Aripiprazole

Approved Indications:

• Schizophrenia
• Adults and adolescents (13–17 years)
• For acute and maintenance treatment
• Bipolar I Disorder
• Acute manic and mixed episodes in adults and pediatric patients (10–17 years)
• Maintenance treatment (adults)
• Major Depressive Disorder (MDD)
• Adjunctive treatment to antidepressants in adults with inadequate response
• Irritability associated with Autistic Disorder
• In pediatric patients aged 6–17 years
• Tourette’s Disorder
• In children and adolescents aged 6–18 years
• Agitation associated with schizophrenia or bipolar mania
• Injectable formulation for adults

Off-Label/Clinically Accepted Uses:

• Borderline Personality Disorder (adjunctive therapy for impulsivity/mood stabilization)
• Delusional Disorder
• Obsessive-Compulsive Disorder (OCD) (augmentation with SSRIs)
• Post-Traumatic Stress Disorder (PTSD) (augmentation strategy)
• Behavioral disturbances in dementia (used cautiously due to risk of cerebrovascular events)
• Tic disorders beyond Tourette's

Schizophrenia:

• Adults: Starting dose: 10–15 mg once daily; effective dose range: 10–30 mg/day
• Adolescents (13–17 years): Start at 2 mg/day, increase to 10 mg/day after 2 days

Bipolar I Disorder (manic/mixed episodes):

• Adults: Start at 15 mg once daily
• Pediatric (10–17 years): Start at 2 mg/day, titrate to target 10 mg/day; max: 30 mg/day

Major Depressive Disorder (adjunct):

• Start at 2–5 mg/day, target dose: 5–10 mg/day; max: 15 mg/day

Irritability in Autism:

• 6–17 years: Start at 2 mg/day, titrate to 5–10 mg/day; max: 15 mg/day

Tourette’s Disorder:

• 6–18 years: Start at 2 mg/day, target dose varies by weight:
• <50 kg: 5–10 mg/day
• ≥50 kg: 10–20 mg/day

Agitation (IM injection):

• Adults: 9.75 mg as a single IM dose; range: 5.25–15 mg

Renal or Hepatic Impairment:

• No dosage adjustment recommended, but use caution in severe impairment.

Elderly:

• Start at lower end of dosage range due to increased sensitivity to side effects, particularly extrapyramidal symptoms.

Administration:

• Oral tablet or solution: with or without food.
• IM injection: for acute agitation, not for chronic use.

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and an antagonist at 5-HT2A receptors. Its D2 partial agonism modulates dopaminergic activity—reducing dopamine in hyperdopaminergic states (e.g., psychosis) and enhancing it when dopamine is low (e.g., depression). This unique activity helps stabilize mood and cognition with a lower risk of extrapyramidal symptoms compared to typical antipsychotics. Its serotonin antagonism contributes to mood stabilization and anxiolytic effects, and the 5-HT1A agonism is thought to promote antidepressant action.

• Absorption: Well-absorbed orally; peak plasma levels at 3–5 hours
• Bioavailability: >87%
• Distribution: Highly protein-bound (>99%, mainly to albumin)
• Metabolism: Extensively metabolized in the liver via CYP2D6 and CYP3A4 pathways to active metabolite dehydro-aripiprazole
• Elimination Half-life:
• Aripiprazole: ~75 hours
• Dehydro-aripiprazole: ~94 hours
• Excretion: Feces (~55%) and urine (~25%)

• Pregnancy: No longer assigned traditional FDA categories; however, risk of extrapyramidal and withdrawal symptoms in neonates when used in the third trimester. Use only if benefits outweigh risks.
• Lactation:
• Excreted into human breast milk
• May cause somnolence, irritability, or poor feeding in breastfed infants
• Consider alternative therapy or avoid breastfeeding during use
• Recommendation: Use only if absolutely necessary during pregnancy or lactation; monitor infant closely.

• Primary Class: Atypical Antipsychotic (Second-Generation Antipsychotic)
• Subclassification: Dopamine D2 Partial Agonist
• Related Categories: Mood Stabilizer, Antidepressant Augmenter

• Known hypersensitivity to aripiprazole or any excipients
• Recent myocardial infarction, unstable cardiovascular disease, or QT prolongation (relative contraindication)
• Use in elderly patients with dementia-related psychosis (increased risk of death)

• Increased mortality in elderly with dementia-related psychosis (Black Box Warning)
• Suicidal thoughts and behaviors: especially in younger patients (closely monitor)
• Neuroleptic Malignant Syndrome (NMS): life-threatening; discontinue if suspected
• Tardive Dyskinesia: may become irreversible; risk increases with long-term use
• Metabolic changes: Hyperglycemia, dyslipidemia, and weight gain (monitor metabolic profile regularly)
• Orthostatic hypotension: Use caution in elderly or volume-depleted patients
• Seizures: Use cautiously in patients with seizure disorders
• Impulse control problems: Pathological gambling, binge eating, compulsive shopping or sexual behaviors reported

Common Side Effects:

• Neurological: Akathisia, restlessness, tremor, insomnia, headache
• Gastrointestinal: Nausea, vomiting, constipation
• Metabolic: Weight gain, increased appetite
• Psychiatric: Anxiety, agitation

Serious Side Effects:

• Extrapyramidal symptoms (dystonia, tardive dyskinesia, parkinsonism)
• Neuroleptic Malignant Syndrome (fever, rigidity, autonomic instability)
• Hyperglycemia and diabetes mellitus
• Seizures
• Suicidal ideation

Rare Side Effects:

• Blood dyscrasias
• QT prolongation
• Hyponatremia

Onset: Most side effects emerge within the first few weeks of therapy; dose-dependent symptoms like akathisia are more common at higher doses.

• CYP3A4 and CYP2D6 Inhibitors (e.g., ketoconazole, fluoxetine): ↑ aripiprazole levels; reduce dose accordingly
• CYP3A4 Inducers (e.g., carbamazepine, rifampin): ↓ aripiprazole levels; increase dose as needed
• Alcohol/CNS depressants: Additive sedation and impairment
• Antihypertensives: May increase risk of hypotension
• QT-prolonging agents: Monitor closely for arrhythmia risk

Avoid abrupt dose changes or additions of strong CYP modulators without clinical monitoring.

• FDA Labeling Update: Continued black box warnings for suicidal thoughts (in young adults) and dementia-related psychosis mortality.
• NICE Guidance: Aripiprazole may be used in early-onset psychosis or treatment-resistant schizophrenia as part of individualized plans.
• AACAP Guidelines: Aripiprazole is included among first-line agents for pediatric bipolar disorder and schizophrenia.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Permitted excursion: 15°C–30°C
• Light Protection: Store away from direct sunlight
• Humidity: Keep in a dry place, tightly closed
• Oral solution: Use within 6 months of opening or before expiry date, whichever is sooner
• Injectables: Store vials at room temperature; do not freeze