Aripiprazole
1. Drug Name
Generic Name: Aripiprazole
Brand Names: Abilify, Abilify Maintena, Aristada, Abilify MyCite (digital pill), among others.
2. Drug Classification
Class: Atypical Antipsychotic
Subclass: Dopamine System Stabilizer (DSS)
3. Mechanism of Action
Aripiprazole is an atypical antipsychotic with a unique mechanism of action. It functions primarily as a partial agonist at dopamine D2 receptors, meaning it can both stimulate and block dopamine receptors depending on the surrounding dopamine levels, which is why it is often referred to as a dopamine system stabilizer (DSS).
It also acts as a serotonin (5-HT1A) partial agonist, which contributes to its antipsychotic and antidepressant effects.
Additionally, Aripiprazole is an antagonist at 5-HT2A receptors, which is a typical action for atypical antipsychotics and is thought to improve the drug's side effect profile, particularly in terms of lessening the likelihood of extrapyramidal symptoms (EPS).
The drug's actions on various neurotransmitter systems help balance dopamine activity in the brain, reducing psychotic symptoms while minimizing side effects such as sedation and weight gain that are common with other antipsychotics.
4. Pharmacokinetics
Absorption: Aripiprazole is well absorbed after oral administration with a bioavailability of approximately 87%. Its absorption is not significantly affected by food. However, the oral solution has higher bioavailability compared to tablets.
Distribution:
Volume of distribution (Vd): Approximately 4.9 L/kg.
It is highly protein-bound (about 99%), primarily to albumin.
Metabolism: Aripiprazole is extensively metabolized in the liver via the CYP450 enzyme system, predominantly by CYP3A4 and CYP2D6. Its active metabolite, dehydro-aripiprazole, also contributes to its therapeutic effect.
Excretion:
The half-life (t½) of aripiprazole is approximately 75 hours, with its active metabolite having a similar half-life.
It is primarily excreted in the urine (approximately 60%), with a small amount excreted in the feces.
Special Considerations:
Patients with liver dysfunction may have prolonged clearance, and dose reduction may be necessary.
Renal impairment does not require specific dosage adjustments, but caution should be exercised.
5. Indications
Primary Indications:
Schizophrenia: Approved for the treatment of schizophrenia in both adult and pediatric populations (ages 13-17).
Bipolar I Disorder: Used for the acute treatment of manic and mixed episodes associated with bipolar I disorder, and as maintenance therapy.
Major Depressive Disorder (MDD): Used as an adjunctive treatment in combination with antidepressants for MDD.
Tourette Syndrome: Used to treat symptoms associated with Tourette's disorder.
Off-label Uses:
Autism Spectrum Disorder (for irritability in children).
Anxiety Disorders (sometimes prescribed when other treatments fail).
Psychotic Symptoms in Dementia (though not FDA-approved for this indication due to risks of mortality in elderly patients).
Special Populations:
Aripiprazole is beneficial in pediatric patients (ages 13-17) with schizophrenia or bipolar disorder, and in children (6-17 years) with Tourette syndrome.
6. Dosage and Administration
Adult Dosing:
Schizophrenia: Initial dose of 10-15 mg/day, with a maintenance dose typically between 10-30 mg/day.
Bipolar Disorder: Initial dose of 15 mg/day, titrated to the desired effect.
MDD (adjunct): Start with 2-5 mg/day, increasing gradually to 10 mg/day if needed.
Pediatric Dosing:
Schizophrenia: For ages 13-17 years, start with 10 mg/day.
Bipolar Disorder (Mania): For ages 10-17 years, begin with 10 mg/day, titrating up if needed.
Route of Administration:
Oral tablets, oral solution, and intramuscular (IM) formulations (for acute psychotic episodes).
Dosing Adjustments:
Adjustments may be needed for those with hepatic impairment (e.g., reduce dose or titrate slowly).
7. Contraindications
Absolute Contraindications:
Known hypersensitivity to aripiprazole or any of its components.
Relative Contraindications:
Use in patients with a history of severe cardiovascular disease (e.g., arrhythmias) should be done with caution.
Elderly patients with dementia-related psychosis due to increased risk of mortality.
8. Warnings and Precautions
Black Box Warning:
Increased risk of mortality in elderly patients with dementia-related psychosis (due to cardiovascular or infectious causes).
Suicidal thoughts and behaviors: Monitor closely for worsening depression, suicidality, or unusual changes in behavior, especially in children, adolescents, and young adults.
Special Warnings:
Tardive dyskinesia (TD): Although rare, this movement disorder is a potential side effect of prolonged use.
Metabolic Effects: Risk of weight gain, diabetes, and hyperlipidemia, although it is generally considered to have a lower risk compared to other atypical antipsychotics.
Monitoring:
Regular monitoring of weight, glucose levels, and lipid profile.
QT interval: Electrocardiogram (ECG) monitoring is recommended, especially in patients with preexisting heart conditions.
9. Adverse Effects
Common Adverse Effects:
Insomnia, anxiety, akathisia, sedation, headache, dizziness.
Less Common but Clinically Significant:
Extrapyramidal symptoms (EPS): Includes tremors, rigidity, and bradykinesia, though less common than with typical antipsychotics.
Metabolic changes: Weight gain, increased blood glucose, and cholesterol.
Rare/Serious:
Neuroleptic malignant syndrome (NMS): Characterized by hyperthermia, muscle rigidity, altered mental status, and autonomic dysregulation.
Tardive dyskinesia: Irreversible movement disorder.
Severe allergic reactions: Such as angioedema or anaphylaxis.
10. Drug Interactions
Major Drug Interactions:
CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may increase aripiprazole levels.
CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) can also increase levels of aripiprazole.
Dopamine antagonists (e.g., other antipsychotics) may enhance adverse effects.
Food-Drug Interactions:
Food does not significantly affect the absorption of oral aripiprazole.
Lab Test Interactions:
May increase prolactin levels in some patients, though not as commonly as other antipsychotics.
11. Clinical Pharmacology
Aripiprazole exerts antipsychotic effects through its partial agonist action at dopamine and serotonin receptors, stabilizing neurotransmitter activity in areas of the brain responsible for mood, cognition, and perception.
The drug has a low propensity to cause sedation or weight gain due to its unique receptor profile compared to other atypical antipsychotics.
12. Special Populations
Pregnancy: Category C. Use only if the potential benefit justifies the potential risk to the fetus. Limited human data available.
Lactation: Present in breast milk in low amounts; caution is advised, and breastfeeding should be discontinued if possible.
Pediatrics: Safe and effective for use in children ≥6 years for certain indications like Tourette syndrome and schizophrenia.
Geriatrics: Use with caution in elderly patients, especially those with dementia-related psychosis.
Renal and Hepatic Impairment: Dose adjustments may be necessary for hepatic impairment, but no adjustment is required for mild renal impairment.
13. Therapeutic Uses
First-Line Indications:
Schizophrenia, bipolar disorder (mania), adjunctive therapy for MDD.
Second-Line Indications:
Off-label use for irritability in autism and Tourette syndrome.
Clinical trials have demonstrated its efficacy in controlling both positive and negative symptoms of schizophrenia, as well as reducing manic symptoms in bipolar disorder.
14. Monitoring and Follow-Up
Before treatment: Baseline assessment of weight, glucose, lipid profile, and ECG.
During treatment: Regular monitoring of metabolic parameters, especially in the long term.
Therapeutic levels: No routine monitoring for drug levels is required, but response to treatment should be evaluated clinically.
15. Overdose Management
Symptoms of Overdose: Drowsiness, agitation, aggression, confusion, tachycardia, hypotension, and extrapyramidal symptoms.
Treatment Protocol:
Activated charcoal if within an hour of ingestion.
Supportive care, including IV fluids and cardiovascular monitoring.
Antidote: No specific antidote. Symptomatic treatment is required.
16. Patient Counseling Information
Key Points:
Take aripiprazole as prescribed, with or without food.
Avoid alcohol and limit activities that require alertness until you know how the drug affects you.
Notify the doctor if you experience unusual movements, tremors, or uncontrollable urges to move.
Signs for Immediate Medical Attention:
Severe dizziness, fainting, heart palpitations, difficulty breathing, or unusual thoughts.