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EMCrit 399 – Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) – Primer Episode

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So this week, neuroleptic malginant syndrome (NMS) and serotonin syndrome (SS). I do not have a burning desire to cover these two, but they are on the list and I must just take my medicine and get them over with. Now is the time, because next week, I'll have Eelco Wijdicks on to discuss his take on NMS, so I need to get the primer over with.

 

from Wijdicks E, Ropper A. NEJM 2024

To this table we should probably add Anticholinergic Toxicity which will have dry skin and decreased bowel sounds (in contradistinction to SS)

 

Serotonin Syndrome (SS)

Diagnosis

Serotonergic Drug(s) or Drug Interactions

Overdose of serotoninergic medications or interactions between medications that may cause an increase in serotoninergic activity

Serotonergic Agents

from Wijdicks et al. Mayo Clinic Critical and Neurocritical Care Board Review

Serotonin precursors or agonists

  • Tryptophan
  • 5-HTP
  • SAMe
  • DHE
  • Triptans
  • LSD
  • 5-MeO-DIPT
  • Lithium
  • Mirtazapine
  • Buspirone

Decreased serotonin reuptake

Serotonin reuptake inhibitors:
  • Fluoxetine
  • Paroxetine
  • Fluvoxamine
  • Sertraline
  • Citalopram
  • Escitalopram
  • Trazodone
  • Nefazodone
  • Vilazodone
Serotonin-norepinephrine reuptake inhibitors:
  • Duloxetine
  • Venlafaxine
  • Desvenlafaxine
  • Milnacipran
  • Atomoxetine
  • Sibutramine
Tricyclic antidepressants:
  • Amitriptyline
  • Nortriptyline
  • Clomipramine
  • Imipramine
  • Desipramine
  • Doxepin
Antiemetics:
  • Ondansetron
  • Granisetron
  • Metoclopramide
Others:
  • Dextromethorphan
  • Cyclobenzaprine
  • Chlorpheniramine
  • St John’s wort
  • Yohimbine

Decreased serotonin breakdown

Monoamine oxidase inhibitors:
  • Selegiline
  • Rasagiline
  • Phenelzine
  • Tranylcypromine
  • Isocarboxazid
  • Moclobemide
Antibiotics:
  • Linezolid
  • Tedizolid
  • Cycloserine
Others:
  • Methylene blue
  • Procarbazine
  • Syrian rue
  • Nutmeg
  • Ginseng

Opiates with mixed serotonin agonism

  • Tramadol
  • Tapentadol
  • Meperidine
  • Fentanyl
  • Methadone
  • Pentazocine
  • Buprenorphine
  • Dextropropoxyphene

Stimulants with serotonergic activity

Drugs of abuse:
  • Amphetamines
  • MDMA
  • MDA
  • Cocaine
Anorectics:
  • Phentermine
  • Fenfluramine
  • Dexfenfluramine
  • Sibutramine
  • Amfepramone

Other agonists

Antipsychotics:
  • Risperidone
  • Olanzapine
  • Clozapine
Antiepileptics:
  • Valproate
  • Carbamazepine

Peripheral inhibitors of metabolism

  • Fluconazole
  • Erythromycin
  • Ciprofloxacin
  • Ritonavir
Abbreviations: DHE, dihydroergotamine; 5-HTP, hydroxytryptophan; 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; LSD, lysergic acid diethylamide; MDA, methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; SAMe, S-adenosyl-L-methionine

 

Signs and Symptoms

Early presentation will have diaphoresis, myoclonus, and increased GI activity. Think sympathomimetic toxidrome + hyperreflexia + AMS.

from nejm
from Boyer et al. N Engl J Med 2005;352:1112-20

 

from Francescangeli J et al.

 

Use SHIVERS to recall serotonin syndrome features

Must have the presence of some medication combination to cause increased serotoninergic effects


S hivering, one of the neuromuscular symptoms unique to SS, helps distinguish it from other hyperthermic syndromes

H yperreflexia and myoclonus are frequently seen in mild to moderate cases and are especially notable in the lower extremities; muscular rigidity occurs only in more severe cases, in which case it is usually spasticity rather than the lead pipe rigidity of NMS

I ncreased temperature, although variable in SS and usually observed in severe cases, is likely caused by muscular hypertonicity

V ital sign instability can present as tachycardia, tachypnea, and/or labile blood pressure

E ncephalopathy—characterized by mental status changes such as anxiety, agitation, delirium, confusion, and to a lesser extent obtundation—can develop from hyperthermia

R estlessness and incoordination are common because of excess serotonin activity

S weating (diaphoresis) is an autonomic response to excessive serotonin stimulation; by comparison, anticholinergic toxicity usually manifests with hot, dry skin

from Christensen RC

[Current Psychiatry. 2006 February;5(2):114-114By Richard C. Christensen, MD, MA]
Lower extremity > upper extremity
Tremor, Akathisia (inability to stay still), rigidity,

3-Category Breakdown

Mental Status Changes

Sympathomimetic Effects

Muscle

From Mayo Neurocritical and Critical Care Board Review

Severity

from Boyer et al. NEJM 2005

Timing

Rapid Presentation 6-24 hours

Goes away or gets markedly better after 24 hours after medication changes

Scoring

Hunter Criteria

[10.1093/qjmed/hcg109]

Retrospective Study, sensitivity 84%, specificity 97%

This adaption is by Bartakke et al. [10.1016/j.bjae.2019.10.003] from the Hunter Criteria [10.1093/qjmed/hcg109]
SS is unlikely in the absence of either clonus (spontaneous or inducible) or tremor

 

Treatment

Stop Offending Agents

Stop anything that you can that has serotonergic effects

Sedate safely

  • benzos or dexmedetomidine

Control the Temperature

  • Benzos!!!
  • Fans
  • Cooling Devices
  • Intubation +/- paralysis +/- Ice baths

Control the Muscle Rigidity

  • Benzos
  • Dantrolene-some would consider this, but I would only in the most extreme cases

Consider/Treat Rhabdomyolysis

  • Send a CPK in any of these to check for rhabdo
  • Give adequate IV fluids

Serotonin Blockers

  • Speak to the housestaff about Cyproheptadine so they can get the question right on their boards. Cyproheptadine has very little evidence of effectiveness [10.1111/1742-6723.14554]

 

 

Great Papers on Serotonin Syndrome

More on EMCrit

 

Neuroleptic Malignant Syndrome (NMS)

Seen within 2-4 weeks of starting a new anti-psychotic, but illness may precipitate it even in chronic therapy

Median interval from drug to NMS is 4 days and the median duration of illness was 9 days. [39321364], but can occur up to 30 days after a drug has been administered

Anti-Psychotics (1st generation more than 2nd generation, and the latter may have milder symptoms)

Medications Associated with Neuroleptic Malignant Syndrome (From statpearls)

Typical Neuroleptics

  • Haloperidol
  • Chlorpromazine
  • Fluphenazine
  • Thioridazine
  • Trifluordazine
  • Thiothixene
  • Loxapine
  • Bromperidol
  • Promazine
  • Clopenthixol

Atypical Neuroleptics

  • Olanzapine
  • Clozapine
  • Risperidone
  • Quetiapine
  • Ziprasidone
  • Aripiprazole
  • Zotepine
  • Amisulpride

Antiemetics

  • Droperidol
  • Domperidone
  • Metoclopramide
  • Promethazine
  • Prochlorperazine

Others

  • Tetrabenazine
  • Reserpine
  • Amoxapine
  • Diatrizoate
  • Lithium
  • Phenelzine
  • Dosulepin
  • Trimipramine
  • Desipramine

Withdrawal of Dopaminergic Agents (can give a similar syndrome: Parkisonism-Hyperpyrexia Syndrome)

  • Levodopa
  • Amantadine
  • Tolcapone
  • Dopamine agonists

Presentation

Fever, muscular rigidity, and dysautonomia

  • Exposure to a dopamine blocking drug
  • Fever is usually high, >=40 C
  • Some form of altered mental status from delirium all the way to catatonia
  • Increased muscle tone progressing to rigidity. Lead pipe rigidity, referring to uniform resistance throughout range of limb. Can also be cogwheel with intermittent releases. Rigidity is less prominent with 2nd generation anti-psychotics
  • Tachycardia and elevated, potentially labile blood pressure

Muscle rigidity and fever may lead to rhabdomyolysis (always send a CPK)

Absence of increased muscle tone effectively rules out NMS

 

Scoring

DSM-5 Criteria for NMS

Major Criteria (all required)

  • Exposure to dopamine-blocking agent
  • Severe muscle rigidity
  • Fever

Other Criteria (at least two required)

  • Diaphoresis
  • Dysphagia
  • Tremor
  • Incontinence
  • Altered level of consciousness
  • Mutism
  • Tachycardia
  • Elevated or labile blood pressure
  • Leukocytosis
  • Elevated creatine phosphokinase (4x upper limit of normal)

 

Treatment

Discontinue offending medication

 

What to treat?

Blood pressure, hyperthermia and rhabdomyolysis from severe muscle rigidity, and potential respiratory compromise

Potential respiratory compromise

  • Strongly consider intubating severe NMS
  • Can give agents like glycopyrrolate to counter sialorrhea

Blood Pressure

  • Short acting agents as the blood pressure can be labile

Hyperthermia

  • Benzos
  • Active cooling measures

Rhabdo

  • Adequate IV fluids to maintain urine output

Sedation

  • Dexmedetomidine
  • Benzos
  • Ketamine

Muscle Rigidity

  • Benzodiazepenes
  • Dantrolene-monitor LFTS. Initiate with a temp of 38-40 C and rigidity is moderate to severe

Dopamine Agonists (If on a board question)

  • Bromocriptine
  • Amantadine

ECT

to treat refractory cases, especially when having difficulty discerning from malignant catatonia

Papers on NMS

  • Wijdicks & Ropper. NEJM 2024;391:1130
  • Case Series of DSM-5 Criteria Diagnosed NMS Neurocrit Care  [10.1007/s12028-024-02192-y]

More on EMCrit

 

 

Additional New Information

Ondansetron Issue https://pmc.ncbi.nlm.nih.gov/articles/PMC4883185/

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Scott Weingart, MD FCCM
Latest posts by Scott Weingart, MD FCCM (see all)

Cite this post as:

Scott Weingart, MD FCCM. EMCrit 399 – Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) – Primer Episode. EMCrit Blog. Published on April 17, 2025. Accessed on May 15th 2025. Available at [https://emcrit.org/emcrit/serotonin-syndrome-neuroleptic-malignant-syndrome/ ].

Financial Disclosures:

The course director, Dr. Scott D. Weingart MD FCCM, reports no relevant financial relationships with ineligible companies. This episode’s speaker(s) report no relevant financial relationships with ineligible companies unless listed above.

CME Review

Original Release: April 17, 2025
Date of Most Recent Review: April 17, 2025
Termination Date: Jul 1, 2027

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Simone Gherardi
Simone Gherardi
24 days ago

Just want to add some reference suggesting for dexdemetomidine a role as an antidote for serotonin toxicity (and other toxidromes) PMID: 36346349 , PMID: 1690141 etc

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