What is the mechanism of action (MOA) of Abilify (aripiprazole)?

Mechanism of Action of Abilify (Aripiprazole)

Aripiprazole functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, combined with antagonist activity at serotonin 5-HT2A receptors—a unique "functionally selective" profile that distinguishes it from all other antipsychotics. 1

Primary Receptor Activity

The core mechanism involves partial agonism at dopamine D2 receptors, meaning aripiprazole binds with high affinity (Ki = 0.34 nM) but produces only partial activation of these receptors rather than full blockade or full activation. 1, 2 This partial agonist activity is thought to stabilize dopaminergic neurotransmission—reducing excessive dopamine activity in hyperactive pathways while maintaining some dopamine function in hypoactive pathways. 3

Key Receptor Affinities

Aripiprazole demonstrates the following binding profile:

• Highest affinity targets (sub-nanomolar to low nanomolar range):

  • Dopamine D2 receptors (Ki = 0.34 nM) - partial agonist 1
  • Dopamine D3 receptors (Ki = 0.8 nM) - partial agonist 1, 2
  • Serotonin 5-HT1A receptors (Ki = 1.7 nM) - partial agonist 1
  • Serotonin 5-HT2A receptors (Ki = 3.4 nM) - antagonist 1
  • Serotonin 5-HT2B receptors - inverse agonist 2

• Moderate affinity targets (5-200 nM range):

  • Dopamine D4 receptors (Ki = 44 nM) 1
  • Serotonin 5-HT2C receptors (Ki = 15 nM) - partial agonist 2
  • Serotonin 5-HT7 receptors (Ki = 39 nM) 1
  • Alpha-1 adrenergic receptors (Ki = 57 nM) 1
  • Histamine H1 receptors (Ki = 61 nM) 1
  • Serotonin reuptake site (Ki = 98 nM) 1

• Minimal affinity: Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM), which contributes to its favorable side effect profile regarding anticholinergic effects. 1

Functional Selectivity: A Unique Property

Aripiprazole exhibits "functionally selective" actions at D2 receptors, meaning its functional effect (agonism vs. antagonism) varies depending on the cellular context and the specific signaling pathway examined. 2 This cell-type selective behavior allows aripiprazole to act as an agonist, partial agonist, or antagonist at D2 receptors depending on the local dopaminergic tone and cellular environment. 2

This functional selectivity is considered the primary reason aripiprazole can effectively treat positive symptoms of schizophrenia (by reducing excessive dopamine activity) while having a lower propensity for extrapyramidal symptoms and hyperprolactinemia compared to traditional D2 antagonists. 3, 4

Clinical Translation of Mechanism

The unique pharmacological profile translates to clinical benefits:

• Efficacy for positive and negative symptoms results from the combination of D2 partial agonism and 5-HT1A partial agonism. 5, 3
• Lower risk of extrapyramidal symptoms stems from partial rather than full D2 blockade. 4
• Reduced prolactin elevation occurs because partial D2 agonism in the tuberoinfundibular pathway maintains some dopamine tone. 4
• Better tolerability profile compared to olanzapine and other atypicals is attributed to the partial agonist mechanism. 5

Active Metabolite Contribution

Dehydro-aripiprazole, the major active metabolite, has similar affinity for D2 receptors as the parent compound and represents approximately 40% of aripiprazole exposure in plasma. 1 This metabolite contributes to the overall pharmacological activity, with a mean elimination half-life of 94 hours compared to 75 hours for aripiprazole. 1

Important Clinical Caveat

Aripiprazole is described as the first "third-generation" antipsychotic specifically because of its partial dopamine receptor agonist activity, which fundamentally distinguishes it from second-generation "atypical" antipsychotics that function as serotonin-dopamine receptor antagonists. 5 This distinction is critical when predicting clinical effects and side effect profiles—aripiprazole may cause paradoxical activation or agitation in some patients due to its partial agonist properties, as documented in PTSD nightmare treatment studies where one patient discontinued due to paradoxical excitement. 5