## Extrapyramidal Side Effects (EPS) Risk by Antipsychotic Class **Key Point:** Atypical antipsychotics (second-generation) have significantly lower EPS risk compared to typical antipsychotics (first-generation), with clozapine having the LOWEST risk among all agents. ### Mechanism of EPS Risk EPS occurs due to dopamine D2 receptor blockade in the basal ganglia. Atypical antipsychotics have: - Faster dissociation from D2 receptors - Greater affinity for serotonin 5-HT2A receptors relative to D2 - Lower occupancy of striatal D2 receptors ### Risk Stratification by Agent | Antipsychotic | Class | EPS Risk | Mechanism | |---|---|---|---| | Haloperidol | Typical | Very High | High D2 affinity, slow dissociation | | Fluphenazine | Typical | Very High | Potent D2 blockade | | Perphenazine | Typical | High | Intermediate D2 potency | | Clozapine | Atypical | Minimal | Rapid D2 dissociation, 5-HT2A > D2 | | Quetiapine | Atypical | Low | Rapid D2 dissociation | | Aripiprazole | Atypical | Low | Partial D2 agonist | **High-Yield:** Clozapine is the ONLY antipsychotic with virtually NO risk of tardive dyskinesia and minimal acute EPS. It is the gold standard for antipsychotic-induced movement disorders. **Clinical Pearl:** Clozapine's low EPS profile is offset by serious adverse effects (agranulocytosis, myocarditis, metabolic syndrome), limiting its use to treatment-resistant schizophrenia or when EPS is a major concern. **Mnemonic:** **ATYPICAL agents = LESS EPS** — Aripiprazole, Amisulpride, Quetiapine, Risperidone, Olanzapine, Clozapine, Paliperidone all carry lower EPS burden than typical agents.
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