Chapter 44.

Serotonin Syndrome and Neuroleptic Malignant Syndrome

Daina L. Wells

Serotonin Syndrome (SS)

Pathophysiology
(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
1997;13:763)

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

The effects of fluoxetine& MAOIs can last more than a week, 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. Serotonergic medications must be stopped 2wk before starting linezolid (5wk for fluoxetine). Serotonergic medications may be
restarted 24h after last dose of linezolid.
FIGURE 44-1.

Serotonin syndrome pathogenesis. (Data from Rusyniak DE, Sprague JE: Toxin-induced hyperthermic syndromes, Med Clin North Am 2005:
Nov;89(6):1277.)
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

Metoclopramide

Ergotamine

Ergoloid

Dihydroergotamine

Mirtazapine
Nefazodone

Fentanyl

Paroxetine

Frovatriptan

Sertraline

Naratriptan

Citalopram

Rizatriptan

Escitalopram

Sumatriptan

St. John's wort

Zolmitriptan

Valproate

Data from Medicine 2000;79:201; N Engl J Med 2005;352:1112; Crit Care Clin 1997;13:763.

Diagnosis & Evaluation

Signs & Symptoms
(N Engl J Med 2005;352:1112; Med Clin North Am 2005;89:1277)

Neurologic changes: AMS, agitation, confusion, ataxia, akathisia; neuromuscular abnormalities (greater in lower extremities): tremor, muscle
rigidity, hyperreflexia, clonus (most sensitive physical finding; most obvious in patellar deep tendon reflexes)

Autonomic hyperactivity: diaphoresis, tachycardia, hypertension, tachypnea, hyperthermia ( mortality if temp >41.1C), nausea, diarrhea,
shivering

Clinical Pearl 44-4

NMS vs SS if you're unsure, give a BZD & supportive care only!

Tableattr1_c044s001s002s001t00257295422
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Characteristic
NMS
Offending medication
DA antagonist or abrupt d/c of DA agonist
Onset
Slow (days)
Any time during treatment
Presentation
Lead pipe rigidity, mute & staring
Data from Med Clin North Am 2005;89:1277.

SS
Serotonergic medications
Quick (within hrs)
Soon after med added or dose
Clonus, hyperreflexia, agitation, 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, mute & staring

Clonus, hyperreflexia, agitation, incoherent speech

Onset

Presentation

Data from Med Clin North Am 2005;89:1277.

Clinical Pearl 44-5

Hypotension reported to occur in 1015% of cases & is associated with a poor prognosis (Crit Care Clin 1997;13:763)
Clinical Pearl 44-6

Fever O2 consumptiongive O2
Table 442 Moderateto-Severe SS

Characteristics

Sustained clonus
Tremor
Temp 38.5C
Severe HTN/tachycardia
Delirium
Muscular hypertonicity
Seizures
Rhabdomyolysis
Metabolic acidosis
Coagulopathy
Data from N Engl J Med 2005;352:1112; Q J Med 2003;96:635.

Treatment & Follow-Up

Discontinue offending drug(s); fluid resuscitation: goal hemodynamic stability, adequate hydration, & electrolyte balance; crystalloids (0.9%
NaCl or LR) preferred; oxygen administration: goal maintain O2sat >93%

Benzodiazepines: bind to BZD receptors on GABA channels cell excitability central catecholamine release BP & HR; causes
sedation, skeletal muscle relaxation; possesses anticonvulsant & anxiolytic properties; 5min onset; dose-limiting side effects: respiratory
depression (unlikely but monitor O2 sat)

Clinical Pearl 44-7

Antidepressant discontinuation symptoms may resemble SS symptoms (agitation, irritability, ataxia, movement disorders, cognitive
impairment, flu-like symptoms, diaphoresis)
Clinical Pearl 44-8

Lorazepam usually preferred due to rapid onset & intermediate DOA

Clinical Pearl 44-9

Antipyretics like APAP&ibuprofen are not useful in SS because the hyperthermia is due to muscular activity, not an alteration in the
hypothalamic temperature set point (N Engl J Med 2005;352:1112)
Additional Treatment Options
5-HT receptor antagonists

Cyproheptadine (Periactin): 5-HT receptor antagonist; doses of 1232mg bind to 8595% of 5-HT receptors (Crit Care Med
2010;38:S244); onset 13h; dose-limiting side effects: anticholinergic properties may temp; thickening of bronchial secretions (monitor
O2 stat in patients with AMS); dizziness, drowsiness

Chlorpromazine (Thorazine): 5-HT receptor antagonist; usually 2nd choice after cyproheptadine 2/2 AE; onset 1530min; doselimiting side effects: hypotension, QTc prolongation, temp

Olanzapine (Zyprexa): 5-HT2A receptor antagonist; not routinely used 2/2 AE & 5-HT; onset 510min; 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; if required nitroprusside & esmolol preferred; -blockers
may mask tachycardia that can be used to monitor effectiveness of treatment (N Engl J Med 2005;352:1112)

Vasopressors (N Engl J Med 2005;352:1112): use ONLY in patients with severe hypotension; need central line & ICU admission for
vasopressor administration; for patients previously on MAOIs:norepinephrine, phenylephrine, epinephrine preferred
Nonpharmacologic treatment

Core or external cooling: useful in patients with life-threatening hyperthermia (Med Clin North Am 2005;89:1277); potential cooling
methods may include IV fluids, cooling blankets, sponging, fans, ice packs

Endotracheal intubation & ventilator support: recommended for severe cases of SS (ex. temp >41.1C) (Medicine 2000;79:201);
avoid succinylcholine due to risk of arrhythmia from hyperkalemia associated with rhabdomyolysis (N Engl J Med 2005;352:1112); sedation &
analgesia

AVOID use of physical restraints: promotes muscle contractions & can lead to lactic acidosis & temp (N Engl J Med
2005;352:1112)

Monitoring: vital signs, serum electrolytes (K+, Na+, Cl) mental status, SCr/BUN, CPK, 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. depression); if serotonergic
medications are necessary, restart only after symptoms of SS have resolved (risk of SS recurrence unknown); use lower doses & titrate slowly;
avoid combining drugs with serotonergic activity; educate pts regarding: s/sx of SS; OTC meds with serotonergic activity (ex. St. John's
wort, dextromethorphan, 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;89:1277); activation of D 2 receptors: D2 blocker, DA
depletion; 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;22:389); high doses & rapid titration risk of NMS (Pharmacotherapy 2008;28:530)

Clinical Pearl 44-11

Dehydration may predispose a patient to NMS (Neurol Clin North Am 2004;22:389)

Clinical Pearl 44-12

Drugs that D2 Receptor Activation

D2 ActivatorsAvoid 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;22:389.

FIGURE 44-2.

NMS pathogenesis. (Data from NEJM 2005;352:1112, Q J Med 2003;96:635.)

Diagnosis & Evaluation

Signs & Symptoms
(Med Clin North Am 2005;89:1277)

Can last 710d after discontinuation of oral antipsychotics & 1mo after discontinuation of depot injections (Neurol Clin North Am
2004;22:389)

Hyperthermia, altered mental status (usually mild confusion), mutism, skeletal muscle rigidity (described as lead pipe) tachycardia, hyper- or
hypotension, diaphoresis
Atypical antipsychotics may cause abnormal presentation of NMS

Hyperthermia & muscle rigidity less common (Pharmacotherapy 2008; 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; 28: 530)

Clinical Pearl 44-14

Do not mistake NMS with catatonia due to worsening psychosis; use of anticholinergics may worsen NMS-associated hyperthermia. If you
are unsure, give supportive care, a BZD, & consult psychiatry.
Clinical Pearl 44-15

Stop antipsychotics for AT LEAST 514d after onset of NMS (The Maudsley Prescribing Guidelines. 10th ed. London: Informa Healthcare,

2009; Am J Psychiatry 2007;164:870)

Stages of NMS
(Pharmacotherapy 2008;28:530; Curr Drug Saf 2009;4:84)
I.

Mild rigidity, tremor

II.

Mild-to-moderate rigidity, mutism, or stupor

III.

Moderate rigidity, catatonia, or confusion, temp <39C, HR <100bpm

IV.

Moderate rigidity, catatonia, or confusion, temp 3940C, HR 100120bpm

V.

Severe rigidity, catatonia, or confusion, temp >40C, HR >120bpm

Potential abnormal labs: WBC (with or without a left shift), CK, serum iron, magnesium, &calcium; LFTs (Med Clin North Am
2005;89:1277; Neurol Clin North Am 2004;22:389)

Treatment & Follow-Up

(Med Clin North Am 2005;89:1277)
Treatment goals: control signs/symptoms & D2 receptor activity; provide supportive care

All stages: discontinue offending drug(s) OR restart DA agonist; fluid resuscitation: achieve hemodynamic stability, maintain adequate
hydration & electrolyte balance; oxygen to maintain O2 sat >93%

Benzodiazepines: onset 5min; may cause respiratory depression

Moderate-to-severe NMS; DA agonists: may cause/worsen psychosis; dosed based on severity of symptoms; ICU admission likely
required

Bromocriptine (Parlodel): most commonly used ( data) (Med Clin North Am 2005;89:1277); D2 agonist; can 5-HT; DO
NOT use if diagnosis (serotonin syndrome vs NMS) unclear; 2.5mg PO 34 daily; up to 45mg/d; onset 12h; dose-limiting side effects:
hypotension, heart palpitations, N/V/D; monitor BP, HR

Amantadine (Symmetrel): usually 2nd line after bromocriptine; exact mechanism unknown; may block reuptake of DA &/or
release of DA from neurons; 100200mg PO BID; max 300400mg/d; onset 24h; dose-limiting side effects: hypotension, heart
palpitations; caution in patients with underlying CV disease

Dantrolene (Dantrium): use only if patient has severe muscle rigidity; peripheral skeletal muscle relaxant
thermogenesis; onset of treatment effects: fever should within hours; dose-limiting side effects: dizziness, vomiting, sedation; monitor
LFTs, BP, HR, CCBs (CV collapse); CNS depression (Am J Psychiatry 2007;164:870)
risk of VTE during NMS consider VTE prophylaxis

Nonpharmacologic treatment: external cooling (Neurol Clin North Am 2004;22:389): cooling blankets, ice packs

Clinical Pearl 44-16

If patient responds to drug therapy, continue 1014d after resolution of NMS due to an oral agent & 23wk after NMS due to a depot agent
(Neurol Clin North Am 2004;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 25mg of PO haloperidol in some pts.
Table 44-3 Drugs Used in the Treatment of SS

Drug Name & Availability

Dosing

Adverse Effects

Contraindications

Drug-Drug
Interactions

Clinical Notes

Lorazepam (Ativan) 2,
4mg/1mL IV; dilute in equal
vol of D5W or NS

0.5 2mg IV over 2

5min; may repeat
Q1015min PRN

Sedation, RR,
BP, HR

Severe resp.
insufficiency

Cyproheptadine(Periactin)
4mg tabs; 2mg/5mL syrup

4mg PO Q24h OR
12mg 1 followed by
2mg Q2h as
symptoms continue,
then 8mg PO Q6h
(D/C if no response
after 16mg)
25mg IM; may repeat
in 14h 1

Anti-Ach side
effects, sedation,
thickening of
bronchial
secretions

Acute asthma attack, CNS depressants

MAOI use within 14d

BP, HR,
QTc

Coma; CV instability; Drugs that affect

QT prolongation
BP or QTc

500mcg/kg load over

1min, 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
2040mg Q10min
PRN
0.1mcg/kg/min IV,
titrate to effect; max:
10mcg/kg/min (best
2mcg/kg/min)

Nausea

Cardiogenic shock,
cardiac failure, heart
block, hypotension,
bradycardia

Chlorpromazine(Thorazine)
25mg/mL IM
Esmolol (Brevibloc) 10,
20mg/mL IV

Labetolol (Trandate) 5mg/mL

IV
Nitroprusside(Nitropress)
25mg/mL IV in (D5W)

Dizziness,
nausea,
bronchospasm
Palpitations,
restlessness,
sweating

Don't use in patients

with ACS, ischemic
stroke, liver or renal
failure

CNS depressants

TCAs, MAOIs,
low-potency
antipsychotics
potentate BP
from -blockers

MAOIs
potentiate
hypotension

IV soln. contains
propylene glycol
renal failure, lactic
acidosis
1st line 5-HT
antagonist; caution
w/BZDs due to
CNS depression;
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); concomitant
anemia may prolong
DOA; good for
renal/liver failure
patients
Avoid hypotension
(harder to treat than
HTN)
Avoid using max
dose >10min; doses
>2mcg/kg/min
cyanide toxicity;

monitor for sudden

changes in MAP
Table 44-4 Drugs Used in the Treatment of NMS

Drug Name & Availability

Dosing

Lorazepam (Ativan) 2,
4mg/1mL IV; dilute in equal
vol of D5W or NS

0.52mg IV over
25min; may
repeat Q1015min
PRN
2.5 PO 34 daily;
max: 45mg/d

Bromocriptine (Parlodel) 5mg

caps; 2.5mg tabs

Amantadine (Symmetrel)
100mg tabs, caps; 50mg/5mL
syrup
Dantrolene (Dantrium) 25, 50,
100mg caps; 20mg IV (sterile
water for injection)

100200mg PO
BID; max: 300
400mg/d
12.5mg/kg IV
then 1mg/kg Q6h
(over 1h) max:
10mg/kg, then
taper or switch to
oral: 25200mg/d
PO divided 4/d

Adverse
Effects
Sedation,
RR, BP, HR

Contraindications

BP, heart
palpitations,
N/V/D,
dizziness

Ischemic heart disease,

peripheral vascular
disease, ergot alkaloid
allergy

Antihypertensives,
serotonergic
medications

N/A

Medications that
alter DA or BP

Active hepatic disease;

Black Box Warning for
hepatotoxicity

CNS depressants

Dizziness,
rash, V/D,
muscle
weakness

Severe resp.
insufficiency

Monitoring: Vital signs, serum electrolytes (Mag, Ca++, K+), SCr/BUN, CK/CPK
Prevention

Drug-Drug
Interactions
CNS depressants

Clinical Notes
IV sol. contains
propylene glycol
renal failure,
lactic acidosis
1st line DA agonist;
don't d/c abruptly
can cause
recurrence of
NMS; caution if
underlying CV
disease
Not usually 1st line;
don't d/c abruptly
Reserve for severe
cases; monitor
LFTs, HR, & BP

3050% experience recurrence of NMS when D2 antagonist restarted (Crit Care Med 2010;38:S244); risk of recurrence with interval
between NMS & restarting a D2 antagonist (Crit Care Med 2010;38:S244)
When restarting an antipsychotic (The Maudsley Prescribing Guidelines. 10 th ed. London: Informa Healthcare, 2009)

1.

If possible, use an agent structurally unrelated to offending agent

2.

Avoid high-potency typical antipsychotics& depot injections rates of NMS

3.

High-potency typicals: fluphenazine, haloperidol, loxapine, perphenazine, thiothixene, trifluoperazine

Depot injections: fluphenazine decanoate, haloperidol decanoate, olanzapine, paliperidone palmitate, risperidone

Atypical or low-potency antipsychotics preferred (note: ALL antipsychotics have the potential to cause NMS because they all block
D2 receptors)

4.

Those theoretically least likely to cause NMS: low-dose aripiprazole, quetiapine, clozapine
Start with small doses, titrate SLOWLY & monitor BP, HR, & temp closely

Acronyms

ACS:acute coronary syndrome

APAP:acetaminophen

AMS: altered mental status

Anti-Ach: anticholinergic

CK: creatine kinase

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, Tuite PJ. The evaluation & management of patients with neuroleptic malignant syndrome. Neurol Clin North Am
2004;22:389. [PubMed: 15062519]
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112. [PubMed: 15784664]
Rusyniak DE, Sprague JE. Toxin-induced hyperthermic syndromes. Med Clin North Am 2005;89:1277. [PubMed: 16227063]
www.nmsis.org or 1-888-667-8367 (maintained by The Neuroleptic Malignant Syndrome Information Service)
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