What are the mechanisms of action for all second-generation antipsychotics, including Risperidone (risperidone), Paliperidone (paliperidone), Olanzapine (olanzapine), Quetiapine (quetiapine), Aripiprazole (aripiprazole), Asenapine (asenapine), Iloperidone (iloperidone), Lurasidone (lurasidone), Ziprasidone (ziprasidone), and Clozapine (clozapine)?

Mechanisms of Action of Second-Generation Antipsychotics

Core Pharmacological Framework

All second-generation antipsychotics share a fundamental mechanism: serotonin 5-HT2A receptor antagonism combined with dopamine D2 receptor antagonism or partial agonism, though each agent has a unique receptor binding profile that determines its clinical effects and side effect profile. 1, 2

The Serotonin-Dopamine Hypothesis

The defining characteristic separating second-generation from first-generation antipsychotics is the combination of:

• Potent 5-HT2A receptor blockade paired with weaker D2 receptor antagonism 2, 3
• This dual mechanism reduces extrapyramidal symptoms while maintaining antipsychotic efficacy 2
• The 5-HT2A antagonism facilitates dopamine release in the prefrontal cortex, potentially improving cognitive and negative symptoms 2, 3

Individual Agent Mechanisms

Standard D2/5-HT2A Antagonists

Risperidone, Paliperidone, Olanzapine, Quetiapine, and Ziprasidone function primarily as serotonin-dopamine receptor antagonists with varying receptor affinities 1, 4:

• Risperidone and Paliperidone: High 5-HT2A and D2 receptor affinity with dose-dependent D2 occupancy 4
• Olanzapine: Broad receptor profile including significant histamine H1, muscarinic, and alpha-1 adrenergic blockade in addition to 5-HT2A/D2 antagonism 4
• Quetiapine: Lower D2 affinity with "fast-off" kinetics from D2 receptors, significant 5-HT2A antagonism 4, 3
• Ziprasidone: Balanced 5-HT2A/D2 antagonism with additional 5-HT1A partial agonism and serotonin/norepinephrine reuptake inhibition 4

Agents with 5-HT1A Agonism

Lurasidone, Asenapine, and Iloperidone add 5-HT1A partial agonism to the standard 5-HT2A/D2 antagonism 4:

• The 5-HT1A agonism enhances prefrontal dopamine release, potentially improving cognitive function and negative symptoms 2, 3
• Lurasidone demonstrates the best metabolic profile among newer agents with minimal weight gain 4
• Asenapine has sublingual administration with high 5-HT2A/D2 receptor affinity 4
• Iloperidone shows lower propensity for metabolic effects compared to olanzapine or clozapine 4

Dopamine Partial Agonists (Third-Generation)

Aripiprazole represents a mechanistically distinct class as a dopamine D2 partial agonist 1, 5:

• Acts as a dopamine system stabilizer: antagonist activity in hyperdopaminergic states, agonist activity in hypodopaminergic states 5
• Significant 5-HT1A partial agonism and 5-HT2A antagonism contribute to prefrontal dopaminergic activation 2
• Superior metabolic profile with low weight gain risk and minimal prolactin elevation 1
• Should be considered first-line due to better metabolic side effects 1

Clozapine: The Unique Outlier

Clozapine has the most complex and atypical mechanism 6, 7:

• Weak D2 receptor antagonism combined with potent 5-HT2 receptor inhibition 7
• Efficacy likely stems from effects on multiple neurotransmitter systems beyond simple D2 blockade 6, 7
• Treats both positive and negative symptoms more effectively than other agents 7
• Produces fewer extrapyramidal symptoms due to weak D2 binding 7
• Reserved for treatment-resistant schizophrenia (34% of patients who fail other antipsychotics) 6
• Poor cardiometabolic profile with significant weight gain and metabolic effects 7

Clinical Implications

Metabolic Risk Stratification

• Highest metabolic risk: Clozapine and olanzapine 1, 4
• Lowest metabolic risk: Aripiprazole, ziprasidone, lurasidone, asenapine, iloperidone 1, 4
• Intermediate risk: Risperidone, paliperidone, quetiapine 4

Mechanism-Based Selection Strategy

Treatment decisions must be based on specific receptor profiles and side effect vulnerabilities, not generational labels 1:

• Start with aripiprazole as first-line for its superior metabolic profile 1
• Consider agents with 5-HT1A agonism (lurasidone, aripiprazole) for prominent negative or cognitive symptoms 2, 3
• Reserve clozapine for treatment-resistant cases after failure of at least two other antipsychotics 7
• Avoid agents with high anticholinergic properties in elderly or cognitively impaired patients 1

Critical Monitoring Requirements

Before initiating any second-generation antipsychotic, measure: BMI, waist circumference, blood pressure, HbA1c, glucose, lipids, prolactin, liver function, electrolytes, complete blood count, and EKG 1. Follow-up includes glucose at 4 weeks, weekly BMI/waist/blood pressure for 6 weeks, then comprehensive metabolic panels at 3 months and annually 1.

Important Caveat

Never combine multiple QT-prolonging antipsychotics due to fatal arrhythmia risk 1. Second-generation antipsychotics as a class carry increased atrial fibrillation risk, with clozapine (OR 2.81), olanzapine (OR 1.81), and quetiapine (OR 1.55) showing highest risk 6.