Clozapine is the only antipsychotic consistently effective in treatment-resistant schizophrenia. Its superior efficacy has been linked to its receptor binding profile. Which receptor occupancy pattern distinguishes clozapine from typical antipsychotics?

• A Very high D2 occupancy (>90%) in the striatum with low cortical binding
• B Low striatal D2 occupancy (<65%), high D4 and 5-HT2A blockade with muscarinic and histamine H1 antagonism ✓
• C High D1 and D5 receptor blockade in the prefrontal cortex without D2 involvement
• D Selective D3 receptor partial agonism in the limbic system

Explanation

Clozapine has a distinctive 'loose binding' profile with relatively low D2 striatal occupancy (50-60%), which explains its virtual absence of extrapyramidal side effects and tardive dyskinesia. Its efficacy is attributed to multireceptor blockade including D4, 5-HT2A (strong), histamine H1, muscarinic M1, and alpha-1 receptors. High D4 blockade in limbic areas is thought to underpin treatment-resistant efficacy. Typical antipsychotics maintain >70-80% D2 occupancy, causing EPS at therapeutic doses.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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