Mechanism of Action of Atypical Antipsychotics
Atypical antipsychotics exert their therapeutic effects through combined serotonin-dopamine receptor antagonism, specifically blocking both 5-HT2A (serotonin) and D2 (dopamine) receptors, which distinguishes them from typical antipsychotics that act almost exclusively on dopamine receptors. 1
Core Pharmacological Mechanism
The defining characteristic of second-generation atypical antipsychotics is their dual receptor antagonism:
- Serotonin 5-HT2A receptor blockade combined with weaker dopamine D2 receptor antagonism represents the fundamental mechanism underlying their "atypical" profile 1
- This serotonin-dopamine hypothesis explains why atypicals cause significantly fewer extrapyramidal side effects compared to typical antipsychotics while maintaining antipsychotic efficacy 2
- The relatively potent 5-HT2A blockade coupled with weaker D2 antagonism is the only pharmacological feature common to most atypical antipsychotics 2
Multiple Neurotransmitter System Modulation
Beyond the primary serotonin-dopamine mechanism, atypical antipsychotics affect multiple neurotransmitter systems:
- They modulate serotonin, norepinephrine, and histamine neurotransmission in addition to dopamine pathways 3
- This multimodal mechanism of action underlies their effectiveness not only for positive symptoms but also for negative symptoms and cognitive dysfunction 1
- Different atypicals have varying abilities to block other CNS neurotransmitters, which combined with their disparate affinity for postsynaptic D2 receptors, accounts for each medication's unique side effect profile 1
Special Case: Third-Generation Antipsychotics
Aripiprazole represents a distinct mechanism as the first "third-generation" antipsychotic:
- It functions as a partial dopamine D2 receptor agonist rather than a pure antagonist, distinguishing it from other antipsychotics 1
- Aripiprazole also acts as a significant 5-HT1A agonist and 5-HT2A antagonist, contributing to dopaminergic activation in the prefrontal cortex 2
Clinical Implications of the Mechanism
The serotonin-dopamine antagonism translates to specific clinical advantages:
- Lower risk of extrapyramidal symptoms (EPS) including tardive dyskinesia compared to typical antipsychotics, though risperidone produces more EPS than other atypicals 4, 5
- Efficacy against both positive and negative symptoms of schizophrenia, whereas typical antipsychotics primarily address positive symptoms 1
- Potential cognitive benefits through modulation of prefrontal cortex dopamine release, possibly mediated by 5-HT1A receptor activation 2
Important Caveats
While the serotonin-dopamine hypothesis is widely accepted, an alternative "fast-off" theory proposes that the atypical profile may be determined by loose D2-binding kinetics alone, suggesting 5-HT2A blockade may be neither necessary nor sufficient 2. However, the preponderance of guideline evidence supports the dual receptor antagonism model as the primary mechanism 1.