ICU · Toxicology
Serotonin syndrome and neuroleptic malignant syndrome
Also known as Serotonin syndrome (SS) · Neuroleptic malignant syndrome (NMS) · Serotonin toxicity · Cyproheptadine · Dantrolene · Bromocriptine · Malignant hyperthermia (MH) · Hunter Serotonin Toxicity Criteria · Sternbach criteria · Drug-induced hyperthermia · Ryanodine receptor (RYR1)
Serotonin syndrome (SS) = excess serotonergic activity from drug combinations (SSRIs + MAOIs, tramadol, linezolid, fentanyl, St John's wort). Triad: mental status change + autonomic instability + neuromuscular hyperactivity (clonus, hyperreflexia). Onset: HOURS. Treatment: stop serotonergic drugs, benzodiazepines, cyproheptadine (serotonin antagonist), cooling, supportive. Neuroleptic malignant syndrome (NMS) = idiosyncratic reaction to dopamine antagonists (antipsychotics). Triad: mental status change + muscle rigidity (lead-pipe) + hyperthermia + autonomic instability. Onset: DAYS-WEEKS. Treatment: stop antipsychotic, dantrolene, bromocriptine, cooling, supportive. KEY DIFFERENCE: SS has clonus/hyperreflexia (onset hours); NMS has rigidity/hyporeflexia (onset days). Malignant hyperthermia (MH) — the third hyperthermia differential — is a pharmacogenetic crisis of the ryanodine receptor (RYR1) triggered by volatile anaesthetics (halothane, sevoflurane, desflurane, isoflurane) and succinylcholine: rapid onset (minutes-hours) of profound hypercapnia refractory to ventilation, generalised rigidity (especially masseter), rhabdomyolysis, hyperthermia, treated with immediate cessation of trigger + IV dantrolene 2.5 mg/kg repeat to 10 mg/kg.
Checked against its sources on 3 Sept 2026
Practise this topic
On this page
Study tools
Your progress
Saved on this device.
Target exams
Red flags
- Serotonin syndrome onset is HOURS; NMS onset is DAYS-WEEKS; malignant hyperthermia onset is MINUTES — the single most discriminating feature
- SS: CLONUS and HYPERREFLEXIA (lower > upper limbs); NMS: LEAD-PIPE RIGIDITY and bradyreflexia; MH: masseter/generalised rigidity + refractory hypercapnia
- Do NOT give more serotonergic drugs (including tramadol, fentanyl, ondansetron, metoclopramide, linezolid) to SS patients
- Severe hyperthermia with rigidity in any of the three conditions = life-threatening — aggressive evaporative + intravascular cooling, intubation + non-depolarising paralysis
- AVOID succinylcholine for RSI in any rigidity/hyperthermia syndrome — hyperkalaemia from rhabdomyolysis, and it is the MH trigger — use rocuronium
- Do NOT give antipsychotics for agitation in SS or NMS — they worsen both (serotonergic and dopamine-blocking); use benzodiazepines only
- Cyproheptadine is only available ORALLY/NG — limits use in the intubated patient; the NG route is mandatory in severe SS
- Dantrolene treats BOTH NMS and MH (direct ryanodine-receptor antagonist at the sarcoplasmic reticulum) but is NOT indicated for SS
Meet the patient
A 34-year-old on phenelzine, an MAOI, arrives agitated and diaphoretic six hours after taking tramadol for back pain — tremulous, with sustained ankle clonus, patellar hyperreflexia, heart rate 128, BP 164 over 95, temperature 39.4, pupils dilated, bowels hyperactive, rigidity worst in the legs.[3]
One question sorts the whole viva: how fast did it come on, and what is the motor sign? Hours plus clonus is serotonin syndrome; days plus lead-pipe rigidity is NMS; minutes plus refractory hypercapnia in theatre is malignant hyperthermia. The antidote then follows the mechanism.[10]
References14ShowHide
- [1]Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity QJM, 2003.PMID 12925718
- [2]Chiew AL, Isbister GK Management of serotonin syndrome (toxicity) Br J Clin Pharmacol, 2025.PMID 38926083
- [3]Prakash S, Patel H, Kumar S, Shah CS Cyproheptadine in serotonin syndrome: A retrospective study J Family Med Prim Care, 2024.PMID 38827706
- [4]Nagy A, Nasir A, Haque M, Judge R, Lee J Therapeutic cyproheptadine regimen in serotonin syndrome: Complications after cardiovascular surgery Clin Case Rep, 2023.PMID 37476598
- [5]Shouan A, Kumar R, Lal V, Grover S Linezolid-induced serotonin syndrome Ind Psychiatry J, 2020.PMID 34158725
- [6]Harada T, Hirosawa T, Morinaga K, Shimizu T Metoclopramide-induced Serotonin Syndrome Intern Med, 2017.PMID 28321081
- [7]Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method J Clin Psychiatry, 2011.PMID 21733489
- [8]Pileggi DJ, Cook AM Neuroleptic Malignant Syndrome Ann Pharmacother, 2016.PMID 27423483
- [9]Sen MS, Kushwaha S, Dhamija RK, et al. Neuroleptic Malignant Syndrome: A Retrospective Chart Review from a Tertiary Neuropsychiatric Facility Neurol India, 2025.PMID 40652478
- [10]Perry PJ, Wilborn CA Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management Ann Clin Psychiatry, 2012.PMID 22563571
- [11]Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K Malignant hyperthermia: a review Orphanet J Rare Dis, 2015.PMID 26238698
- [12]Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F Dantrolene--a review of its pharmacology, therapeutic use and new developments Anaesthesia, 2004.PMID 15023108
- [13]Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists Anaesthesia, 2021.PMID 33399225
- [14]Pinyavat T, Riazi S, Deng J, et al. Malignant Hyperthermia Crit Care Med, 2024.PMID 39171998