Mechanism of Action of Aripiprazole
Aripiprazole functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, combined with antagonist activity at serotonin 5-HT2A receptors, distinguishing it as the first "third-generation" antipsychotic. 1
Primary Receptor Activity
Aripiprazole's unique pharmacological profile centers on its partial agonist activity at D2 dopamine receptors, which fundamentally differentiates it from first-generation antipsychotics (full D2 antagonists) and second-generation antipsychotics (serotonin-dopamine antagonists) 2. This partial agonism means aripiprazole can both activate and block D2 receptors depending on the dopaminergic tone in different brain regions 1.
Key Receptor Binding Profile
The FDA label specifies that aripiprazole exhibits:
- High affinity binding for dopamine D2 (Ki = 0.34 nM), D3 (Ki = 0.8 nM), serotonin 5-HT1A (Ki = 1.7 nM), and 5-HT2A receptors (Ki = 3.4 nM) 1
- Moderate affinity for dopamine D4 (Ki = 44 nM), serotonin 5-HT2C (Ki = 15 nM), 5-HT7 (Ki = 39 nM), alpha-1 adrenergic (Ki = 57 nM), and histamine H1 receptors (Ki = 61 nM) 1
- No appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM), which explains its low anticholinergic side effect profile 1
Functional Selectivity: A Critical Concept
A particularly important aspect of aripiprazole's mechanism is "functional selectivity" at D2 receptors 3. Research demonstrates that aripiprazole's actions at D2 receptors are cell-type selective, meaning it can function as an agonist, partial agonist, or antagonist depending on the specific cellular environment and the function being examined 3. This explains how aripiprazole can:
- Reduce dopaminergic hyperactivity in mesolimbic pathways (treating positive symptoms of schizophrenia)
- Enhance dopaminergic activity in mesocortical pathways (potentially improving negative symptoms and cognitive function)
Clinical Translation of Mechanism
The American Academy of Pediatrics notes that aripiprazole's efficacy for both positive and negative symptoms results from the combination of D2 partial agonism and 5-HT1A partial agonism 4. This dual partial agonism, coupled with 5-HT2A antagonism, provides:
- Lower risk of extrapyramidal symptoms compared to typical antipsychotics due to partial rather than full D2 blockade 5, 6
- Reduced sedation compared to antipsychotics with higher histamine H1 affinity 7
- Minimal prolactin elevation or even prolactin reduction, unlike full D2 antagonists 6
- Lower propensity for metabolic side effects including weight gain compared to other atypical antipsychotics 5, 6
Important Caveats
Paradoxical activation or agitation can occur in some patients due to aripiprazole's partial agonist properties, particularly documented in PTSD nightmare treatment studies 4. This represents a critical clinical consideration when initiating therapy, as the partial agonism that provides therapeutic benefit can occasionally produce activating effects rather than sedation.
The mechanism also involves moderate affinity for serotonin reuptake sites (Ki = 98 nM), though this is not considered a primary mechanism of action 1. Additionally, aripiprazole's functional effects extend beyond simple receptor binding—it acts as an inverse agonist at 5-HT2B receptors and displays partial agonist actions at 5-HT2A, 5-HT2C, D3, and D4 receptors 3.
Metabolic Considerations
Aripiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes through dehydrogenation, hydroxylation, and N-dealkylation pathways 1. The active metabolite dehydro-aripiprazole represents approximately 40% of parent drug exposure and has similar D2 receptor affinity, contributing to the overall therapeutic effect 1. In CYP2D6 poor metabolizers, the elimination half-life extends to approximately 146 hours compared to 75 hours in extensive metabolizers, necessitating dose adjustments 1.