Mechanism of Action of Olanzapine in Schizophrenia
The therapeutic effects of olanzapine in schizophrenia are best accounted for by blockade of 5-HT2 and D2 receptors.
Primary Mechanism
Olanzapine's antipsychotic efficacy is mediated through combined dopamine D2 and serotonin 5-HT2A receptor antagonism. 1 This dual mechanism distinguishes it from traditional neuroleptics, which rely solely on dopamine D2 blockade for their antipsychotic properties. 2
Receptor Binding Profile
Olanzapine demonstrates high-affinity binding to multiple receptors, but its therapeutic action specifically stems from:
- Serotonin 5-HT2A/2C receptors (Ki = 4 and 11 nM respectively) 1
- Dopamine D1-4 receptors (Ki = 11-31 nM) 1
The drug achieves near-saturation of 5-HT2 receptors even at low doses (5 mg/day), while D2 occupancy increases dose-dependently from 43-80% at standard clinical doses (5-20 mg/day). 3 This higher 5-HT2 than D2 occupancy at all therapeutic doses is a defining characteristic. 3
Why This Mechanism Matters Clinically
Efficacy Against Multiple Symptom Domains
The combined 5-HT2/D2 antagonism explains olanzapine's effectiveness against:
- Positive symptoms (hallucinations, delusions) - primarily through D2 blockade 2
- Negative symptoms (social withdrawal, flat affect) - enhanced by 5-HT2A antagonism 2, 4
- Depressive symptoms - through non-D2-mediated pathways, with 57% of mood improvement being a direct primary effect 5
Reduced Extrapyramidal Side Effects
The preferential 5-HT2A blockade relative to D2 blockade accounts for olanzapine's lower risk of extrapyramidal symptoms compared to traditional neuroleptics. 2 At standard doses (10-20 mg/day), D2 occupancy remains in the 71-80% range, below the 80% threshold associated with increased extrapyramidal symptoms and prolactin elevation. 3
Why Other Answer Choices Are Incorrect
Activation of α2 receptors: Olanzapine actually binds to α1-adrenergic receptors as an antagonist (Ki = 19 nM), not α2 receptors, and this is not its primary therapeutic mechanism 1
Blockade of GABAA receptors: Olanzapine has very low affinity for GABAA receptors (Ki > 10 μM) and does not exert therapeutic effects through this mechanism 1
Blockade of M1 receptors: While olanzapine does antagonize muscarinic receptors (Ki = 73 nM for M1), this contributes to anticholinergic side effects rather than therapeutic efficacy 1
Serotonin and norepinephrine reuptake inhibition: This is the mechanism of SNRIs used for depression, not atypical antipsychotics like olanzapine 1
Important Clinical Context
The American Academy of Child and Adolescent Psychiatry explicitly states that atypical agents like olanzapine "are considered atypical because their antipsychotic properties stem, at least in part, from their being serotonergic antagonists," while "traditional neuroleptics are all dopamine antagonists (specifically D2)." 2 This fundamental pharmacological distinction underlies both the therapeutic advantages and different side-effect profile of olanzapine compared to first-generation antipsychotics.