Aripiprazole (Abilify)
SGA • Last reviewed 2025-09-23
General information
Aripiprazole (brand name Abilify) is an atypical second-generation antipsychotic approved in the United States for schizophrenia (adults and adolescents ≥13 years), acute manic or mixed episodes associated with bipolar I disorder (monotherapy or adjunct to lithium/valproate in adults and pediatric patients ≥10 years), adjunctive treatment of major depressive disorder in adults, irritability associated with autistic disorder (ages 6–17), and Tourette disorder (ages 6–18). Oral generics have been available since 2015. Long-acting injectable formulations (aripiprazole monohydrate monthly and aripiprazole lauroxil every 4–8 weeks) are available separately and can be considered when adherence support is needed.
Oral dosage forms include tablets (2, 5, 10, 15, 20, 30 mg), orally disintegrating tablets (10, 15 mg), an oral solution (1 mg/mL), and a short-acting intramuscular injection (9.75 mg/mL) for acute agitation. For schizophrenia and bipolar I mania, recommended maintenance is 10–30 mg once daily (target 15 mg/day). Adjunctive therapy in major depressive disorder begins at 2–5 mg/day with titration to 2–15 mg/day. Pediatric irritability in autism is typically 5–15 mg/day, while Tourette disorder dosing ranges 5–20 mg/day depending on weight. Aripiprazole may be taken with or without food. Therapeutic drug monitoring is not routinely recommended, though trough levels of ~150–500 ng/mL may be informative in adherence or interaction assessments.
Aripiprazole exerts partial agonist activity at dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, while acting as an antagonist at serotonin 5-HT2A receptors. This receptor profile stabilizes dopaminergic transmission—damping excess mesolimbic signaling but preserving baseline nigrostriatal tone—resulting in antipsychotic efficacy with relatively low extrapyramidal and prolactin-related effects. Antagonism at adrenergic α1 and histamine H1 receptors contributes to orthostatic hypotension and sedation; minimal muscarinic activity limits anticholinergic adverse effects.
Aripiprazole is metabolized hepatically to an active metabolite, dehydro-aripiprazole, via CYP2D6 and CYP3A4 pathways. After oral dosing, peak concentrations occur 3–5 hours post-dose; bioavailability is ~87% and unaffected by food. The elimination half-life is ~75 hours in CYP2D6 extensive metabolizers (94 hours for dehydro-aripiprazole) and can extend to 146 hours in CYP2D6 poor metabolizers, leading to steady state in about 14 days. Elimination is primarily fecal, with minimal renal clearance.
Dosing & administration
Initiate 10–15 mg once daily for schizophrenia; adjust in 5 mg increments to 10–30 mg/day based on response and tolerability.
Bipolar I mania: start 15 mg once daily (monotherapy) or 10–15 mg/day (adjunct to lithium/valproate); usual range 15–30 mg/day.
Adjunctive major depressive disorder: begin 2–5 mg/day; titrate to 2–15 mg/day per antidepressant response and adverse effects.
Irritability associated with autism (ages 6–17): weight-based titration to 5–15 mg/day.
Tourette disorder (ages 6–18): target 5–20 mg/day depending on weight and tic response.
Dose adjustments are required with strong CYP2D6 or CYP3A4 inhibitors (reduce dose by 50%) and with strong CYP3A4 inducers (avoid combination).
Dose guidance by indication
- Schizophrenia (adults)
- 10–30 mg once daily; start 10–15 mg
- Bipolar I mania (monotherapy)
- 15 mg once daily; max 30 mg
- Bipolar I mania (adjunct)
- 10–15 mg once daily with lithium or valproate
- Adjunctive MDD
- 2–15 mg/day (start 2–5 mg/day)
- Autistic irritability
- 5–15 mg/day (weight-based titration)
- Tourette disorder
- 5–20 mg/day based on patient weight
Mechanism of action
Partial agonism at D2/D3 receptors allows aripiprazole to modulate dopaminergic activity contextually—reducing excessive stimulation while preserving baseline signaling. This underlies antipsychotic efficacy with limited EPS and prolactin elevation.
Partial agonism at 5-HT1A and antagonism at 5-HT2A receptors contribute to antidepressant and anxiolytic properties, while relatively weak H1 and α1 antagonism accounts for modest sedation and orthostasis.
The active metabolite dehydro-aripiprazole provides prolonged receptor occupancy, supporting once-daily dosing despite variable metabolism.
- High-affinity partial agonist at dopamine D2 (Ki 0.34 nM) and D3 receptors.
- Partial agonist at 5-HT1A; antagonist at 5-HT2A/5-HT2B.
- Moderate antagonism at α1-adrenergic and histamine H1 receptors.
- Minimal muscarinic activity (limited anticholinergic effects).
Metabolism & pharmacokinetics
Oral bioavailability is ~87%, with peak plasma levels 3–5 hours after dosing. Distribution is extensive (Vd > 4.9 L/kg) and plasma protein binding is >99%.
Metabolism occurs via CYP2D6 and CYP3A4 to the active dehydro-aripiprazole metabolite. Poor CYP2D6 metabolizers or patients on strong inhibitors exhibit prolonged half-lives and require lower target doses.
Terminal half-life is ~75 hours for aripiprazole and ~94 hours for dehydro-aripiprazole, leading to steady state after ~14 days. Elimination is primarily biliary/fecal; renal clearance is minimal, so dose adjustment for renal impairment is generally unnecessary.
- Time to peak concentration (Tmax)
- 3–5 hours
- Bioavailability
- ~87% (oral)
- Elimination half-life
- ~75 h (parent); ~94 h (dehydro-aripiprazole)
- Steady state
- ≈14 days (longer in CYP2D6 poor metabolizers)
Drug interactions
Strong CYP2D6 or CYP3A4 inhibitors (e.g., fluoxetine, paroxetine, ketoconazole) increase exposure; reduce aripiprazole dose by ~50% while co-administered.
Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) decrease exposure and should generally be avoided; if necessary, double the aripiprazole dose with close monitoring.
Additive CNS depression may occur with alcohol, benzodiazepines, or opioids. Impulse-control disorders have been reported; monitor when combined with dopaminergic agents.
| Mechanism | Agents / factors | Management |
|---|---|---|
| Strong CYP2D6 inhibition | Fluoxetine, paroxetine, quinidine | Reduce aripiprazole dose by 50%; monitor for akathisia, sedation. |
| Strong CYP3A4 inhibition | Ketoconazole, clarithromycin, ritonavir | Reduce dose by 50%; consider monitoring plasma levels if available. |
| Strong CYP3A4 induction | Carbamazepine, rifampin, St. John’s wort | Avoid; if unavoidable, consider doubling dose with clinical monitoring. |
| CNS depressant coadministration | Alcohol, benzodiazepines, opioids | Counsel on sedation and psychomotor impairment. |
Monitoring & safety checks
Weight/BMI and waist circumference
Baseline, 3 months, then annually • Detect metabolic changes (weight gain observed though lower than many SGAs).
Fasting lipids & glucose/A1c
Baseline, 3 months, then annually • Monitor metabolic syndrome risk.
Movement disorder assessment (EPS/akathisia)
Each visit during titration • Akathisia/restlessness are common early adverse effects.
Impulse-control symptom review
Periodically • Rare reports of compulsive behaviors (gambling, binge eating).
Mood and suicidality checks
Each visit • Indicated for mood disorders; monitor for worsening depression or mania.
Advise patients about delayed onset due to long half-life; dose adjustments may take 2+ weeks to show full effect.
Educate on signs of akathisia and impulse-control issues; encourage prompt reporting.
Discontinuation guidance
Aripiprazole can typically be tapered over 1–2 weeks; abrupt discontinuation is seldom associated with severe withdrawal, but gradual reduction helps avoid relapse or rebound agitation.
Because of the long half-life and active metabolite, residual effects may persist for several weeks after discontinuation; monitor clinical status and consider coverage with another antipsychotic if needed.
Special populations
Hepatic impairment: no initial adjustment for mild-to-moderate impairment; use caution and slow titration in severe impairment (limited data).
Renal impairment: no adjustment required (minimal renal clearance).
Pregnancy/Lactation: limited human data; enroll in National Pregnancy Registry for Atypical Antipsychotics. Monitor neonates for extrapyramidal and withdrawal symptoms if exposed in third trimester.
Pediatrics: approved for schizophrenia (≥13), bipolar mania (≥10), autism irritability (6–17), and Tourette disorder (6–18); titrate carefully due to higher akathisia risk.
Key adverse effects
Common: akathisia, anxiety, insomnia, nausea, somnolence, headache, constipation.
Metabolic: generally modest weight gain and metabolic changes compared with other SGAs, but monitoring remains necessary.
Rare but serious: impulse-control disorders, neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, seizures (especially with risk factors).
LAI availability
Clozapine does not have an FDA-approved long-acting injectable formulation. Related LAI options for the treatment class are listed below.
References
- ABILIFY (aripiprazole) Prescribing Information — Otsuka Pharmaceutical Co., Ltd. (2024)
- Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018) DOI: 10.1007/s00213-017-4813-7
- Pharmacokinetics, safety, and tolerability of aripiprazole once-monthly in schizophrenia — Journal of Psychopharmacology (2016) DOI: 10.1177/0269881116666647
- Aripiprazole versus other atypical antipsychotics for schizophrenia — Cochrane Database of Systematic Reviews (2010) DOI: 10.1002/14651858.CD006569.pub3
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.