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Chapter 44.

Serotonin Syndrome and Neuroleptic Malignant Syndrome
Daina L. Wells

Serotonin Syndrome (SS)
(Medicine 2000;79:201; N Engl J Med 2005;352:1112)

Central & peripheral serotonin (5-HT) receptors responsible for SS → excess stimulation caused by excess serotonin precursors or agonists, ↑
serotonin release, ↓ serotonin reuptake, ↓ serotonin metabolism
Pharmacologic treatment → control signs/symptoms & ↓ 5-HT receptor activation if symptoms are severe

∼60% of SS cases occur ≤6h after change in dose or addition of medication (The ICU book. 3rd ed. 2007; N Engl J Med 2005;352:1112) 25%
of cases present after 24h (Med Clin North Am 2005;89:1277); just as likely to develop with therapeutic doses as with overdoses (Crit Care Clin

Left untreated → seizures, coma, rhabdomyolysis, metabolic acidosis, renal failure, cardiac failure, DIC; ↑ death in environments with ↑
ambient temp (Med Clin North Am 2005;89:1277)

Most cases resolve within 24h after appropriate management (supportive care, stop serotonergic meds) (The ICU book. 3rd ed. 2007; N Engl J
Med 2005;352:1112)

Clinical Pearl 44-1

Bupropion (Wellbutrin®) is the only antidepressant without significant serotonergic activity; may exhibit some at 10× the recommended dose
Clinical Pearl 44-2

Serotonergic medications may be restarted 24h after last dose of linezolid. so monitor for persistent symptoms of SS Clinical Pearl 44-3 What about linezolid? FDA warning (7/26/11) indicates linezolid should not be combined with serotonergic medications due to its MAOI-A inhibition. .The effects of fluoxetine & MAOIs can last more than a week. FIGURE 44-1. Serotonergic medications must be stopped 2wk before starting linezolid (5wk for fluoxetine).

) Table 44-1 Medications Associated with SS Serotonergic Medications Amphetamines Ginseng Ondansetron TCAs Atypical antipsychotics Granisetron Pentazocine  Amoxapine Lithium Reserpine Linezolid Ritonavir  Clomipramine LSD Sibutramine  Desipramine SNRIs  Doxepin  Aripiprazole  Clozapine  Olanzapine L-tryptophan  Quetiapine MAOIs  Risperidone   Ziprasidone  Duloxetine  Imipramine Phenelzine  Venlafaxine  Nortriptyline  Isocarboxazid  Desvenlafaxine  Protriptyline Bromocriptine  Tranylcypromine  Milnacipran Tramadol Buspirone  Selegiline SSRIs  Rasagiline  Fluvoxamine  Fluoxetine Cocaine Dextromethorphan Ergot alkaloids MDMA (ecstasy) Meperidine Trazodone Triptans  Almotriptan  Eletriptan .89(6):1277. Med Clin North Am 2005: Nov. Sprague JE: Toxin-induced hyperthermic syndromes. (Data from Rusyniak DE.Serotonin syndrome pathogenesis.

13:763.1°C).89:1277)  Neurologic changes: AMS. Diagnosis & Evaluation Signs & Symptoms (N Engl J Med 2005. hyperthermia (↑ mortality if temp >41. Med Clin North Am 2005. muscle rigidity. agitation. Crit Care Clin 1997.352:1112. John's wort Zolmitriptan  Valproate Data from Medicine 2000. tachycardia. akathisia. confusion. neuromuscular abnormalities (greater in lower extremities): tremor.352:1112. hyperreflexia. clonus (most sensitive physical finding. hypertension. most obvious in patellar deep tendon reflexes)  Autonomic hyperactivity: diaphoresis. diarrhea. nausea.79:201. tachypnea. N Engl J Med 2005.Metoclopramide  Ergotamine  Ergoloid  Dihydroergotamine Mirtazapine Nefazodone Fentanyl  Paroxetine  Frovatriptan  Sertraline  Naratriptan  Citalopram  Rizatriptan  Escitalopram  Sumatriptan St. shivering Clinical Pearl 44-4 . ataxia.

mute & staring Clonus. give a BZD & supportive care only! Tableattr1_c044s001s002s001t00257295422 Save Table | Print Characteristic NMS Offending medication DA antagonist or abrupt d/c of DA agonist Onset Slow (days) Any time during treatment Presentation “Lead pipe” rigidity. Clinical Pearl 44-5 Hypotension reported to occur in 10–15% of cases & is associated with a poor prognosis (Crit Care Clin 1997. mute & staring Data from Med Clin North Am 2005.89:1277. agitation. agitation.13:763) Clinical Pearl 44-6 Fever ↑ O2 consumption—give O2 Table 44‐2 Moderate‐to-Severe SS Characteristics .89:1277. incoherent speech Onset Presentation Data from Med Clin North Am 2005. SS Serotonergic medications Quick (within hrs) Soon after med added or dose ↑ Clonus. hyperreflexia.NMS vs SS… if you're unsure. hyperreflexia. incoherent speech Characteristic NMS SS Offending medication DA antagonist or abrupt d/c of DA agonist Serotonergic medications Slow (days) Quick (within hrs) Any time during treatment Soon after med added or dose ↑ “Lead pipe” rigidity.

flu-like symptoms. possesses anticonvulsant & anxiolytic properties. fluid resuscitation: goal → hemodynamic stability. diaphoresis) Clinical Pearl 44-8 Lorazepam usually preferred due to rapid onset & intermediate DOA Clinical Pearl 44-9 . adequate hydration. ataxia. causes sedation. Treatment & Follow-Up  Discontinue offending drug(s). irritability. ≤ 5min onset.Sustained clonus Tremor Temp ≥38. Q J Med 2003. skeletal muscle relaxation. oxygen administration: goal → maintain O2sat >93%  Benzodiazepines: bind to BZD receptors on GABA channels → ↓ cell excitability → ↓ central catecholamine release → ↓ BP & HR. cognitive impairment. movement disorders. crystalloids (0.5°C Severe HTN/tachycardia Delirium Muscular hypertonicity Seizures Rhabdomyolysis Metabolic acidosis Coagulopathy Data from N Engl J Med 2005. & electrolyte balance.9% NaCl or LR) preferred.96:635.352:1112. dose-limiting side effects: respiratory depression (unlikely but monitor O2 sat) Clinical Pearl 44-7 Antidepressant discontinuation symptoms may resemble SS symptoms (agitation.

doses of 12–32mg bind to 85–95% of 5-HT receptors (Crit Care Med 2010. QTc prolongation.352:1112): use ONLY in patients with severe hypotension. need central line & ICU admission for vasopressor administration. doselimiting side effects: hypotension. usually 2nd choice after cyproheptadine 2/2 AE. onset 5–10min.Antipyretics like APAP & ibuprofen are not useful in SS because the hyperthermia is due to muscular activity.352:1112) Additional Treatment Options 5-HT receptor antagonists   Cyproheptadine (Periactin®): 5-HT receptor antagonist. dizziness. ↑ temp  Olanzapine (Zyprexa®): 5-HT2A receptor antagonist. onset ≤1–3h. cooling blankets. not routinely used 2/2 AE & ↑ 5-HT. β-blockers may mask tachycardia that can be used to monitor effectiveness of treatment (N Engl J Med 2005. potential cooling methods may include IV fluids. sponging. ice packs . if required nitroprusside & esmolol preferred. for patients previously on MAOIs:norepinephrine.38:S244). drowsiness  Chlorpromazine (Thorazine®): 5-HT receptor antagonist. not an alteration in the hypothalamic temperature set point (N Engl J Med 2005. dose-limiting side effects: anticholinergic properties → may ↑ temp. epinephrine preferred Nonpharmacologic treatment   Core or external cooling: useful in patients with life-threatening hyperthermia (Med Clin North Am 2005. onset 15–30min. do not use within 1h of BZD to avoid respiratory depression (BZDs are mainstay of SS treatment)  Antihypertensives: avoid if possible → may lead to refractory hypotension. fans. phenylephrine.89:1277).352:1112)  Vasopressors (N Engl J Med 2005. thickening of bronchial secretions (monitor O2 stat in patients with AMS).

89:1277).28:530) . sedation & analgesia  AVOID use of physical restraints: promotes muscle contractions & can lead to lactic acidosis & ↑ temp (N Engl J Med 2005. restart only after symptoms of SS have resolved (risk of SS recurrence → unknown). John's wort. depression). ↓ activation of D 2 receptors: D2 blocker. educate pts regarding: s/sx of SS. LFTs Prevention   Use bupropion if possible (no 5-HT activity) Future exposure to serotonergic drugs in pts not recommended but in some cases cannot be avoided (ex. if serotonergic medications are necessary. DA depletion. ginseng) Clinical Pearl 44-10 Consult psychiatry before starting or stopping psychiatric medications if you are unsure of the MOA or potential adverse effects Neuroleptic Malignant Syndrome (Nms) Pathophysiology  Caused by ↓ in central dopaminergic (DA) transmission (Med Clin North Am 2005. OTC meds with serotonergic activity (ex. use lower doses & titrate slowly. CPK. temp >41.22:389).352:1112).1°C) (Medicine 2000. SCr/BUN. Endotracheal intubation & ventilator support: recommended for severe cases of SS (ex.352:1112) Monitoring: vital signs. Cl−) mental status. avoid combining drugs with serotonergic activity. Na+. high doses & rapid titration ↑ risk of NMS (Pharmacotherapy 2008. St. serum electrolytes (K+.79:201). dextromethorphan. sudden withdrawal of D2 activators  Debate in regard to onset of NMS: no relationship between the intensity or duration of drug therapy & risk of NMS (Neurol Clin North Am 2004. avoid succinylcholine due to risk of arrhythmia from hyperkalemia associated with rhabdomyolysis (N Engl J Med 2005.

22:389) Clinical Pearl 44-12 Drugs that ↓ D2 Receptor Activation D2 Activators—Avoid Abrupt Discontinuation Metoclopramide Amphetamines Prochlorperazine Atypical antipsychotics Promethazine    Aripiprazole Reserpine Amantadine    Clozapine Typical antipsychotics Bromocriptine    Olanzapine    Chlorpromazine Entacapone    Paliperidone    Fluphenazine Levodopa    Quetiapine    Haloperidol Pramipexole    Risperidone    Loxapine Ropinirole    Ziprasidone    Perphenazine Lithium (incombo w/antipsychotics)    Thiothixene Tetrabenazine Data from Neurol Clin North Am 2004. FIGURE 44-2. .Clinical Pearl 44-11 Dehydration may predispose a patient to NMS (Neurol Clin North Am 2004.22:389.

352:1112. (Data from NEJM 2005.96:635.NMS pathogenesis. Q J Med 2003.) .

If you are unsure. skeletal muscle rigidity (described as “lead pipe”) tachycardia. London: Informa Healthcare. a BZD. mutism. diaphoresis Atypical antipsychotics may cause abnormal presentation of NMS   Hyperthermia & muscle rigidity less common (Pharmacotherapy 2008. hyper. Clinical Pearl 44-15 Stop antipsychotics for AT LEAST 5–14d after onset of NMS (The Maudsley Prescribing Guidelines.22:389)  Hyperthermia. 10th ed. 28: 530) Clinical Pearl 44-14 Do not mistake NMS with catatonia due to worsening psychosis. altered mental status (usually mild confusion).89:1277)  Can last 7–10d after discontinuation of oral antipsychotics & ≥1mo after discontinuation of depot injections (Neurol Clin North Am 2004. give supportive care.Diagnosis & Evaluation Signs & Symptoms (Med Clin North Am 2005. & consult psychiatry. use of anticholinergics may worsen NMS-associated hyperthermia. 28:530)  5-HT receptor blockade in nigrostriatal pathway leads to ↑ DA ∴ ↓ rigidity & ↓ temp Clinical Pearl 44-13  3% of patients starting clozapine experience transient benign hyper-thermia  25% of patients starting risperidone or clozapine experience hemodynamic changes (Pharmacotherapy 2008. .or hypotension.

may cause respiratory depression Moderate-to-severe NMS. Moderate rigidity. oxygen to maintain O2 sat >93%   Benzodiazepines: onset ≤5min. Neurol Clin North Am 2004. magnesium. HR >120bpm Potential abnormal labs: ↑ WBC (with or without a left shift). maintain adequate hydration & electrolyte balance. dosed based on severity of symptoms. Am J Psychiatry 2007. Mild rigidity. temp 39–40°C. Curr Drug Saf 2009. catatonia. or confusion.22:389) Treatment & Follow-Up (Med Clin North Am 2005.28:530. or confusion. provide supportive care   All stages: discontinue offending drug(s) OR restart DA agonist. ↑ LFTs (Med Clin North Am 2005.89:1277. HR <100bpm IV. Moderate rigidity. temp <39°C. ICU admission likely required . ↓ serum iron. DA agonists: may cause/worsen psychosis. or stupor III.4:84) I. temp >40°C. or confusion. HR 100–120bpm V. ↑ CK. tremor II. catatonia.164:870) Stages of NMS (Pharmacotherapy 2008. mutism.89:1277) Treatment goals: control signs/symptoms & ↑ D2 receptor activity.2009. Mild-to-moderate rigidity. fluid resuscitation: achieve hemodynamic stability. Severe rigidity. catatonia. & calcium.

D2 agonist. ice packs Clinical Pearl 44-16 If patient responds to drug therapy. dose-limiting side effects: hypotension. max 300–400mg/d.164:870) ↑ risk of VTE during NMS → consider VTE prophylaxis Nonpharmacologic treatment: external cooling (Neurol Clin North Am 2004. HR. continue ×10–14d after resolution of NMS due to an oral agent & ×2–3wk after NMS due to a depot agent (Neurol Clin North Am 2004. HR  Amantadine (Symmetrel®): usually 2nd line after bromocriptine.22:389) Clinical Pearl 44-17 Do not discontinue DA agonists abruptly → may cause recurrence of NMS Clinical Pearl 44-18 Maximal D2 blockade can occur with doses as low as 2–5mg of PO haloperidol in some pts. can ↑ 5-HT.22:389): cooling blankets. N/V/D. onset ≤1–2h. CCBs (CV collapse). may block reuptake of DA &/or ↑ release of DA from neurons. monitor BP. vomiting. 2.5mg PO 3–4 × daily.89:1277).   Bromocriptine (Parlodel®): most commonly used (↑ data) (Med Clin North Am 2005. caution in patients with underlying CV disease  Dantrolene (Dantrium®): use only if patient has severe muscle rigidity. exact mechanism unknown. dose-limiting side effects: dizziness. CNS depression (Am J Psychiatry 2007. sedation. heart palpitations. Table 44-3 Drugs Used in the Treatment of SS Drug Name & Availability Dosing Adverse Effects Contraindications Drug-Drug Interactions Clinical Notes . DO NOT use if diagnosis (serotonin syndrome vs NMS) unclear. onset of treatment effects: fever should ↓ within hours. onset ≤24h. up to 45mg/d. BP. monitor LFTs. heart palpitations. dose-limiting side effects: hypotension. peripheral skeletal muscle relaxant → ↓ thermogenesis. 100–200mg PO BID.

max: 10mcg/kg/min (best ≤2mcg/kg/min) Nausea Cardiogenic shock. insufficiency Cyproheptadine(Periactin®) 4mg tabs. CNS depressants MAOI use within 14d ↓ BP.1mcg/kg/min IV. Drugs that affect QT prolongation BP or QTc 500mcg/kg load over 1min. ischemic stroke. 4mg/1mL IV.Lorazepam (Ativan®) 2. bronchospasm Palpitations. hypotension. nausea. 2mg/5mL syrup 4mg PO Q24h OR 12mg ×1 followed by 2mg Q2h as symptoms continue. restlessness. liver or renal failure CNS depressants TCAs. contains propylene glycol → renal failure. heart block. .5 2mg IV over 2– 5min. good for renal/liver failure patients Avoid hypotension (harder to treat than HTN) Avoid using max dose >10min. cardiac failure. ↑ QTc Coma. may repeat Q10–15min PRN Sedation. titrate to effect. concomitant anemia may prolong DOA. ↑ HR. then 50mcg/kg/min to max of 300mcg/kg/min (titrate by 25mcg/kg/min Q10– 20min to goal HR/BP) Load 20mg IV then 20–40mg Q10min PRN 0. CV instability. BP. then 8mg PO Q6h (D/C if no response after 16mg) 25mg IM. thickening of bronchial secretions Acute asthma attack. HR Severe resp. caution w/BZDs due to ↑ CNS depression. bradycardia Chlorpromazine(Thorazine®) 25mg/mL IM Esmolol (Brevibloc®) 10. only available PO but can crush & put down NG tube 2nd line 5-HT antagonist due to SEs Avoid hypotension (harder to treat than HTN). doses >2mcg/kg/min ↑ cyanide toxicity. low-potency antipsychotics potentate ↓ BP from β-blockers MAOIs potentiate hypotension IV soln. dilute in equal vol of D5W or NS 0. MAOIs. sedation. may repeat in 1–4h ×1 Anti-Ach side effects. sweating Don't use in patients with ACS. lactic acidosis 1st line 5-HT antagonist. ↓ RR. 20mg/mL IV Labetolol (Trandate®) 5mg/mL IV Nitroprusside(Nitropress®) 25mg/mL IV in (D5W) Dizziness.

HR Contraindications ↓ BP. CK/CPK Prevention Drug-Drug Interactions CNS depressants Clinical Notes IV sol. dizziness Ischemic heart disease. K+). contains propylene glycol → renal failure. 100mg caps. Black Box Warning for hepatotoxicity CNS depressants Dizziness. muscle weakness Severe resp.5mg tabs Amantadine (Symmetrel®) 100mg tabs. heart palpitations. dilute in equal vol of D5W or NS 0. BP. max: 300– 400mg/d 1–2. may repeat Q10–15min PRN 2. lactic acidosis 1st line DA agonist. 20mg IV (sterile water for injection) 100–200mg PO BID. peripheral vascular disease. V/D. caution if underlying CV disease Not usually 1st line. 50mg/5mL syrup Dantrolene (Dantrium®) 25. caps.5–2mg IV over 2–5min. SCr/BUN. 50. serum electrolytes (Mag. don't d/c abruptly Reserve for severe cases.monitor for sudden changes in MAP Table 44-4 Drugs Used in the Treatment of NMS Drug Name & Availability Dosing Lorazepam (Ativan®) 2. & BP .5 PO 3–4 × daily. 2. serotonergic medications N/A Medications that alter DA or BP Active hepatic disease. HR. N/V/D. Ca++. max: 45mg/d Bromocriptine (Parlodel®) 5mg caps. then taper or switch to oral: 25–200mg/d PO divided 4×/d Adverse Effects Sedation. rash. don't d/c abruptly → can cause recurrence of NMS. ergot alkaloid allergy Antihypertensives.5mg/kg IV then 1mg/kg Q6h (over 1h) max: 10mg/kg. ↓ RR. monitor LFTs. insufficiency Monitoring: Vital signs. 4mg/1mL IV.

Those theoretically least likely to cause NMS: low-dose aripiprazole. clozapine Start with small doses. If possible. trifluoperazine  Depot injections: fluphenazine decanoate. use an agent structurally unrelated to offending agent 2. haloperidol decanoate. haloperidol. olanzapine. 10 th ed.38:S244). titrate SLOWLY & monitor BP.  High-potency typicals: fluphenazine. 2009)  1.38:S244) When restarting an antipsychotic (The Maudsley Prescribing Guidelines. & temp closely Acronyms  ACS: acute coronary syndrome  APAP: acetaminophen  AMS: altered mental status  Anti-Ach: anticholinergic  CK: creatine kinase . quetiapine. paliperidone palmitate. perphenazine. HR. thiothixene. ↓ risk of recurrence with ↑ interval between NMS & restarting a D2 antagonist (Crit Care Med 2010. London: Informa Healthcare. Avoid high-potency typical antipsychotics & depot injections—↑ rates of NMS 3. 30–50% experience recurrence of NMS when D2 antagonist restarted (Crit Care Med 2010. loxapine. risperidone Atypical or low-potency antipsychotics preferred (note: ALL antipsychotics have the potential to cause NMS because they all block D2 receptors)  4.

org or 1-888-667-8367 (maintained by The Neuroleptic Malignant Syndrome Information Service) McGraw Hill .nmsis. [PubMed: 15784664] ▪ Rusyniak DE. Med Clin North Am 2005. The serotonin syndrome. [PubMed: 15062519] ▪ Boyer EW. Toxin-induced hyperthermic syndromes. D2: dopamine 2 receptor  DIC: disseminated intravascular coagulation  LFTs: liver function tests  MAOIs: monoamine oxidase inhibitors  NG: nasogastic tube  SNRIs: serotonin & norephinephrine reuptake inhibitors  SSRIs: selective serotonin reuptake inhibitors  TCAs: tricyclic antidepressants  VTE: venous thromboembolism Supplemental Readings ▪ Bhanushali MJ.89:1277. N Engl J Med 2005. [PubMed: 16227063] ▪ www. Tuite PJ. Sprague JE. Neurol Clin North Am 2004. The evaluation & management of patients with neuroleptic malignant syndrome.352:1112.22:389. Shannon M.