AACN Advanced Critical Care

Volume 24, Number 1, pp.1520

2013, AACN

Complex

Rhythms

Earnest Alexander, PharmD, and

Gregory M. Susla, PharmD
Department Editors

Serotonin Syndrome: Recognition and Treatment

Brad E. Cooper, PharmD
Celeste A. Sejnowski, PharmD

erotonin syndrome (SS) is a complication resulting from excessive effects of

serotonin on the central nervous system, and it usually results from taking
medications, such as the antidepressant agents known as selective serotonin reuptake inhibitors (SSRIs), that elevate levels of serotonin either therapeutically or
with intentional overdoses. Many reported cases are the result of unintended
drug interactions that elevate the effects of the serotonergic medication.1,2 Because
prompt recognition and appropriate treatment are necessary for patient recovery, all critical care practitioners should be aware of this syndrome. However, a
study reported that more than 85% of physicians are unaware of SS as a clinical
diagnosis.3 The purpose of this column is to review the pathophysiology, epidemiology, signs and symptoms, and appropriate treatment of SS.
Pathophysiology
Serotonin is produced by decarboxylation and hydroxylation of l-tryptophan.
Several serotonin receptors are divided into seven 5-hydroxytryptophan (5-HT)
families, and several of these receptors have subtypes.1 Agonism of 5-HT2A receptors contributes most substantially to SS. Serotonin is involved in regulating
wakefulness, affective behavior, thermoregulation, emesis, and sexual behavior as
well as regulation of vascular tone and gastrointestinal motility.
Epidemiology
The first cases of SS were reported in the 1950s with monoamine oxidase inhibitors (MAOIs). Reports have increased as the use of SSRIs has increased. A 2002
report from the Toxic Exposure Surveillance System identified 26 733 exposures
to SSRIs, resulting in 7349 major or moderate adverse effects and 93 deaths.4
A 2004 report from the Toxic Exposure Surveillance System identified 48 204
exposures to SSRIs that resulted in moderate or major adverse outcomes in 8187
patients and death in 103 patients, with most fatalities associated with coingestions of other substances.5
Diagnosis of SS
The signs and symptoms of SS can run the spectrum from mild to life-threatening
and are summarized in Table 1. As reviewed by McAllen and Rhoney,6 3 sets of
criteria have been developed to diagnose SS: the Sternbach criteria, the Hunter

Brad E. Cooper is Clinical Pharmacist, Critical Care, UPMC Hamot, 201 State St, Erie, PA 16550
(cooperbe@upmc.edu).
Celeste A. Sejnowski is PGY1 Pharmacy Resident, UPMC Hamot, Erie, Pennsylvania.
The authors declare no conflicts of interest.
DOI: 10.1097/NCI.0b013e31827eecc6

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antiemetics, antimigraine agents, illicit drugs,

and over-the-counter drugs (eg, St. Johns
wort, dextromethorphan). Table 3 lists serotonergic agents that can cause SS either alone
or in combination with other agents. Serotonin
syndrome can be precipitated when MAOIs
are given in combination with serotonin agonists, especially SSRIs. Taking multiple causative agents, self-poisoning with serotonergic
agents, and drug interactions among SSRIs can
lead to SS. People who are on a chronic regimen of SSRIs have a higher risk of SS, but it
also has been documented in patients taking
therapeutic doses of SSRIs.16

Table 1: Signs and Symptoms of

Serotonin Syndrome
Mild

Moderate

Severe

Tachycardia

Tachycardia

Tachycardia

Shivering

Hypertension

Hypertension (but
can deteriorate
to shock)

Diaphoresis

Hyperthermia
(as high as
40C)

Delirium

Mydriasis

Mydriasis

Muscle rigidity

Tremor or
myoclonus

Hyperactive
bowel
sounds

Hypertonicity

Hyperreflexia

Diaphoresis

Severe
hyperthermia
(41C)

Hyperreflexia
and clonus
greater in
the lower
extremities
(may be
inducible)

Metabolic
acidosis

Ocular clonus

Rhabdomyolysis

Drug Interactions
Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors are used to treat

depression and anxiety, but they are used rarely
because of the risk of toxicity and food and drug
interactions. Examples of MAOIs include phenelzine and isocarboxazid. Selective serotonin
reuptake inhibitors and MAOIs can interact,
overstimulating the serotonin receptors in the
brain. The serotonin transporter on presynaptic
terminals of neurons mediates the reuptake of
serotonin into the presynaptic terminal. Treatment with an SSRI blocks reuptake and results
in enhanced and prolonged serotonergic neurotransmission. Normally, serotonin in a neuron
is removed from the synapse by active transport
back into the presynaptic neuron. In the presynaptic neuron, serotonin is either repackaged
for release into the synapse or broken down
by monoamine oxidase.10 Monoamine oxidase
is an intracellular enzyme that is bound to the
mitochondrial membrane, and its function is to
inactivate norepinephrine, dopamine, and serotonin via oxidation. When monoamine oxidase
is inhibited, neurotransmitters accumulate in
the presynaptic nerve.17
When an MAOI is taken concomitantly with
an SSRI, the serotonin reuptake mechanism
as well as serotonin breakdown is blocked by
the MAOI. As a result, no serotonin is released
into the synapse. To avoid potential interaction between medications causing SS, clinicians
should wait an adequate length of time between
discontinuation of one medication and initiation of another; this waiting time is known as
a washout period. For example, the SSRI
fluoxetine has a long half-life as a result of its
metabolite, so a 5-week washout period between discontinuing fluoxetine and adding an

Elevation
of serum
aminotransaminases and
creatinine
Seizure
Disseminated
intravascular
coagulopathy

Serotonin Toxicity criteria, and the Radomski

criteria.79 Table 2 summarizes the criteria for
each of these sets. The Sternbach criteria rely
heavily on mental status changes, and patients
with delirium due to anticholinergics may be
diagnosed as positive for SS by the Sternbach
criteria.9 The Radomski criteria differentiate
mild and severe SS. The Hunter criteria may be
the most accurate criteria, with 84% sensitivity
and 97% specificity when compared to diagnosis by a medical toxicologist.8
Causative Drugs
Serotonin syndrome is most commonly caused
by SSRIs. Other drugs that can lead to the development of SS include tricyclic antidepressants
(TCAs), opiate analgesic agents, antibiotics,
16

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Drug Update

Table 2: Diagnostic Criteria for Serotonin Syndromea

Sternbach

Radomski

Hunter

Must have recent addition of known

serotonergic agent, absence
of other causes, and no recent
addition of a neuroleptic agent
and must exhibit at least 3 of the
following:

Mild state:

Must have taken a serotonergic

agent and meet one of the
following criteria:

Restlessness
Insomnia

Spontaneous clonus

Incoordination

Inducible clonus plus agitation

or diaphoresis

Mental status changes

Dilated pupils

Agitation

Akathisia

Hyperreflexia

Tachycardia

Myoclonus

Tachypnea/dyspnea

Diaphoresis

Diarrhea

Shivering
Tremor
Diarrhea

Autonomic instability

Ocular clonus plus agitation or

diaphoresis
Tremor plus hyperreflexia
Hypertonia plus temperature
higher than 38C plus ocular
clonus or inducible clonus

Severe state:

Incoordination

Impaired level of
consciousness

Elevated temperature

Elevated mood
Coma
Myoclonus
Tremor
Shivering
Rigidity
Hyperreflexia
Hyperthermia
Sweating

Adapted from McAllen and Rhoney.6 Reproduced with permission of the publisher. Copyright 2012 Society of Critical Care Medicine.

MAOI is required to decrease the risk of SS.18

Other SSRIs should have a washout period of
2 weeks.10

Other Antidepressants

Trazodone and nefazodone are weak inhibitors of serotonin uptake. Serotonin syndrome
can occur if MAOIs are administered with these
drugs. Of note, trazodone has serotonin reuptake inhibition at antidepressant doses of 150
mg or higher.20
Tricyclic antidepressants (TCAs) have actions similar to those of the SNRIs but have
more adverse effects than SNRIs. Each TCA
has different selectivity toward serotonin and
norepinephrine. For example, clomipramine
is a potent serotonin reuptake inhibitor. The
other TCAs can be used with caution for patients who are severely resistant to treatment.20
Tricyclic antidepressants should not be used
concurrently with MAOIs or within 14 days

Serotonin-Norepinephrine Reuptake
Inhibitors

Venlafaxine is a serotonin-norepinephrine
reuptake inhibitor (SNRI) that binds both
serotonin and norepinephrine inhibitors. A
14-day washout period is required after ending
MAOI therapy and before starting venlafaxine
treatment.19 Only a 7-day washout is required
after discontinuing venlafaxine and beginning an MAOI. Duloxetine, another SNRI,
requires only a 5-day washout period after
discontinuing duloxetine and before beginning
MAOI treatment.19
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of discontinuing MAOI therapy. Cyclobenzaprine, carbamazepine, and oxcarbazepine are

structurally related to the TCAs; however, these
drugs do not block serotonin or norepinephrine
uptake, so they can be used with caution.20

Table 3: Serotonergic Agentsa

Inhibitors of serotonin reuptake
Amphetamines
Analgesic agents: tramadol, meperidine,
methadone

Other Prescription Medications

Cocaine

Opiates such as dextromethorphan, fentanyl,

meperidine, methadone, and tramadol have
serotonin reuptake inhibition. The level of risk
with serotonergic opiates is most likely low
based on the level of evidence that exists, but
opiates not known to be serotonergic reuptake
inhibitors should be used with caution.18 Morphine, hydromorphone, aspirin, and acetaminophen are presumed safe analgesic alternatives.2
Buspirone is a 5-HT1A partial agonist, and
it could theoretically contribute to SS; therefore, it should be administered with caution.20
However, no good evidence has shown that buspirone causes SS when administered with SSRIs
and MAOIs.21
Linezolid is an oxazolidinone antibiotic drug
that was originally found to have psychotropic effects through mild reversible nonselective
inhibition of monoamine oxidase.12 This drug
was also found to have activity against drugresistant bacteria such as methicillin-resistant
Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. When linezolid is
taken with serotonin agonists, a small risk of SS
exists. Quinn and Stern12 and Lawrence et al14
concluded that decisions about discontinuing
or not initiating SSRIs with linezolid need to be
based on risks versus benefits of need for this
antibiotic versus the risk of SS.
5-Hydroxytryptamine receptor agonists
(triptans) are antimigraine agents that activate
the 5-HT1B and 5-HT1D receptors in the brain.
When used in combination with an SSRI or
SNRI, SS can occur. However, the evidence supporting this association is controversial. In July
2006, the US Food and Drug Administration
(FDA) issued a warning that SS can occur when
a triptan is taken with an SSRI or SNRI. Evans
et al22 concluded that only class IV evidence (uncontrolled studies, case series, case reports, expert opinions) is provided in the literature and
through the FDA registration of adverse events
to support the July 2006 FDA statement. They
also concluded that data were conflicting and
that no evidence-based recommendations could
be made. Sclar et al23 reviewed the number of
patients who were prescribed triptan and an
SSRI or SNRI after the FDA warning in 2006

Dextromethorphan
Serotonin-norepinephrine reuptake inhibitors:
venlafaxine
Selective serotonin reuptake inhibitors:
citalopram, escitalopram, fluvoxamine,
fluoxetine, paroxetine, sertraline
St. Johns wort
Tricyclic antidepressants: amitriptyline,
desipramine, clomipramine, imipramine,
doxepin, nortriptyline
Trazodone, nefazodone
Inhibitors of serotonin metabolism (decreased
serotonin degradation)
Linezolid
Monamine oxidase inhibitors: isocarboxazid,
phenelzine, rasagiline, selegiline,
tranylcypromine
Increased serotonin release
Amphetamines
Cocaine
Codeine
Dextromethorphan
Fenfluramine
Levodopa
MDMA (Ecstasy)
Meperidine
Methadone
Mirtazapine
Pentazocine
Reserpine
Direct serotonin receptor agonists
5-HT1 agonists: almotriptan, eletriptan,
frovatriptan, naratriptan, rizatriptan,
sumatriptan, zolmitriptan
Buspirone
Dihydroergotamine
Indirect serotonin receptor agonist
Lithium
a

Based on data from references 10 to 15.

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(1.8% of patients). They concluded that not

enough literature is available as to the number
of cases of SS resulting from the concomitant
use of triptan with SSRI or SNRI. Note that ergotamine and its analogs do not seem to cause
SS as reported in the literature.21

Table 4: Treatment Options for Serotonin

Syndromea
Severity
Mild

Treatment
Remove causative agents
Intravenous fluids for hydration and
diuresis

Other Agents

Benzodiazepines for agitation

MDMA (Ecstasy) is a recreational drug that is

an amphetamine derivative and directly releases
serotonin from the nerve terminals, which can
induce SS when used alone or facilitated by high
temperatures and dehydration. Lysergic acid
diethylamide does not seem to cause SS in either
usual doses or overdoses.21
Synthetic cathinones, also known as bath
salts, have been associated with SS. Bath salts
increase the synaptic concentration of serotonin
and inhibit monoamine uptake transporters.24
Hypericum perforatum, commonly known
as St. Johns wort, is an herb available over
the counter that is used to treat depression. St.
Johns wort has been associated with SS when
taken with 5-HT reuptake inhibitors.13

Moderate

Above therapy
Cyproheptadine
Dosing: 12 mg PO/NG initially
followed by 2 mg every 2 h if
symptoms continue
Maintenance dose: 8 mg PO/NG
every 6 h once the patient is
stabilized
Chlorpromazine (not first choice)
Dosing: 50-100 mg IM 1
Use with caution in patients who are
hypotensive
Olanzapine (not first choice)
Dosing: 10 mg SL 1

Severe

Treatment of SS
Early recognition of SS is crucial. If a patient
is taking multiple agents that can cause SS, clinicians should counsel him or her on the signs
and symptoms of SS. The treatment of SS is
summarized in Table 4. First-line treatment
includes withdrawal of the serotonergic drugs.
Benzodiazepines, such as diazepam, can be used
to control agitation in mild, moderate, and severe cases. Mild cases are typically managed
by supportive care, withdrawal of causative
agents, and treatment with benzodiazepines.1
Moderate cases include cardiorespiratory and
thermal abnormalities, and these patients may
benefit from an antidote such as cyproheptadine.
Cyproheptadine is a 5-HT2A antagonist; however, evidence is inconclusive on its effectiveness
in SS. Cyproheptadine is available only in oral
form, but tablets may be crushed and administered via a nasogastric tube.1 Chlorpromazine
or olanzapine can also be used, but they have
adverse and toxic effects. Chlorpromazine can
cause hypotension, lower the seizure threshold,
and cause dystonic reactions.18,26 Olanzapine has
a potential to lower the seizure threshold as well.
Severe cases caused by hyperthermia may
require intubation, neuromuscular paralysis,
and sedative agents.25 Antipyretic agents do
not help with hyperthermia in these cases, because hyperthermia in SS is caused by muscle

Above therapies
Cooling blankets
Muscle relaxants (dantrolene)
Paralysis (vecuronium)
Intubation
Sedative agents

Abbreviations: IM, intramuscularly; NG, nasogastric; PO, by

mouth; SL, sublingual.
a
Based on data from references 1, 2, 7, 10, 18, and 25 to 27.

hypermetabolism and not by central nervous

system effects. Muscle relaxants can be used for
muscle rigidity and hyperthermia caused by SS;
however, the use is controversial, because no
controlled trials support it.1,10,28 In severe cases,
nondepolarizing agents, such as vecuronium,
can be used in conjunction with intubation and
ventilation. Note that succinylcholine should
not be used in these patients for paralysis because of risk for arrhythmias.1
Summary
Serotonin syndrome can be a life-threatening
adverse reaction to SSRIs and other drugs and
supplements that have serotonergic effects or
that may interact with these agents. Prompt recognition, withdrawal of precipitating agents, and
treatment may prevent complications from SS.
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