Mechanism of Action of Aripiprazole (Abilify)

Introduction

Aripiprazole is an atypical antipsychotic used to treat schizophrenia, bipolar disorder, major depressive disorder (as adjunct), irritability in autism, and Tourette’s syndrome. Its unique action as a dopamine D₂ partial agonist, along with effects on serotonin receptors, sets it apart from other agents, providing antipsychotic efficacy with a lower risk of certain side effects.

---

---

Step-by-Step Mechanism of Action

1. Partial agonism at dopamine D₂ receptors
   Acts as a dopamine D₂ receptor partial agonist—modulating dopamine activity by inhibiting excess signaling while providing baseline activation to avoid severe dopamine blockade.
2. Partial agonism at serotonin 5-HT₁A receptors
   Enhances mood and anxiety regulation via 5-HT₁A receptor activation.
3. Antagonism at serotonin 5-HT₂A receptors
   Reduces dopaminergic overstimulation and mitigates extrapyramidal symptoms (EPS).
4. Additional receptor effects
   • Partial agonist at D₃ receptors
   • Antagonist at 5-HT₂C and 5-HT₇ receptors
   • Minimal affinity for histaminergic, muscarinic, and adrenergic receptors—resulting in less sedation, weight gain, and metabolic side effects.
5. Neurotransmission modulation
   Combined receptor actions regulate dopamine and serotonin pathways, improving psychosis, mood, and cognition with reduced adverse profiles.

---

Pharmacokinetic Parameters

Parameter	Value
Route	Oral tablet, or long-acting injectable (IM)
Bioavailability	~87%
Time to Peak (Tmax)	3–5 hours
Protein Binding	~99%
Metabolism	Hepatic via CYP3A4 and CYP2D6
Half-life	75 hours (oral); 30–46 days (LAI)
Excretion	Urine (25%), feces (60%)

---

Clinical Uses

• Schizophrenia
• Acute and maintenance bipolar mania or mixed episodes
• Adjunctive therapy in major depressive disorder
• Irritability in autism
• Tourette’s syndrome

---

Adverse Effects

• Akathisia (most common)
• Nausea, vomiting, constipation
• Headache and insomnia
• Low risk of weight gain, sedation, metabolic syndrome
• Rare: orthostatic hypotension
• Lower risk for EPS compared to typical antipsychotics

---

Comparative Analysis

Agent	D₂ Receptor Action	5‑HT₂A Antagonism	EPS Risk	Metabolic Risk
Aripiprazole	Partial agonist	Yes	Low	Low
Risperidone	Antagonist	Yes	Moderate	Moderate
Olanzapine	Antagonist	Yes	Low	High

---

MCQs

1. Aripiprazole acts at D₂ receptors as a:
   a) Full antagonist b) Full agonist c) Partial agonist d) Inverse agonist
   Answer: c) Partial agonist
2. Its effect on 5-HT₁A receptors is:
   a) Antagonist b) Partial agonist c) Full agonist d) No action
   Answer: b) Partial agonist
3. Aripiprazole’s interaction at 5-HT₂A receptors is:
   a) Agonist b) Partial agonist c) Antagonist d) Inverse agonist
   Answer: c) Antagonist
4. Compared to olanzapine, metabolic risk is:
   a) Higher b) Similar c) Lower d) Unstudied
   Answer: c) Lower
5. Akathisia during treatment is:
   a) Uncommon b) Common c) Never occurs d) Extremely rare
   Answer: b) Common
6. Long-acting injectable half-life is:
   a) 1 day b) 75 hours c) 30–46 days d) 1 year
   Answer: c) 30–46 days
7. Which enzyme primarily metabolizes aripiprazole?
   a) CYP3A4 b) CYP2D6 c) Both CYP3A4 and CYP2D6 d) CYP1A2
   Answer: c) Both CYP3A4 and CYP2D6
8. It has the lowest risk for:
   a) EPS b) Weight gain c) Akathisia d) Orthostatic hypotension
   Answer: b) Weight gain
9. Aripiprazole’s protein binding is approximately:
   a) 50% b) 75% c) 99% d) 100%
   Answer: c) 99%
10. Aripiprazole is NOT indicated for:
    a) Autism irritability b) Major depressive disorder adjunct c) Tourette’s syndrome d) Dementia-related psychosis
    Answer: d) Dementia-related psychosis

---

FAQs

1. Does aripiprazole cause weight gain?
It has a low metabolic risk, with minimal weight gain compared to other antipsychotics.

2. Can it be used for depression?
Yes, as an adjunct in treatment-resistant major depressive disorder.

3. What is the risk of akathisia?
Akathisia is common and may require dose adjustment or symptomatic treatment.

4. Is a long-acting injectable available?
Yes, the long-acting IM formulation can be administered monthly or quarterly.

5. Are dose adjustments needed in liver impairment?
Yes—lower initial doses are recommended for moderate hepatic impairment.

---

References

• FDA Label: Aripiprazole (Abilify)
• DrugBank: Aripiprazole Summary
• StatPearls: Aripiprazole Pharmacology
• PubMed Review: Multimodal Mechanism of Aripiprazole
• PMC: Partial agonist mechanism and clinical outcomes