PharmacologyTier 1Medical Sciences concept

Serotonin syndrome vs neuroleptic malignant syndrome

Core concept

Both give fever, altered mental state, autonomic instability and raised CK. The neuromuscular examination and the time course separate them

	Serotonin toxicity	Neuroleptic malignant syndrome
Onset	Hours (<24 h of a dose change)	Days to 2 weeks
Drug	Serotonergic added or combined	D2 antagonist started/increased, or dopamine agonist withdrawn
Tone	Hyperreflexia, clonus, tremor	Lead-pipe rigidity, bradyreflexia
Gradient	Lower limbs > upper	Generalised
Pupils	Mydriasis	Normal
Bowel sounds	Hyperactive, diarrhoea	Normal or dec
CK	Normal or mildly inc	Markedly inc, rhabdomyolysis
WCC	Normal	inc
Resolution	<24 h after stopping the drug	Days to weeks

Clonus - spontaneous, inducible or ocular - is the single most discriminating sign, and the core of the Hunter Serotonin Toxicity Criteria

Hunter criteria - a serotonergic agent PLUS any one of

Serotonin toxicity is a spectrum with a dose-response, not an idiosyncratic reaction
- Highest risk from combinations, especially MAOI + SSRI/SNRI/TCA or MAOI + pethidine/tramadol/methylene blue
- Other culprits: linezolid, fentanyl, tramadol, St John's wort, MDMA, triptans (weak), lithium, ondansetron
NMD triggers: haloperidol, risperidone, olanzapine, metoclopramide, prochlorperazine, promethazine, and abrupt withdrawal of levodopa or a dopamine agonist
- Idiosyncratic, not dose-related
Malignant hyperthermia is the third in the family - volatile anaesthetics or suxamethonium, RYR1, treated with dantrolene

Management - both

Stop the offending drug, aggressive cooling, IV fluids, benzodiazepines for agitation and rigidity
Watch for rhabdomyolysis, AKI, DIC, seizures; ICU if temperature >39-40 C
Avoid physical restraint - isometric muscle contraction worsens hyperthermia and CK
Antipyretics do not work - the heat is muscular, not hypothalamic prostaglandin-driven

Specific

Serotonin toxicity: cyproheptadine (5-HT2A antagonist) 12 mg then 2 mg 2-hourly; chlorpromazine is an alternative but risks hypotension
NMS: bromocriptine or amantadine (restore dopaminergic tone), dantrolene for severe rigidity/hyperthermia
- Restart an antipsychotic only after 2 weeks, preferring a low-potency or clozapine/quetiapine
The commonest real-world scenario is an SSRI plus tramadol, or an antidepressant plus linezolid - check the whole list, including analgesics and antibiotics
Dopamine-antagonist antiemetics (metoclopramide, prochlorperazine) cause NMS in medical wards, not just psychiatry

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