Diferencia entre revisiones de «Serotonin syndrome»

Revisión del 19:57 21 mar 2026

Background

Drug-induced excess serotonergic activity in CNS and peripheral nervous system
Usually results from combination of serotonergic agents or dose increase of a single agent
Onset typically within 6-24 hours (usually within 6 hours of medication change)
Mild cases are common; severe cases can be life-threatening
Mortality ~2-12% in severe cases

Common Causative Agents

SSRIs: fluoxetine, sertraline, paroxetine, citalopram, escitalopram
SNRIs: venlafaxine, duloxetine
MAOIs: phenelzine, tranylcypromine, selegiline, linezolid, methylene blue
TCAs: amitriptyline, clomipramine
Opioids: tramadol, meperidine (Demerol), fentanyl, methadone
Triptans: sumatriptan (controversial, risk likely low)
Other: dextromethorphan, lithium, MDMA ("ecstasy"), cocaine, ondansetron (rare)
Most dangerous combination: MAOI + serotonergic agent

Clinical Features

Rapid onset (hours) — distinguishes from neuroleptic malignant syndrome (days)
Hunter Serotonin Toxicity Criteria^[1] (most sensitive/specific):
- In setting of serotonergic agent + any ONE of:
  - Spontaneous clonus (most important finding)
  - Inducible clonus + agitation or diaphoresis
  - Ocular clonus + agitation or diaphoresis
  - Tremor + hyperreflexia
  - Hypertonia + temperature >38°C + ocular or inducible clonus

Clinical Triad

Neuromuscular excitation: clonus (spontaneous, inducible, or ocular), hyperreflexia, tremor, myoclonus, rigidity (severe)
Autonomic dysfunction: diaphoresis, tachycardia, hyperthermia, hypertension, mydriasis, hyperactive bowel sounds, diarrhea
Altered mental status: agitation, anxiety, confusion, delirium

Severity Spectrum

Mild: tremor, hyperreflexia, tachycardia, diaphoresis
Moderate: agitation, clonus, mydriasis, hyperthermia (≤40°C)
Severe: hyperthermia >40°C, rigidity, seizures, rhabdomyolysis, DIC, cardiovascular collapse

Differential Diagnosis

Feature	Serotonin Syndrome	Neuroleptic malignant syndrome	Anticholinergic toxicity	Malignant hyperthermia
Onset	Hours	Days	Hours	Minutes (OR)
Key finding	Clonus/hyperreflexia	Lead-pipe rigidity	Mydriasis, dry	Generalized rigidity
Bowel sounds	Hyperactive	Normal/decreased	Absent	Normal
Skin	Diaphoresis	Diaphoresis	Dry, flushed	Mottled
Pupils	Mydriasis	Normal	Mydriasis	Normal
CK	Mildly elevated	>1000	Normal	Markedly elevated

Evaluation

Clinical diagnosis based on Hunter criteria — no confirmatory lab test
CK: mildly elevated (markedly elevated if severe → rhabdomyolysis)
BMP: electrolytes, creatinine (renal injury), bicarbonate (acidosis)
CBC, LFTs
Lactate
Coagulation studies (DIC in severe cases)
Core temperature
Medication reconciliation is essential — identify all serotonergic agents

Management

Immediate

Discontinue ALL serotonergic agents
Most mild cases resolve within 24-72 hours after drug cessation

Mild (Tremor, Hyperreflexia)

Observation, IV fluids, benzodiazepines PRN for agitation
Supportive care

Moderate (Agitation, Clonus, Hyperthermia <40°C)

Benzodiazepines for agitation and autonomic instability:
- Lorazepam 2-4 mg IV q5-10min, or midazolam
Active cooling for hyperthermia (evaporative cooling, ice packs)
IV fluid resuscitation

Severe (Hyperthermia >40°C, Rigidity, Seizures)

Cyproheptadine (serotonin antagonist):
- 12 mg PO/NG initial dose, then 2 mg q2h until clinical improvement
- Maintenance: 8 mg PO q6h
- Only available PO/NG — crush and give via NG if intubated
Intubation with neuromuscular blockade for severe rigidity/hyperthermia
- Use non-depolarizing agent (avoid succinylcholine if hyperkalemia/rhabdomyolysis risk)
Aggressive cooling
Benzodiazepines for seizures

What to Avoid

NO antipyretics (not effective — hyperthermia is from muscle activity, not altered setpoint)
NO bromocriptine (for NMS, not SS)
NO dantrolene (limited role; rigidity in SS is different from NMS)
Avoid restraints alone without chemical sedation (isometric muscle contraction worsens hyperthermia)

Disposition

Mild: observe 6-12 hours; discharge if improving after drug cessation
Moderate: admit to monitored bed
Severe: ICU admission
Symptoms typically resolve within 24-72 hours (longer for fluoxetine/MAOIs — longer half-life)
Before restarting serotonergic medications: allow washout period (5 half-lives)
- Fluoxetine: 5 weeks; MAOIs: 2 weeks

References

↑ Dunkley EJ, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules. QJM. 2003;96(9):635-642. PMID 12925718

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. PMID 15784664
Isbister GK, et al. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007;187(6):361-365. PMID 17874986
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142. PMID 20433130

Authors:

[1] Dunkley EJ, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules. QJM. 2003;96(9):635-642. PMID 12925718

[1]

@@ Línea 1: / Línea 1: @@
 ==Background==
-*Can be produced by any serotonergic medication
+*'''Drug-induced excess serotonergic activity''' in CNS and peripheral nervous system
-*1 in 6 U.S. adults take at least one psychoactive medication<ref>Moore TJ and Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. Published online December 12, 2016. doi:10.1001/jamainternmed.2016.7507.</ref>
+*Usually results from '''combination of serotonergic agents''' or '''dose increase''' of a single agent
-*Majority of cases occur within therapeutic drug dosages
+*Onset typically within '''6-24 hours''' (usually within 6 hours of medication change)
-*Most common cause is ingestion of foods high in L-Tryptophan while taking an MAOI. Second most common is ingestion of both SSRI and MAOI<ref>Stork CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. In: Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th Ed. New York, NY: McGraw-Hill; 2006: 1070-1082</ref>
+*Mild cases are common; '''severe cases can be life-threatening'''
-*Most common cause of death is severe hyperthermia
+*Mortality ~2-12% in severe cases
-===Causative Agents<ref>Brown CH. Drug-induced Serotonin Syndrome. US Pharm. 2010;35(11):HS-16-HS-21.</ref>===
+===Common Causative Agents===
-====Antidepressants====
+*'''SSRIs''': fluoxetine, sertraline, paroxetine, citalopram, escitalopram
-*[[SSRIs]]
+*'''SNRIs''': venlafaxine, duloxetine
-*[[SNRIs]]
+*'''MAOIs''': phenelzine, tranylcypromine, selegiline, linezolid, methylene blue
-*[[Bupropion]]<ref>Thorpe EL, Pizon AF, Lynch MJ, Boyer J. Bupropion induced serotonin syndrome: a case report. J Med Toxicol. 2010;6(2):168-171. doi:10.1007/s13181-010-0021-x</ref>
+*'''TCAs''': amitriptyline, clomipramine
-*[[Buspirone]]
+*'''Opioids''': '''tramadol''', '''meperidine''' (Demerol), fentanyl, methadone
-*[[TCAs]]
+*'''Triptans''': sumatriptan (controversial, risk likely low)
-*[[Lithium]]
+*'''Other''': dextromethorphan, [[lithium]], MDMA ("ecstasy"), cocaine, ondansetron (rare)
-*[[Mirtazapine]]
+*'''Most dangerous combination: MAOI + serotonergic agent'''
-*[[Trazodone]]
-*[[Valproic acid]]
-*MAOIs (should have washout period of 2+ weeks prior to starting a SSRI)
-**Phenelzine
-**Selegiline
-**Tranylcypromine
-====Drugs of Abuse====
+==Clinical Features==
-*[[Cocaine]]
+*'''Rapid onset''' (hours) — distinguishes from [[neuroleptic malignant syndrome]] (days)
-*[[Ecstasy (MDMA)]]
+*'''Hunter Serotonin Toxicity Criteria'''<ref>Dunkley EJ, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules. ''QJM''. 2003;96(9):635-642. PMID 12925718</ref> (most sensitive/specific):
-*[[Methamphetamine]]
+**In setting of serotonergic agent + '''any ONE of''':
-*[[LSD]]
+***'''Spontaneous clonus''' (most important finding)
+***'''Inducible clonus + agitation or diaphoresis'''
+***'''Ocular clonus + agitation or diaphoresis'''
+***Tremor + hyperreflexia
+***Hypertonia + temperature >38°C + ocular or inducible clonus
-====Analgesics====
+===Clinical Triad===
-*[[Fentanyl]]
+*'''Neuromuscular excitation''': '''clonus''' (spontaneous, inducible, or ocular), hyperreflexia, tremor, myoclonus, rigidity (severe)
-*[[Meperidine]] (Demerol)
+*'''Autonomic dysfunction''': diaphoresis, [[tachycardia]], [[hyperthermia]], hypertension, mydriasis, '''hyperactive bowel sounds''', diarrhea
-*[[Methadone]]
+*'''Altered mental status''': agitation, anxiety, confusion, delirium
-*[[Tramadol]]
-====[[Antiemetics]]====
+===Severity Spectrum===
-*[[Metoclopramide]]
+*'''Mild''': tremor, hyperreflexia, tachycardia, diaphoresis
-*[[Ondansetron]]
+*'''Moderate''': agitation, clonus, mydriasis, hyperthermia (≤40°C)
+*'''Severe''': hyperthermia >40°C, rigidity, seizures, [[rhabdomyolysis]], [[DIC]], '''cardiovascular collapse'''
-====Over the counter Medications====
+==Differential Diagnosis==
-*[[Dextromethorphan]]
+{| class="wikitable"
-*Oral decongestants ([[Pseudoephedrine]])
+|-
+! Feature !! '''Serotonin Syndrome''' !! '''[[Neuroleptic malignant syndrome]]''' !! '''[[Anticholinergic toxicity]]''' !! '''[[Malignant hyperthermia]]'''
+|-
+| Onset || '''Hours''' || Days || Hours || Minutes (OR)
+|-
+| Key finding || '''Clonus/hyperreflexia''' || Lead-pipe rigidity || Mydriasis, dry || Generalized rigidity
+|-
+| Bowel sounds || '''Hyperactive''' || Normal/decreased || '''Absent''' || Normal
+|-
+| Skin || Diaphoresis || Diaphoresis || '''Dry, flushed''' || Mottled
+|-
+| Pupils || Mydriasis || Normal || Mydriasis || Normal
+|-
+| CK || Mildly elevated || >1000 || Normal || Markedly elevated
+|}
-====Herbal products====
+==Evaluation==
-*St John’s Wort, Ginseng, Nutmeg, Yohimbe
+*'''Clinical diagnosis''' based on Hunter criteria — no confirmatory lab test
+*'''CK''': mildly elevated (markedly elevated if severe → [[rhabdomyolysis]])
+*'''BMP''': electrolytes, creatinine (renal injury), bicarbonate (acidosis)
+*'''CBC, LFTs'''
+*'''Lactate'''
+*'''Coagulation studies''' (DIC in severe cases)
+*'''Core temperature'''
+*'''Medication reconciliation is essential''' — identify all serotonergic agents
-====Other Medications====
+==Management==
-*Triptans
+===Immediate===
-*Ergot alkaloids
+*'''Discontinue ALL serotonergic agents'''
-*Bromocriptine
+*Most mild cases resolve within '''24-72 hours''' after drug cessation
-*[[Linezolid]]
-*[[Carbamazepine]]
-*[[Cyclobenzaprine]]
-*L-tryptophan, 5-hydroxytryptophan
-*[[Methylene blue]]
-==Clinical Features==
+===Mild (Tremor, Hyperreflexia)===
-*[[Altered mental status]]: Agitated delirium.  Patients generally hyperactive.
+*Observation, IV fluids, benzodiazepines PRN for agitation
-*Autonomic Instability: Hyperthermia, tachycardia, hypertension, diaphoresis, gastrointestinal illness <ref>Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867</ref>
+*Supportive care
-**Often labile blood pressure, HR
-*Neuromuscular Abnormalities: Clonus, ocular clonus, myoclonus, rigidity, hyperreflexia, tremor, seizures
-**More pronounced in the lower extremities
-**Clonus (inducible or spontaneous): most common finding<ref>Farkas, J. Serotonin Syndrome. The Internet Book of Critical Care. https://emcrit.org/ibcc/serotonin/. Published June 13th, 2019. Accessed December 31st, 2020.</ref>
-***Important to identify because it does not occur in other conditions that mimic serotonin syndrome
-**Hyperactivity as opposed to rigidity in [[neuroleptic malignant syndrome]]
-==Differential Diagnosis==
+===Moderate (Agitation, Clonus, Hyperthermia <40°C)===
-{{Movement disorder DDX}}
+*'''Benzodiazepines''' for agitation and autonomic instability:
-{{AMS and fever DDX}}
+**'''Lorazepam 2-4 mg IV''' q5-10min, or midazolam
+*Active cooling for hyperthermia (evaporative cooling, ice packs)
+*IV fluid resuscitation
-==Evaluation==
+===Severe (Hyperthermia >40°C, Rigidity, Seizures)===
-===Hunter Toxicity Criteria Decision Rules===
+*'''Cyproheptadine''' (serotonin antagonist):
-Serotonergic agent plus 1 of the following<ref>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;96:635-642</ref>:
+**'''12 mg PO/NG initial dose''', then '''2 mg q2h''' until clinical improvement
-*Spontaneous clonus
+**Maintenance: '''8 mg PO q6h'''
-*Inducible clonus AND (agitation or diaphoresis)
+**Only available PO/NG — '''crush and give via NG if intubated'''
-*Ocular Clonus AND (agitation or diaphoresis)
+*'''Intubation with neuromuscular blockade''' for severe rigidity/hyperthermia
-*Tremor AND hyperreflexia
+**Use '''non-depolarizing agent''' (avoid succinylcholine if hyperkalemia/rhabdomyolysis risk)
-*Hypertonia AND temperature >38 AND (ocular clonus or inducible clonus)
+*'''Aggressive cooling'''
+*'''Benzodiazepines for seizures'''
-''84% Sn, 97% Sp''
+===What to Avoid===
+*'''NO antipyretics''' (not effective — hyperthermia is from muscle activity, not altered setpoint)
-{{Serotonin syndrome vs neuroleptic malignant syndrome}}
+*'''NO bromocriptine''' (for NMS, not SS)
+*'''NO dantrolene''' (limited role; rigidity in SS is different from NMS)
-==Management==
+*'''Avoid restraints alone''' without chemical sedation (isometric muscle contraction worsens hyperthermia)
-*Discontinue all serotonergic drugs
-*Aggressive supportive care
-**If pressors required, direct acting (e.g. norepinephrine, epi) preferred, MAO inhibition causes erratic response to dopamine
-*[[Benzos]]
-**Goal is to eliminate agitation, neuromuscular abnormalities, elevations in HR/BP
-**In severe cases, large doses are required (diazepam IV 10-20 mg, titrated with 10 mg increments)
-*[[Cyproheptadine]]<ref>Graudins, A., Stearman, A. and Chan, B. (1998) ‘Treatment of the serotonin syndrome with cyproheptadine’, The Journal of Emergency Medicine, 16(4), pp. 615–619. doi: 10.1016/s0736-4679(98)00057-2</ref>
-**Give if benzodiazepines and supportive care fail to improve agitation and abnormal vitals
-**Serotonin antagonist
-***Also has antihistamine and anticholinergic properties that may exacerbate other mixed toxicology picture
-**Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
-**Give 4mg q6hr x48hr if patient is responsive to initial dose
-*[[Chlorpromazine]]<ref>Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109</ref>
-**Phenothiazine with antiserotonergic effects
-**50mg to 100mg IM
-**Avoid in:
-***Hemodynamically unstable patients as can cause serious hypotension<ref>Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.</ref>
-***Cases in which NMS may still be on the differential
-*[[Dexmedetomidine]]<ref>Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.</ref><ref>Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.</ref>
-**Small case series found this helpful in adolescent cases refractory to benzos
-*Dantrolene generally not recommended as it can worsen serotonin toxicity<ref>Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.</ref>
-*Treat hyperthermia
-**Hyperthermia due to increase in muscular activity, not change in set point
-**[[Intubate]] and paralyze if temperature > 41.1
-**Standard [[cooling measures]]
-***Fans, water sprays, ice packs, cooled crystalloids, cooling blankets
 ==Disposition==
-*Severe cases may require [[intubation]] and [[ventilation]] in ICU
+*'''Mild''': observe 6-12 hours; discharge if improving after drug cessation
-*24hr admission for [[altered mental status]] or abnormal [[vital signs]] requiring further supportive care
+*'''Moderate''': admit to monitored bed
-*Discharge mild cases with minimal intervention required after 6 hrs of observation
+*'''Severe''': ICU admission
+*Symptoms typically resolve within '''24-72 hours''' (longer for fluoxetine/MAOIs — longer half-life)
+*Before restarting serotonergic medications: allow '''washout period''' (5 half-lives)
+**Fluoxetine: 5 weeks; MAOIs: 2 weeks
-<div style="display:none">
-<!-- SMW MedicationDose annotations for serotonin syndrome medications -->
-{{MedicationDose|drug=Diazepam|dose=10-20 mg IV, titrate with 10 mg increments|route=IV|context=Benzodiazepine for agitation/neuromuscular abnormalities|indication=Serotonin syndrome|notes=Goal: eliminate agitation, neuromuscular abnormalities, HR/BP elevations}}
-{{MedicationDose|drug=Cyproheptadine|dose=12 mg PO/NG initial, then 2 mg q2h until response (max 32 mg/day); then 4 mg q6h x48h|route=PO/NG|context=Serotonin antagonist (if benzos and supportive care fail)|indication=Serotonin syndrome|max_dose=32 mg/day|notes=Also has antihistamine and anticholinergic properties}}
-</div>
 ==See Also==
-*[[Toxidromes]]
+*[[Neuroleptic malignant syndrome]]
+*[[Anticholinergic toxicity]]
+*[[Malignant hyperthermia]]
+*[[Toxicology]]
+*[[MAOI toxicity]]
 ==References==
 <references/>
+*Boyer EW, Shannon M. The serotonin syndrome. ''N Engl J Med''. 2005;352(11):1112-1120. PMID 15784664
+*Isbister GK, et al. Serotonin toxicity: a practical approach to diagnosis and treatment. ''Med J Aust''. 2007;187(6):361-365. PMID 17874986
+*Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. ''Am Fam Physician''. 2010;81(9):1139-1142. PMID 20433130
 [[Category:Toxicology]]
+[[Category:Psychiatry]]