Aripiprazole - Drug Monograph

Introduction

Aripiprazole is an atypical antipsychotic medication approved by the FDA in 2002. It represents a unique class of psychotropic agents known as dopamine partial agonists, offering a distinct mechanism of action compared to other antipsychotics. Aripiprazole is widely used in the treatment of various psychiatric conditions including schizophrenia, bipolar disorder, and as adjunctive treatment for major depressive disorder.

Mechanism of Action

Aripiprazole exerts its therapeutic effects through a novel mechanism as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptors. This unique pharmacological profile allows it to modulate dopaminergic and serotonergic neurotransmission rather than completely blocking receptors. In areas with excessive dopamine activity, it acts as an antagonist, while in areas with reduced dopamine activity, it functions as an agonist, creating a stabilizing effect on dopamine pathways.

Indications

• Treatment of schizophrenia in adults and adolescents (13-17 years)
• Acute and maintenance treatment of bipolar I disorder (monotherapy and adjunctive) in adults and children (10-17 years)
• Adjunctive treatment of major depressive disorder in adults
• Irritability associated with autistic disorder in children (6-17 years)
• Treatment of Tourette's disorder in children (6-18 years)

Dosage and Administration

• Schizophrenia: Initial dose 10-15 mg daily, target dose 10-30 mg daily
• Bipolar mania: Initial dose 15-30 mg daily, target dose 15-30 mg daily
• Adjunctive MDD: Initial dose 2-5 mg daily, target dose 2-15 mg daily

• Hepatic impairment: No dosage adjustment required
• Renal impairment: No dosage adjustment required
• Elderly: Consider lower starting doses (2-5 mg daily)
• CYP2D6 poor metabolizers: Reduce dose by 50%
• When used with strong CYP3A4 inhibitors: Reduce dose by 50%
• When used with strong CYP2D6 inhibitors: Reduce dose by 50%

Available formulations: tablets, orally disintegrating tablets, oral solution, and intramuscular injection (for acute agitation)

Pharmacokinetics

• Absorption: Well absorbed with peak plasma concentrations occurring within 3-5 hours. Bioavailability is 87%
• Distribution: Extensive tissue distribution with volume of distribution of 4.9 L/kg. 99% protein-bound primarily to albumin
• Metabolism: Extensive hepatic metabolism primarily via CYP3A4 and CYP2D6 enzymes. Active metabolite dehydro-aripiprazole has similar pharmacological activity
• Elimination: Mean elimination half-life is 75 hours (aripiprazole) and 94 hours (dehydro-aripiprazole). Excretion primarily fecal (55%) and renal (25%)

Contraindications

• Hypersensitivity to aripiprazole or any component of the formulation
• Patients with known history of neuroleptic malignant syndrome
• Patients with dementia-related psychosis (increased mortality risk)

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis
• Cerebrovascular adverse events including stroke in elderly patients with dementia
• Neuroleptic malignant syndrome (NMS): Monitor for hyperpyrexia, muscle rigidity, autonomic instability
• Tardive dyskinesia: Monitor for involuntary movements, especially in long-term treatment
• Metabolic changes: Monitor for weight gain, hyperglycemia/diabetes mellitus, dyslipidemia
• Hyperprolactinemia: May cause elevation in prolactin levels
• Orthostatic hypotension: May occur due to alpha-1 adrenergic receptor blockade
• Seizures: Use cautiously in patients with seizure disorders
• Dysphagia: Esophageal dysmotility and aspiration risk
• Suicidal thoughts and behaviors: Monitor particularly in children and young adults

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase aripiprazole exposure → reduce aripiprazole dose by 50%
• Strong CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine): Increase aripiprazole exposure → reduce aripiprazole dose by 50%
• CYP3A4 inducers (carbamazepine, rifampin): Decrease aripiprazole exposure → double aripiprazole dose
• Antihypertensive agents: Enhanced hypotensive effects
• CNS depressants: Additive sedative effects

Adverse Effects

• Akathisia (13%)
• Sedation (8-12%)
• Headache (12-27%)
• Insomnia (8-24%)
• Nausea (10-15%)
• Constipation (6-13%)
• Anxiety (6-17%)

• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Seizures
• Orthostatic hypotension
• Hyperglycemia/diabetes mellitus
• Suicidal ideation
• Leukopenia/neutropenia

Monitoring Parameters

• Baseline:

- Weight, height (pediatrics), BMI - Blood pressure (sitting and standing) - Fasting blood glucose and HbA1c - Lipid profile - CBC with differential - Prolactin level - Assessment for movement disorders (AIMS scale)

• Ongoing:

- Weight and BMI at 4, 8, and 12 weeks, then quarterly - Blood pressure regularly - Glucose and lipids at 12 weeks, then annually - Regular AIMS assessments (every 6 months) - Mental status and symptom assessment - Monitoring for extrapyramidal symptoms

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• May cause dizziness or drowsiness - use caution when driving or operating machinery
• Avoid alcohol consumption during treatment
• Rise slowly from sitting or lying position to prevent dizziness
• Report any unusual movements, muscle stiffness, or fever immediately
• Monitor for weight gain and maintain healthy diet and exercise
• Inform all healthcare providers about aripiprazole use
• Use effective contraception as aripiprazole may cause harm to unborn babies
• Store medication properly and keep out of reach of children

References

1. FDA Prescribing Information: Abilify (aripiprazole) 2. Kane JM, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002 3. Keck PE, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder. J Clin Psychiatry. 2003 4. Marder SR, et al. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003 5. Berman RM, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder. J Clin Psychopharmacol. 2007 6. Stahl SM. Dopamine system stabilizers: aripiprazole and the next generation of antipsychotics. J Clin Psychiatry. 2001 7. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia. 2020 8. Clinical Pharmacokinetics of Aripiprazole. Clin Pharmacokinet. 2013