How do second-generation antipsychotics (SGAs), such as olanzapine (Zyprexa), risperidone (Risperdal), and quetiapine (Seroquel), work?

Mechanism of Action of Second-Generation Antipsychotics

Second-generation antipsychotics work primarily through combined antagonism of dopamine D2 receptors and serotonin 5HT2 receptors, distinguishing them from first-generation antipsychotics that act solely as dopamine D2 antagonists. 1

Core Pharmacological Mechanism

Dual Receptor Antagonism:

• SGAs derive their antipsychotic properties from blocking both dopamine Type 2 (D2) receptors and serotonin Type 2 (5HT2) receptors, though the exact mechanism remains incompletely understood 1, 2, 3
• This dual antagonism is proposed to mediate therapeutic activity in schizophrenia, particularly the efficacy observed in both positive and negative symptoms 1, 3
• First-generation antipsychotics work exclusively through D2 dopamine antagonism, which explains their characteristic extrapyramidal side effect profile that SGAs largely avoid 1

Specific Receptor Binding Profiles

Risperidone:

• High affinity binding (Ki 0.12-7.3 nM) for serotonin 5HT2, dopamine D2, α1 and α2 adrenergic, and H1 histaminergic receptors 2
• Low to moderate affinity for serotonin 5HT1C, 5HT1D, and 5HT1A receptors 2
• Weak affinity for dopamine D1 receptors and no affinity for cholinergic muscarinic or β-adrenergic receptors 2

Olanzapine:

• High affinity binding for serotonin 5HT2A/2C and 5HT6 receptors (Ki=4-11 nM), dopamine D1-4 receptors (Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM) 3
• Moderate affinity antagonism at serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 receptors (Ki=32-132 nM) 3
• Low affinity for GABAA, benzodiazepine, and β-adrenergic receptors 3

Multi-Neurotransmitter System Effects

• SGAs affect multiple neurotransmitter systems beyond dopamine and serotonin, including antidopaminergic and antiserotonergic activity 1
• Antagonism at receptors other than D2 and 5HT2 (such as histaminergic, adrenergic, and muscarinic receptors) explains additional therapeutic and side effects of these medications 2, 3

Clinical Implications of Mechanism

Symptom Profile:

• SGAs are at least as effective as first-generation antipsychotics for positive symptoms (hallucinations, delusions) and possibly more effective for negative symptoms (flat affect, social withdrawal, anhedonia) 1
• The combined serotonin-dopamine antagonism is theorized to provide this broader symptom coverage compared to pure dopamine antagonism 1

Side Effect Profile:

• Lower risk of extrapyramidal symptoms compared to first-generation antipsychotics due to the serotonin 5HT2 antagonism modulating dopamine blockade 1
• However, the broader receptor binding profile creates different side effects, particularly metabolic problems including weight gain, glucose elevation, and cholesterol increases 1

Important Caveats

• The traditional classification into "generations" is clinically misleading and should not guide treatment selection—instead, choose medications based on their specific receptor profiles, side effect profiles, and patient-specific factors 4
• While the serotonin-dopamine hypothesis provides a framework, the precise mechanism by which SGAs achieve therapeutic effects remains unclear 1, 3
• Individual SGAs within the class have distinct receptor binding profiles that result in clinically meaningful differences in efficacy and tolerability 4, 2, 3