What is aripiprazole (mechanism of action, approved indications, dosing, administration, side effects, and contraindications)?

What is Aripiprazole

Aripiprazole is a "third-generation" atypical antipsychotic medication that functions as a dopamine D2 receptor partial agonist, distinguishing it from traditional dopamine antagonists, and is FDA-approved primarily for schizophrenia, bipolar disorder, and adjunctive treatment of major depressive disorder. 1

Mechanism of Action

Aripiprazole's unique pharmacological profile centers on its partial agonist activity rather than pure antagonism:

• Dopamine D2 and D3 receptors: Acts as a partial agonist with high affinity, providing stabilization rather than blockade 2, 3
• Serotonin 5-HT1A receptors: Demonstrates partial agonist activity, which contributes to efficacy for both positive and negative symptoms 1, 2
• Serotonin 5-HT2A receptors: Functions as an antagonist 2, 3
• Active metabolite: Dehydro-aripiprazole has similar D2 receptor affinity and contributes to the overall pharmacological activity 2

The combination of D2 partial agonism and 5-HT1A partial agonism explains aripiprazole's efficacy for positive and negative symptoms in schizophrenia 1.

FDA-Approved Indications

Based on the evidence provided, aripiprazole is indicated for:

• Schizophrenia and schizoaffective disorder: Primary indication with demonstrated efficacy in acute relapse and long-term maintenance 2, 4, 3
• Augmentation therapy: Used to augment clozapine in treatment-resistant schizophrenia, showing the lowest risk of psychiatric hospitalization (HR 0.86,95% CI 0.79–0.94) 5
• Hyperprolactinemia management: Can be used as adjunctive low-dose therapy or as a switch option for antipsychotic-induced hyperprolactinemia 6

Dosing and Administration

Standard Dosing for Schizophrenia

• Initial and maintenance dose: 10-15 mg once daily is effective and well tolerated 2
• Maximum studied dose: 30 mg/day, though no additional therapeutic benefit was observed at higher-than-recommended dosages (20-30 mg/day) compared to 10-15 mg/day 2
• Titration: Not necessary; the drug is effective in the first few weeks of treatment 2
• Time to steady state: 14 days, with 4-fold accumulation from day 1 to day 14 2
• Elimination half-life: Approximately 75 hours 2

Augmentation Dosing

• Clozapine augmentation: 5-15 mg/day for persistent symptoms after optimizing clozapine to plasma levels ≥350 ng/mL 5
• Hyperprolactinemia: Low-dose aripiprazole as adjunctive therapy 6

Dosage Adjustments

• CYP2D6 and CYP3A4 inhibitors: Reduce aripiprazole dose when coadministered with these inhibitors 2
• CYP3A4 inducers: Increase aripiprazole dose when coadministered with these inducers 2
• Body weight consideration: Obese patients may require weight-based dosing adjustments (mean 0.20 ± 0.09 mg/kg body weight) 7

Side Effects and Tolerability Profile

Common Adverse Events

The most frequent treatment-emergent adverse events include:

• Insomnia and anxiety 2
• Headache and agitation (in short-term trials) 2
• Akathisia (in long-term trials) 2
• Behavioral activation or nausea (15.5% incidence, three times more likely in women) 7

Favorable Metabolic Profile

Aripiprazole demonstrates significant advantages over other atypicals:

• Low propensity for weight gain: Placebo-level incidence of clinically significant weight gain 2, 3
• No hyperprolactinemia: Mean prolactin levels actually decreased with aripiprazole, unlike risperidone which showed 5-fold increases 3
• No QTc prolongation: No clinically relevant differences from placebo 2, 3
• Minimal diabetes/dyslipidemia risk: No clinically relevant changes in glucose or lipid parameters 2

Extrapyramidal Symptoms (EPS)

• Placebo-level EPS incidence: The drug was associated with a placebo-level incidence of EPS and EPS-related adverse events 2
• Significantly lower EPS than haloperidol: In 52-week trials, aripiprazole showed significantly lower scores on all EPS assessments (p<0.001) 4
• Tardive dyskinesia: Only 0.2% incidence, similar to placebo 2

Important Caveat: Paradoxical Activation

Aripiprazole may cause paradoxical activation or agitation in some patients due to its partial agonist properties, particularly documented in PTSD nightmare treatment studies 1. This is a critical consideration when selecting aripiprazole over more sedating alternatives.

Contraindications and Monitoring

Pre-Treatment Assessment

Before initiating aripiprazole, obtain:

• BMI, waist circumference, blood pressure 6
• HbA1c, fasting glucose, lipids 6
• Prolactin, liver function tests, urea and electrolytes, full blood count 6
• Electrocardiogram 6

Monitoring Schedule

• Weeks 1-6: Check BMI, waist circumference, and blood pressure weekly 6
• Week 4: Re-check fasting glucose 6
• Month 3: Repeat all baseline measures 6
• Annually thereafter: Continue monitoring all parameters 6

Clinical Efficacy

Acute Treatment

• Onset of action: Significant separation from placebo occurs at week 1 for PANSS total and positive scores 3
• Negative symptoms: Separation from placebo for PANSS negative scores also occurs at week 1 3
• Comparable to risperidone: Both aripiprazole and risperidone were significantly better than placebo on all efficacy measures 3

Long-Term Maintenance

• 52-week efficacy: 77% of aripiprazole recipients maintained response versus 73% of haloperidol recipients 2
• Superior to haloperidol: Significantly greater improvements for PANSS negative subscale scores and MADRS total score (p<0.05) 4
• Time to discontinuation: Significantly greater with aripiprazole than haloperidol for any reason, adverse events, or lack of efficacy (p=0.0001) 4

Treatment-Resistant Schizophrenia

For clozapine-resistant or clozapine-intolerant patients, aripiprazole augmentation improves negative symptoms (standardized mean difference −0.41,95% CI −0.79 to −0.03, p=0.036) 5. First-episode patients show even better outcomes with clozapine-aripiprazole combination (HR 0.78,95% CI 0.63–0.96) 5.

Pharmacokinetics

• Bioavailability: 87% oral bioavailability 2
• Time to peak: 3 hours following multiple-dose administration 2
• Protein binding: >99% bound to plasma protein 2
• Metabolism: Primarily hepatic via CYP3A4 and CYP2D6 to dehydro-aripiprazole 2
• Distribution: Extensive extravascular distribution 2

Clinical Positioning

Aripiprazole should be considered as a first-line option when metabolic side effects are a primary concern, given its superior metabolic profile compared to olanzapine and other atypicals 1. For treatment-resistant schizophrenia, optimize clozapine monotherapy first (plasma level ≥350 ng/mL), then augment with aripiprazole 5-15 mg/day if partial response or metabolic concerns arise 5. When managing antipsychotic-induced hyperprolactinemia, switching to aripiprazole or adding low-dose aripiprazole as adjunctive therapy are both viable strategies 6.