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

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.

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:

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 Christensen RC

3-Category Breakdown

Mental Status Changes

Sympathomimetic Effects

Muscle

Severity

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%

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)

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)

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

Editor-in-Chief, at EMCrit.org

An ED Intensivist from NY.
Professor
Nassau University Medical Center
No conflicts of interest (coi).

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