## Pathophysiology of Neuroleptic Malignant Syndrome **Key Point:** NMS is fundamentally a disorder of dopamine blockade, not serotonin excess. Antipsychotics (especially typical/first-generation agents) antagonize dopamine D2 receptors in multiple brain regions, leading to the characteristic tetrad of symptoms. ### Mechanism 1. **Dopamine D2 receptor blockade** in: - Hypothalamus → loss of temperature regulation - Basal ganglia → extrapyramidal rigidity and dystonia - Brainstem → altered autonomic control 2. **Result:** Unopposed cholinergic activity in the basal ganglia and loss of dopaminergic inhibition of heat production ### Clinical Tetrad of NMS | Feature | Mechanism | |---------|----------| | Hyperthermia | Hypothalamic dysfunction + muscle rigidity | | Muscle rigidity ("lead pipe") | Basal ganglia dopamine blockade | | Altered mental status | Dopamine depletion in cortex/limbic system | | Autonomic instability | Brainstem and hypothalamic involvement | **High-Yield:** NMS is a **dopaminergic crisis**, not a serotonergic one. This distinguishes it fundamentally from serotonin syndrome, which is caused by excessive serotonergic activity (SSRI + MAOI, tramadol overdose, etc.). **Clinical Pearl:** The risk is highest with high-potency typical antipsychotics (haloperidol, fluphenazine) and increases with rapid dose escalation, dehydration, and concurrent medical illness. 
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