Mechanism of Action: Atypical Antipsychotics Block Dopamine
Atypical antipsychotics block dopamine—they do not raise dopamine levels. Specifically, these medications (including olanzapine, quetiapine, and risperidone) function as dopamine D2 receptor antagonists, preventing dopamine from binding to its receptors in the brain 1.
Core Pharmacological Mechanism
The defining characteristic of atypical antipsychotics is their dual receptor antagonism: they block both serotonin 5-HT2A receptors and dopamine D2 receptors 2. This distinguishes them fundamentally from typical antipsychotics (like haloperidol), which act almost exclusively through dopamine D2 receptor blockade 1, 3.
Key Differences in Dopamine Blockade
The critical distinction between typical and atypical antipsychotics lies not in whether they block dopamine, but in how they block it:
Typical antipsychotics (haloperidol, chlorpromazine) bind more tightly than dopamine itself to D2 receptors and dissociate very slowly over 30+ minutes 4
Atypical antipsychotics (quetiapine, clozapine, olanzapine) bind more loosely than dopamine to D2 receptors and dissociate rapidly in less than 60 seconds 4
This "fast-off-D2" property allows atypical antipsychotics to transiently occupy D2 receptors and then rapidly dissociate to allow normal dopamine neurotransmission 4. This mechanism explains why atypicals cause fewer extrapyramidal side effects and maintain normal prolactin levels compared to typical antipsychotics 4.
Multi-Receptor Effects Beyond Dopamine
Atypical antipsychotics affect multiple neurotransmitter systems simultaneously 1:
Serotonin 5-HT2A receptor blockade occurs at clinically effective doses and contributes to their improved side effect profile 5
5-HT1A receptor stimulation (direct or indirect) may contribute to cognitive benefits 5
5-HT2C, 5-HT6, and 5-HT7 receptor antagonism varies among different atypical agents and influences their unique profiles 5
Clinical Threshold for Antipsychotic Action
Both typical and atypical antipsychotics require approximately 65% D2 receptor occupancy for antipsychotic efficacy 4. The threshold for extrapyramidal side effects remains at about 80% D2 occupancy for both classes, regardless of serotonin receptor blockade 4. The key difference is that atypicals achieve therapeutic dopamine blockade while minimizing sustained high-level occupancy that causes movement disorders.
Special Case: Aripiprazole
Aripiprazole functions as a partial dopamine D2 receptor agonist rather than a pure antagonist, distinguishing it as a third-generation antipsychotic 2. This means it partially activates dopamine receptors rather than completely blocking them, representing a fundamentally different mechanism within the atypical class.
Clinical Implications
The antidopaminergic activity of atypical antipsychotics is essential for their therapeutic effects 1. The American Academy of Child and Adolescent Psychiatry guidelines explicitly state that atypical agents possess "both antidopaminergic and antiserotonergic activity" as their mechanism of action 1.
Common Misconception to Avoid
A critical pitfall is confusing the transient nature of D2 blockade by atypicals with an absence of dopamine antagonism. All currently approved antipsychotics (with the experimental exception of SEP-363856) require D2 receptor blockade for antipsychotic efficacy 6. The difference lies in binding kinetics, not the fundamental blocking action.