Aripiprazole

Mechanism

Chemical and Commercial Profile

Common trade names: Abilify, Aristada, Ilimit.
Group: Atypical antipsychotic, derived from quinolinones.

Mechanism of Action

Aripiprazole revolutionized antipsychotic therapy by acting as a partial agonist of the dopamine D₂ receptor (K_i ≈ 0.3 nM) with high intrinsic affinity. This gives it a dual modulatory activity:

Dependent Effect of Basal Dopaminergic Tone \text{Functional Activity} = \begin{cases} \text{Functional antagonist} & \text{in areas with excess Dopamine (mesolimbic pathway)} \\ \text{Functional agonist} & \text{in areas with Dopamine deficiency (mesocortical pathway)} \end{cases}

Additionally it acts as:

• Partial agonist of serotonin 5-HT_1A receptors.
• Pure antagonist of serotonergic 5-HT_2A receptors (K_i ≈ 3 nM).
• Weak affinity for H₁ histaminergic, M₁ muscarinic and α₁ adrenergic receptors, explaining the minimal weight gain and lack of severe sedation of this compound.

Pharmacokinetics

Pharmacokinetics

• Absorption: Excellent oral absorption without dietary interferences; bioavailability of 87%. C_max in 3 to 5 hours.
• Metabolism: Hepatic catalyzed mainly by the isoenzymes CYP2D6 and CYP3A4. The active metabolite dehydro-aripiprazole has similar affinity to the parent compound and constitutes ~40% of the active circulating profile.
• Excretion: Fecal (60%) and renal (25%).
• Half-life (t_1/2): Aripiprazole parent: 75 hours. Dehydro-aripiprazole: 94 hours. It allows stable daily dosing and reduces the immediate clinical impact of therapeutic forgetfulness.

Indicators and dose

Indications

• Schizophrenia in adults and adolescents over 15 years of age.
• Moderate to severe acute manic episodes in bipolar type I disorder.
• Adjuvant treatment in resistant Major Depressive Disorder (MDD), enhancing the response to treatment with SSRIs/SNRIs.
• Irritability and aggressiveness associated with autism spectrum disorder (ASD) in children over 6 years of age.

Dosage and Settings

• Schizophrenia and Mania: Start with 10 mg to 15 mg/day in a single morning dose (due to its activating profile); maximum maintenance dose: 30 mg/day.
• Adjuvant in resistant depression: Extremely low doses: Start with 2 mg to 5 mg/day; maximum adjuvant dose: 15 mg/day.
• Renal / Hepatic Failure: It does not require special dose adjustments in chronic kidney disease or mild to moderate liver disease. In severe decompensated cirrhosis, administer with caution without exceeding 15 mg/day.

Security

Contraindications

• Hypersensitivity to the active ingredient or excipients.
• Fragile geriatric populations with psychosis associated with vascular dementia due to increased cardiovascular risk.

Adverse Effects (ADR)

Cardinal Metabolic Safety

Unlike clozapine, risperidone or olanzapine, aripiprazole has a negligible affinity for H₁ and 5-HT_2C receptors. As a relevant clinical consequence, it shows rates of weight gain, autonomic dyslipidemia, glucose intolerance and prolongation of the QTc interval practically equivalent to placebo. Of choice in patients with previous metabolic syndrome or high cardiovascular risk.

• Akathisia and initial paradoxical agitation: It is the most characteristic adverse effect in the first weeks of treatment, derived from partial central dopaminergic agonism. It is controlled with propranolol or temporary dose reduction.
• Impulse control disorders: Rare cases of new-onset hypersexuality, pathological gambling (pathological gambling), and compulsive buying have been documented after initiation of aripiprazole due to partial stimulation of mesolimbic D₃ receptors. Reversible after discontinuing the drug.
• Nausea and mild initial headache: Self-limited.

Clinical Interactions

• Enzyme inhibitors: In poor CYP2D6 metabolizers or in concomitant treatment with paroxetine or ketoconazole, the dose of aripiprazole should be reduced by half.
• CYP3A4 inducers: Rifampicin or carbamazepine drastically reduce aripiprazole levels, requiring doubling the usual dose.

Pregnancy and Breastfeeding

FDA Category: C. Use only if the potential benefit outweighs the direct fetal risk. Breastfeeding: Not recommended. It is excreted in milk in significant concentrations and its long half-life can favor accumulation in the infant with risk of lethargy.