Mechanism of Action of Atypical Antipsychotics (Second-Generation)

Introduction

Atypical antipsychotics, also known as second-generation antipsychotics (SGAs), are widely used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as adjuncts), and autism-related irritability. Compared to typical antipsychotics, they offer fewer extrapyramidal symptoms (EPS) and better control of negative symptoms of schizophrenia due to their dual action on dopamine and serotonin receptors.

Common SGAs include:

• Clozapine
• Risperidone
• Olanzapine
• Quetiapine
• Aripiprazole
• Ziprasidone
• Lurasidone

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Stepwise Mechanism of Action of Atypical Antipsychotics

1. Dopamine D2 receptor antagonism (weaker than typicals)
   SGAs block dopamine D2 receptors, but with lower affinity, particularly in the mesolimbic pathway, which reduces positive symptoms of schizophrenia.
2. Serotonin 5-HT2A receptor antagonism
   SGAs strongly block 5-HT2A receptors, especially in the mesocortical pathway, which improves negative and cognitive symptoms and reduces EPS.
3. Modulation of dopamine release
   By blocking 5-HT2A receptors, SGAs indirectly increase dopamine release in the nigrostriatal pathway, reducing the risk of motor side effects.
4. Partial agonism (e.g., aripiprazole)
   Some SGAs like aripiprazole act as partial D2 agonists, balancing dopamine activity rather than completely blocking it.
5. Additional receptor interactions
   Many SGAs also block H1, alpha-1, and muscarinic receptors, contributing to sedation, orthostatic hypotension, and anticholinergic effects.

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Pharmacokinetic Parameters of Atypical Antipsychotics

Drug	Half-life	Metabolism	Unique Feature
Clozapine	8–12 hrs	CYP1A2	Agranulocytosis risk; best for treatment-resistant cases
Risperidone	20 hrs	CYP2D6	Causes dose-dependent EPS and prolactin increase
Olanzapine	20–54 hrs	CYP1A2	High risk of weight gain and metabolic syndrome
Quetiapine	6–7 hrs	CYP3A4	Sedating; low EPS risk
Aripiprazole	75 hrs	CYP2D6, 3A4	Partial D2 agonist; minimal weight gain
Ziprasidone	7 hrs	CYP3A4	Low metabolic risk, QT prolongation risk
Lurasidone	18 hrs	CYP3A4	Fewer metabolic effects, requires food for absorption

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Clinical Uses of Atypical Antipsychotics

• Schizophrenia (positive and negative symptoms)
• Bipolar disorder (mania, depression, maintenance)
• Major depressive disorder (adjunctive)
• Autism-related irritability
• Tourette syndrome
• Treatment-resistant schizophrenia (clozapine)

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Adverse Effects of Atypical Antipsychotics

• Metabolic syndrome – weight gain, hyperlipidemia, insulin resistance (especially olanzapine, clozapine)
• Sedation (H1 blockade)
• Orthostatic hypotension (alpha-1 blockade)
• Hyperprolactinemia (risperidone, paliperidone)
• QT prolongation (ziprasidone)
• Agranulocytosis (clozapine – requires CBC monitoring)
• Seizures (dose-dependent with clozapine)
• Minimal EPS (except risperidone at higher doses)

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Comparative Analysis: Atypical vs Typical Antipsychotics

Feature	Atypical Antipsychotics	Typical Antipsychotics
D2 receptor binding	Moderate	High affinity
5-HT2A blockade	Strong	Minimal
EPS risk	Lower	Higher
Effect on negative symptoms	Better	Minimal or worsens
Weight gain/metabolic risk	Higher in some	Lower
Prolactin elevation	Variable (high with risperidone)	High

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Practice MCQs

Q1. Atypical antipsychotics differ from typicals mainly by blocking:
a. D1 receptors
b. 5-HT1A receptors
c. 5-HT2A receptors ✅
d. NMDA receptors

Q2. Which atypical antipsychotic causes agranulocytosis?
a. Risperidone
b. Clozapine ✅
c. Olanzapine
d. Ziprasidone

Q3. Which SGA has minimal weight gain?
a. Olanzapine
b. Aripiprazole ✅
c. Clozapine
d. Quetiapine

Q4. SGAs reduce EPS because of:
a. D1 antagonism
b. Partial 5-HT1A agonism
c. 5-HT2A antagonism ✅
d. Alpha-2 blockade

Q5. Which SGA is approved for treatment-resistant schizophrenia?
a. Risperidone
b. Quetiapine
c. Clozapine ✅
d. Aripiprazole

Q6. What is the MOA of aripiprazole?
a. Full D2 antagonist
b. D2 partial agonist ✅
c. Serotonin agonist
d. NMDA blocker

Q7. Metabolic syndrome is most associated with:
a. Lurasidone
b. Olanzapine ✅
c. Ziprasidone
d. Aripiprazole

Q8. Which SGA prolongs QT interval the most?
a. Risperidone
b. Ziprasidone ✅
c. Quetiapine
d. Aripiprazole

Q9. What blood test is mandatory for clozapine use?
a. LFTs
b. Lipid profile
c. CBC ✅
d. RFTs

Q10. Why are SGAs preferred over FGAs?
a. Faster onset
b. Better for hallucinations
c. Fewer motor side effects ✅
d. Cheaper

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FAQs

Q1: Do SGAs treat both positive and negative symptoms of schizophrenia?
Yes, they are effective against both symptom domains, especially due to 5-HT2A blockade.

Q2: Why is clozapine rarely used despite its efficacy?
Due to risks of agranulocytosis, seizures, and myocarditis, requiring close monitoring.

Q3: Can SGAs be used in children?
Yes. Some like risperidone and aripiprazole are FDA-approved for pediatric use.

Q4: Which SGA causes the most weight gain?
Olanzapine, followed by clozapine.

Q5: What is a unique feature of aripiprazole?
It is a partial D2 receptor agonist, reducing both positive and negative symptoms with fewer side effects.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK519489/