Aripiprazole

Indications

• Schizophrenia in adults and adolescents ages 13-17, and acute manic or mixed episodes of bipolar I as monotherapy or adjunct to lithium or valproate from age 10 upward.
• Adjunctive treatment of major depressive disorder in adults with inadequate response to an antidepressant, usually effective at 2-15 mg/day.
• Irritability associated with autistic disorder in children ages 6-17, and Tourette's disorder in patients ages 6-18.
• Maintenance treatment of bipolar I disorder in adults, with long-acting injectable forms approved for schizophrenia and bipolar I maintenance.
• Off-label augmentation for obsessive-compulsive disorder, and off-label use to reverse antipsychotic-induced hyperprolactinemia while continuing the offending agent.

Mechanism of action

• Partial agonist at dopamine D2 and D3 receptors, acting as a functional antagonist where dopamine tone is high and an agonist where it is low.
• Partial agonism at serotonin 5-HT1A receptors contributes to anxiolytic and antidepressant effect and blunts extrapyramidal liability.
• Potent 5-HT2A antagonism supports activity against negative and affective symptoms and further reduces motor side effects.
• Weak histamine H1 and muscarinic blockade explains the low sedation, low weight gain, and minimal anticholinergic burden seen in practice.
• D2 partial agonism lowers prolactin below baseline rather than raising it, and also drives the characteristic early akathisia and activation.

Pharmacokinetics

• Oral bioavailability is about 87 percent and absorption is not clinically affected by food, although a high-fat meal delays the peak.
• Metabolized by CYP2D6 and CYP3A4 to dehydro-aripiprazole, an active metabolite that carries roughly 40 percent of systemic exposure.
• Terminal half-life is about 75 hours, rising to about 94 hours in CYP2D6 poor metabolizers, so steady state takes roughly two weeks.
• The long half-life makes an occasional missed dose forgiving, but also means every dose change needs 10-14 days before it can be judged.
• Not a clinically meaningful CYP inhibitor or inducer, and renal excretion of unchanged drug is under 1 percent of the dose.

Dosing

• Schizophrenia in adults: start 10-15 mg/day PO once daily with a usual target of 10-15 mg/day and a labeled maximum of 30 mg/day.
• Bipolar mania: start 15 mg/day as monotherapy or 10-15 mg/day as adjunct; pediatric patients start at 2 mg/day with slow weekly steps.
• MDD augmentation: start 2-5 mg/day and titrate by 5 mg at intervals of one week or more, to a labeled maximum of 15 mg/day.
• Halve the dose with a strong CYP3A4 or CYP2D6 inhibitor, reduce to a quarter with both, and double it with a strong CYP3A4 inducer.
• Long-acting injectables include Abilify Maintena 300-400 mg IM monthly, Abilify Asimtufii 720-960 mg IM every 2 months, and Aristada every 4-8 weeks.
• No adjustment is needed for renal or hepatic impairment, and the long half-life provides a self-taper so abrupt stopping is usually tolerated.

Adverse effects

• Akathisia is the signature adverse effect at roughly 10-25 percent, dose related, and frequently misread as worsening anxiety or agitation.
• Insomnia, headache, nausea, and inner restlessness are common early, concentrated in the first two weeks and often improving with dose reduction.
• Metabolic burden is among the lowest in the class, with mean weight gain usually under 2 kg and little change in fasting glucose or lipids.
• Impulse control problems such as pathological gambling, hypersexuality, binge eating, and compulsive shopping are a labeled and reversible risk.
• Tardive dyskinesia and neuroleptic malignant syndrome occur but less often than with high-potency first-generation antipsychotics.
• Prolactin usually falls below baseline, so galactorrhea and amenorrhea are far less common than with risperidone or paliperidone.

Monitoring

• Baseline weight, BMI, waist circumference, blood pressure, fasting glucose or A1c, and a lipid panel, repeated at 12 weeks and then annually.
• Weigh at every visit for the first three months; a gain above 5 percent of body weight should prompt intervention or a switch.
• Assess for akathisia at each early visit, ideally with the Barnes Akathisia Rating Scale, because patients report it as anxiety rather than movement.
• AIMS examination at baseline and every 6-12 months, or every 6 months in patients at elevated risk of tardive dyskinesia.
• Ask directly at each visit about new gambling, spending, eating, or sexual urges, since patients almost never volunteer them.

Interactions

• Strong CYP2D6 inhibitors including fluoxetine, paroxetine, bupropion, and quinidine raise exposure and call for a 50 percent dose reduction.
• Strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, and ritonavir likewise require halving the aripiprazole dose.
• Carbamazepine and other strong CYP3A4 inducers can halve exposure; double the dose, then retitrate downward when the inducer stops.
• Additive sedation and orthostasis with benzodiazepines, opioids, and alcohol; QT effect is negligible relative to ziprasidone or iloperidone.
• Contraindicated only in known hypersensitivity, and best avoided as an antipsychotic choice in Parkinson disease psychosis.

Special populations

• Third-trimester exposure risks neonatal extrapyramidal signs and withdrawal; enroll exposed pregnancies in the National Pregnancy Registry for Atypical Antipsychotics.
• Relative infant dose in lactation is low, but monitor the breastfed infant for sedation and poor feeding, especially in preterm infants.
• Approved from age 6 for autism-related irritability; children require slower titration and show more sedation and weight gain than adults.
• In older adults start at 2-5 mg/day, watch for falls and sedation, and remember the drug is not approved for dementia-related psychosis.
• No dose adjustment for renal impairment including hemodialysis, or for mild to severe hepatic impairment.

Clinical pearls

• Akathisia is dose related; lower the dose before adding propranolol or a benzodiazepine.
• Best metabolic profile in the class, so favor it when weight or glucose is the limiting problem.
• A 75-hour half-life means a dose change needs two weeks to judge; do not chase it early.