS Depressants (e.g., alcohol, benzodiazepines): The sedative effects of quetiapine are potentiated, increasing the risk of CNS depression and respiratory depression.

• Food-Drug Interactions: Quetiapine’s absorption is not significantly affected by food, but it should be taken consistently with or without food to maintain stable absorption.

• Laboratory Interactions: Quetiapine may slightly affect blood glucose levels, which could potentially interfere with the interpretation of lab results in diabetic patients.

11. Clinical Pharmacology

• Pharmacodynamics: Quetiapine's therapeutic effects stem from its dopamine and serotonin receptor antagonism, which helps to balance neurotransmitter signaling in the brain, reducing symptoms of psychosis and mood disorders.

• Pharmacological Effects: In addition to its antipsychotic and mood-stabilizing effects, quetiapine has sedative and anti-anxiety properties, making it useful in managing insomnia and agitation in certain psychiatric disorders.

12. Special Populations

• Pregnancy: Category C. Use should be avoided unless clearly necessary, and potential risks should be weighed against the benefits.

• Lactation: Quetiapine is excreted in breast milk in small amounts. Caution is recommended, especially in neonates or infants.

• Geriatric Use: Older adults are more prone to orthostatic hypotension and sedation, requiring dose reductions.

• Renal and Hepatic Impairment: In patients with hepatic impairment, starting with a lower dose is advised due to decreased clearance. Quetiapine can be used in renal impairment without major dose adjustments, but careful monitoring is recommended.

13. Therapeutic Uses

• Schizophrenia: Quetiapine is used for both the treatment of acute episodes and maintenance therapy, particularly effective for patients with both positive and negative symptoms.

• Bipolar Disorder: Effective for acute mania and depression and as maintenance therapy.

• Adjunct for Major Depressive Disorder: Quetiapine XR is used in combination with other antidepressants for patients with treatment-resistant depression.

14. Monitoring and Follow-Up

• Blood Pressure: Regular monitoring for orthostatic hypotension.

• Weight and Lipid Profile: Monitor for weight gain, hyperglycemia, and dyslipidemia.

• CBC and Liver Function Tests: Periodic monitoring for hematological abnormalities and liver toxicity.

• QT Interval: Ensure that the QT interval is monitored, especially if the patient is on other QT-prolonging drugs.

15. Overdose Management

• Symptoms of Overdose: Include sedation, hypotension, tachycardia, respiratory depression, and QT prolongation.

• Treatment: Overdose is managed with supportive care, including respiratory support and monitoring. There is no specific antidote, but activated charcoal can be used if the overdose occurred within 1–2 hours of ingestion.

16. Patient Counseling Information

• Key Points:

  • Take quetiapine as prescribed, even if symptoms improve, and do not stop it abruptly.

  • Avoid alcohol and other CNS depressants while on this medication.

  • Be aware of side effects such as sedation, weight gain, and changes in mood or behavior.

  • Report any signs of movement disorders (e.g., tremors, restlessness) or extreme changes in weight.

  • Seek medical attention immediately if experiencing symptoms of NMS, severe dizziness, or difficult breathing.