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SEROTONIN SYNDROME
DANA BARTLETT, RN, BSN, MSN, MA
Dana Bartlett is a professional nurse and author. His
clinical experience includes 16 years of ICU and ER
experience and over 20 years of as a poison control
center information specialist. Dana has published
numerous CE and journal articles, written NCLEX
material, written textbook chapters, and done editing
and reviewing for publishers such as Elsevire,
Lippincott, and Thieme. He has written widely on the subject of toxicology and was
recently named a contributing editor, toxicology section, for Critical Care Nurse
journal. He is currently employed at the Connecticut Poison Control Center and is
actively involved in lecturing and mentoring nurses, emergency medical residents
and pharmacy students.
ABSTRACT
Drugs can react to cause the body to have too much serotonin and
lead to serotonin syndrome, which is a potentially life threatening
condition. Serotonin syndrome is caused by therapeutic doses, drug
interactions, or overdoses of medications that directly or indirectly
affect the serotonergic system. An excess stimulation of the
serotonergic receptors is what causes serotonin syndrome. The
stimulation is excitatory and causes symptoms, such as tachycardia,
hypertension, agitation, excessive muscular activity. There is no
proven antidote for serotonin syndrome that is effective and safe. The
best treatment is supportive care. Health care professionals must
consider the possibility of serotonin syndrome in the setting of
serotonergic medications where mental status changes and
neurological hyperexcitability occur.
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Continuing Nursing Education Course Planners
William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,
Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner
Policy Statement
This activity has been planned and implemented in accordance with
the policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's
Commission on Accreditation for registered nurses. It is the policy of
NurseCe4Less.com to ensure objectivity, transparency, and best
practice in clinical education for all continuing nursing education (CNE)
activities.
Continuing Education Credit Designation
This educational activity is credited for 2 hours. Nurses may only claim
credit commensurate with the credit awarded for completion of this
course activity.
Pharmacology content is 30 minutes.
Statement of Learning Need
Nursing knowledge to identify serotonin syndrome and to help patients
avoid it is imperative to avoid complications. Patients that are
prescribed serotonergic medications need to be educated and warned
about the possibility of serotonin syndrome and subtle changes that
could lead to severe adverse outcomes.
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Course Purpose
This course will help nurses identify signs and symptoms of
serotonin syndrome and recommended treatment.
Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses
and Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Dana Bartlett, RN, BSN, MSN, MA, William S. Cook, PhD,
Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC –
All have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Activity Review Information
Reviewed by Susan DePasquale, MSN, FPMHNP-BC.
Release Date: 2/15/2016
Termination Date: 3/3/2017
Please take time to complete a self-assessment of knowledge,
on page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge
learned will be provided at the end of the course.
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1.
Which of the following is the correct definition of serotonin
syndrome?
a. Signs and symptoms caused by excessive stimulation of the
serotonergic system.
b. Signs/symptoms caused by serotonergic drug overdose.
c. A clinical condition that closely resembles neuroleptic
malignant syndrome.
d. A clinical condition characterized hyperthermia, clonus, and
agitation.
2.
Which of these classes of drugs that inhibits the reuptake
of serotonin?
a. Common analgesics
b. Illicit drugs
c. Sympathomimetics
d. SSRIs
3.
Three illicit drugs that may cause serotonin syndrome are:
a. Methamphetamine, heroin, marijuana
b. Cocaine, LSD, ecstasy
c. Marijuana, ecstasy, cocaine
d. Dextromethorphan, LSD, methamphetamine
4.
The criteria used to diagnose serotonin syndrome are:
a. Sternbach’s criteria
b. Hunter’s criteria
c. Modified Glasgow scale
d. Romberg criteria
5.
Two clinical conditions that may be mistaken for serotonin
syndrome are:
a. Cholinergic syndrome, syndrome, malignant hyperthermia
b. Anticholinergic syndrome, Stevens-Johnson syndrome
c. Neuroleptic malignant syndrome, anticholinergic syndrome
d. Sympathomimetic syndrome, drug-induced hypothermia
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Introduction
Serotonin syndrome is a group of signs and symptoms caused by
excessive stimulation of the serotonin receptors. Serotonin syndrome
is caused by therapeutic doses, drug interactions, or overdoses of
medications that directly or indirectly affect the serotonergic system.
The first case of diagnosed serotonin syndrome occurred in the late
1950s, but case reports of unrecognized serotonin syndrome predate
that by at least 20 years. The clinical presentation of serotonin
syndrome can be intense and dramatic, but it can also be mild and
subtle. Serotonin syndrome can be mistaken for an infectious or
metabolic disorder or for the clinical syndromes caused by
anticholinergic or sympathomimetic poisoning, or for the neuroleptic
malignant syndrome or malignant hyperthermia.
Although it is unusual for the serotonin syndrome to cause a fatality, a
severe case of serotonin syndrome is a medical emergency that can
rapidly cause multi-system organ failure. Nurses must be aware of
serotonin syndrome because drugs that can cause it are in common
use, and intentional overdoses with drugs that can cause the serotonin
syndrome are being seen with increasing frequency, which make it
difficult to detect and easily mistaken serotonin syndrome for other
pathologies.
Serotonergic System
Serotonin (also called 5-hydroxytryptamine) is a monoamine
neurotransmitter that acts centrally and peripherally. It is synthesized
in the central nervous system and in enterochromaffin cells in the
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gastrointestinal tract. Serotonin has many complex functions, and the
full range and activity of these is not known.
In the brain, serotonin is involved in mood, personality, affect,
appetite, motor function, temperature regulation, sexual activity, pain
perception, and sleep induction. Serotonin also inhibits gastric
secretion, acts as a smooth muscle stimulant, promotes platelet
aggregation, affects vascular tone, and is a central and peripheral
neurotransmitter.
Serotonin is stored in vesicles in presynaptic neurons. It is released
into the synaptic cleft and binds to a serotonin receptor on the
postsynaptic neuron. There are seven families of serotonin receptors
(5-HT1 to 5HT7) and several of these have different subtypes, for
example, 5-HT1A. Serotonin binding to a 5-HT receptor initiates a wide
variety of effects on the post-synaptic neuron (decreasing or
increasing intracellular cAMP levels, causing Na+ and Ca2+ influx and
depolarization action), however the basic effect of serotonin is
excitatory.
After binding to the receptor, serotonin is transported back to the
presynaptic neuron where it reenters the vesicles or is broken down by
monoamine oxidase.1,2
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Learning Break:
Neurotransmitters such as serotonin, dopamine, and glycine, function by
binding to receptors on the membranes of post-synaptic neurons. These
receptors are ligand-gated ion channels or G protein receptors. When a
neurotransmitter binds to a ligand-gated ion channel, the channel opens and
ions enter or leave the cell: depending on which ions enter or leave, the effect
of the neurotransmitter can be excitatory (causing cell depolarization) or
inhibitory (preventing cell depolarization). When a neurotransmitter binds to a
G protein, the same effects occur.
Example:
When serotonin binds to G proteins of the 5-HT1 receptors, potassium ions
channels open, potassium leaves the cell – increasing membrane potential and
inhibiting depolarization – and cAMP concentrations are decreased, and the
effect is inhibitory. It is important to remember that the terms inhibition and
excitation refer to how the neurotransmitter affects the cell. The physiological
action produced by excitation may be a decrease in a particular function (i.e.,
decreased peristalsis) and the physiological action produced by inhibition may
be an increase in a particular function (i.e., muscle tremor or hyperreflexia).
Serotonin Syndrome: Epidemiology
Serotonin syndrome is not a recent phenomenon. It was first
recognized in animals, and the first case described in a human was
reported in 19593 The term serotonin syndrome was first used by Insel
et al in 1982 to describe a patient who developed serotonin syndrome
from a combination of an monoamine oxidase (MAO) inhibitor and a
tricyclic antidepressant.4
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The exact incidence of serotonin syndrome is not known. One author
noted that 14-16% of all patients who took an overdose of a selective
serotonin reuptake inhibitor (SSRI) had signs and symptoms of
serotonin syndrome.5 Fatality rates have been reported to be between
2-12%, but death from serotonin syndrome is considered to be an
unusual event.6 Serotonin syndrome has been described in all ages
groups, including neonates, children, and the elderly.7-9
Serotonin Syndrome:
How It Happens And The Clinical Presentation
The essential cause of serotonin syndrome is an excess stimulation of
the serotonergic receptors. The stimulation is excitatory and causes
the tachycardia, hypertension, agitation, and excessive muscular
activity. and the other signs and symptoms of the syndrome. The
excess stimulation occurs by one of the following six mechanisms:10-13

Direct stimulation of the serotonergic receptors:
Such as occurs with the medications buspirone, carbamazapine,
lithium, as well as with LSD.

Excessive release of serotonin:
Such as occurs with amphetamines, cocaine, dextromethorphan,
levodopa, monoamine oxidase inhibitors, reserpine, as well as
with ecstasy/MDMA.

Decreased breakdown of serotonin:
Such as occurs with monoamine oxidase inhibitors and St. John’s
wort.
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
Enzyme inhibition:
Cytochrome P450 enzymes that metabolize certain serotonergic
drugs can be inhibited by these drugs, e.g., dextromethorphan,
methadone, oxycodone, tramadol, venlafaxine.

Increase in serotonin precursors:
The essential amino acid, Tryptophan.

Decreased serotonin reuptake:
Selective serotonin-reuptake inhibitors, such as citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine, and
sertraline; as well as, dextromethorphan, monoamine oxidase
inhibitors, methadone, and trazadone.
It is not known exactly which families and subtype of serotonin
receptors are involved in the serotonin syndrome, which could be one
of the factors accounting for the variability of the clinical presentation
of this pathology.14 Some authors, however, have identified the 5-HT1C
and the 5-HT2 receptors as the ones affected in the serotonin
syndrome.15 Although there is a wide range of signs and symptoms
that are possible, serotonin syndrome is definitely characterized and
diagnosed by abnormal autonomic, cognitive, and neuromuscular
changes.16-18 These are further outlined below:

Autonomic:
Autonomic changes include hyperthermia, hypertension,
tachycardia, diaphoresis, flushing, increased bowel sounds,
diarrhea, and mydriasis. The hyperthermia can be very severe
with a body temperature ≥ 38.5° C and higher.
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
Cognitive:
There are many cognitive changes associated with serotonin
syndrome such as agitation, drowsiness, coma, hypomania,
anxiety, confusion, hallucinations, and delirium.

Neuromuscular:
Akathisia, clonus, hyperreflexia, myoclonus, rigidity, shivering,
and tremor.
Learning Break:
Clonus - inducible, ocular, or spontaneous - is the most reliable finding
when diagnosing serotonin syndrome. Clonus is defined as alternate
muscular contraction and relaxation in rapid succession. This will be
discussed in more detail later in the module.
These are the signs and symptoms that have been observed in
patients who have serotonin syndrome. The clinical presentation and
the severity of signs and symptoms are quite variable: the serotonin
syndrome can be mild and quite subtle in presentation or severe and
life threatening.
Patients with a mild case of serotonin syndrome may feel restless and
anxious, they may have a low-grade fever, and mild, intermittent
tremors, and it is easy to overlook or misdiagnose these types of
cases. A severe case of serotonin syndrome is a medical emergency.
These patients may have a body temperature >41° C. Coma,
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metabolic acidosis, renal failure, rhabdomyolysis, and disseminated
intravascular coagulation (DIC) may occur and all of this can develop
very rapidly.19,20
Serotonin syndrome typically begins very quickly: the onset of effects
can be within minutes after exposure. In most cases the patient will
develop signs and symptoms within six hours after exposure to a drug
or drugs,21,22 but a delay of up to 24 hours is possible.23-25 Most cases
resolve within 24 hours, but there have been reports of the serotonin
syndrome lasting for several days.26
Drugs That Cause Serotonin Syndrome
Certain classes of medications have been definitely identified as drugs
that can cause serotonin syndrome, and this makes sense because
their therapeutic effect is based on their action on the serotonergic
system. The SSRIs such as fluoxetine and sertraline, and monoamine
oxidase inhibitors (MAOIs) such as phenelzine and moclobemide, are
common examples of these drugs.
Other drugs may cause serotonin syndrome; however, the connection
between the syndrome and the drug is not as obvious because many
drugs affect uptake or metabolism of multiple neurotransmitters that
does not always translate to a measurable or observable clinical effect.
Two such examples are bromocriptine and tramadol. Both drugs do
have an in vivo effect on the serotenergic system; however, the
therapeutic effect of bromocriptine is caused by dopamine receptor
agonist activity, and the therapeutic effect of tramadol is caused by
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agonism of the mu opioid receptors. Yet, both bromocriptine and
tramodol can cause serotonin syndrome.
Drugs and supplements that have been identified as causing, being
associated with, or suspected of causing serotonin syndrome
include:27-32

Sympathomimetics:
Fenfluramine, phentermine, phenylpropanolamine

5-HT1 agonists:
Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan, zolmitriptan

Monoamine oxidase inhibitors: Isocarboxazid, moclobemide,
phenelzine, selegiline, and tranylcypromine

Selective serotonin reuptake inhibitors:
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline

Tricyclic antidepressants:
Amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, maprotiline, nortriptyline, protriptyline, trimipramine

Opiates/analgesics:
Buprenorphine, codeine, levomethorphan, levorphanol,
meperidine, methadone, oxycodone, pentazocine, pethidine,
tapentadol, tramadol
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
Illicit drugs:
Amphetamine, bath salts, cocaine, ecstasy/MDMA, LSD
(unconfirmed)

Antidepressants and anxiolytics:
Bupropion, buspirone, duloxetine, mirtazapine, nefazodone,
trazodone, venlafaxine.

Antiemetics:
Droperidol, granisetron, metoclopramide, ondansetron

Dietary supplements/herbal product:
Ginseng, St. John’s wort, tryptophan, yohimbe

Other drugs:
Amantadine, bromocriptine, carbamazapine, carisoprodol,
chlorpheniramine, dextromethorphan, dihydroergotamine,
fluconazole, levodopa, linezolid, lithium, methylene blue,
olanzapine, reserpine, ritonavir, and 5methoxydiisopropyltryptamine (a.k.a. foxy methoxy).
An increased dose of a serotenergic drug, or the addition of a
sertonergic drug to the medication regimen of a patient already taking
a SSRI, MAO, or others (discussed further below) usually causes
serotonin syndrome. It can also be a consequence of overdose.
Serotonin syndrome after a single dose of a serotonergic drug is
unusual, but this has been reported;33-35 and, it is far more common
for serotonin syndrome to be caused by a combination of drugs that
act at different 5-HT receptor sites.
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Drug interactions can also be a cause of serotonin syndrome, even if
one of the drugs does not affect the serotonergic system. If a patient
who is taking an SSRI is prescribed a medication that inhibits the
cytochrome P450 enzyme that metabolizes the SSRI, serotonin
syndrome is possible.36
Furthermore, discontinued serotonergic medications can cause
serotonin syndrome if there is an insufficient period of time between
the discontinuation of one medication and beginning therapy with
another.37 An example is Norfluoxetine, which is a metabolite of
fluoxetine that has a half-life of approximately 2.5 weeks. Because of
the long half-life of this drug and its metabolite, fluoxetine may cause
serotonin syndrome if a patient is given another serotonergic drug
within several weeks of the discontinuation of fluoxetine.38
The drug combinations in the list below have been reported to cause,
or be associated with the serotonin syndrome.38-41 It’s important for
health care providers to continuously review an approved drug
database for current information when prescribing or administering
any form of mono- or combination drug therapy. Drug-drug
interactions are one possible cause of serotonin syndrome. Underlying
medical conditions must also be considered. The list below is complete
as of this writing, but there are new reports added all the time in the
medical literature about drug combinations that can cause serotonin
syndrome.

MAOIs and amphetamines, dextromethorphan, meperidine,
SSRIs, TCAs, and serotonin-norepinephrine re-uptake inhibitors
(SNRIs).
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
SSRIs and amphetamines, buspirone, carbamazapine,
dextromethorphan, fluconazole, MAOIs, opiates, L-tryptophan,
phentermine, SNRIs, other SSRIs, TCAs, or St John’s wort.

Opiates and ciprofloxacin, MAOIs, SSRIs, SNRIs, or tramadol.

Tramadol and mirtazapine, olanzapine, opiates, SSRIS, or
sertraline.

Other anti-depressants: buspirone and SSRIs; mirtazapine and
SSRIs; trazodone and amitriptyline, buspirone, or lithium;
venlafaxine and amitriptyline, ciprofloxacin, fluoxetine or other
SSRIs, linezolid, lithium, meperidine, methadone, moclobemide,
quietiapine, or trazodone.

Atypical anti-psychotics and mood stabilizers: Olanzapine and
citalopram or lithium; Risperidone and dextromethorphan,
fluoxetine, or paroxetine

Linezolid and amitriptyline, citalopram, duloxetine escitalopram,
fentanyl, fluoxetine, meperidine, paroxetine, sertraline, and
venlafaxine.
Severe cases of serotonin syndrome appear to be more common if
multiple drugs are taken than when a single serotonergic drug is taken
in overdose or therapeutically. Monoamine oxidase inhibitors are
particularly dangerous when combined with selective serotoninreuptake inhibitors, ecstasy, dextromethorphan, or meperidine.42
Diagnosing Serotonin Syndrome
Serotonin syndrome is a clinical diagnosis. There is no way to confirm
the diagnosis by using laboratory tests. The clinician must make the
diagnosis of serotonin syndrome by including the following: 1) a
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physical exam; 2) taking a health and medication history, and; 3)
ruling out other clinical syndromes that can resemble the serotonin
syndrome.
Outlined in that manner, making the diagnosis of serotonin syndrome
might appear to be relatively simple, but it can be difficult to do. Mild
or even moderately symptomatic cases can easily be overlooked or
misdiagnosed43, and there is some evidence that physicians do not
know about the serotonin syndrome or its diagnostic criteria. Mckay, et
al. (1999) found that slightly over 85% of physicians who were
prescribing a medication that could cause serotonin syndrome were
not aware of the serotonin syndrome.44
Diagnostic Criteria
Although making the diagnosis of serotonin syndrome can be
challenging, there are different diagnostic criteria available that can
help.

Sternbach’s criteria:
This was the first set of criteria that was developed for
diagnosing serotonin syndrome.45 Sternbach’s criteria is a list of
10 clinical findings and three clinical situations. The clinical
findings of Sternbach’s criteria are: Ataxia, changes in mental
status (agitation, confusion, hypomania) diaphoresis, diarrhea,
fever, hyperreflexia, myoclonus, restlessness, shivering, and
tremor. The clinical situations are: 1) a recent addition, or
increase in dose of a known serotonergic drug; 2) confirmed
absence of other etiologies that could explain the patient’s
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clinical condition such as an infectious disease, metabolic
abnormality, or substance intoxication or withdrawal; and, 3) no
recent addition or increase in dose of a neuroleptic drug.
According to the criteria a patient has serotonin syndrome if the
patient has three or more of the clinical findings and the patient
has been exposed to a serotonergic drug, has not been exposed
to a neuroleptic, and other likely causes of the signs and
symptoms have been ruled out.

Hunter criteria:
The Hunter’s criteria were developed in 2003.46 The authors
were dissatisfied with Sternbach’s criteria, and they reviewed
2222 cases of serotonergic drug overdose. The physical findings
in these patients were noted, and then the ones that were seen
most often in patients who been diagnosed by a clinical
toxicologist as having serotonin syndrome were considered to be
the criteria for diagnosing serotonin syndrome.
The Hunter criteria state that a patient has serotonin syndrome
if: 1) there has been an overdose of a serotonergic drug, or
exposure to a serotonergic drug within the prior five weeks; 2)
the patient has inducible clonus, ocular clonus, or spontaneous
clonus; 3) the temperature is > 38°; 4) The patient is agitated
and/or diaphoretic; and, 4) hyperreflexia and/or tremor are
noted.

Radomski criteria:
The Radomski criteria were developed in 2000 and use many of
the same clinical findings as Sternbach’s criteria and the Hunter
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criteria.47 However, the Radomski criteria are intended to
provide diagnostic criteria for establishing the severity of the
serotonin syndrome.
The Hunter criteria (or those criteria, slightly adapted) is the system
that is used most often and is recommended.48 The Sternbach criteria
appear to be biased towards mental status changes, and the Hunter
criteria are felt to be more sensitive and specific and less likely than
the Sternbach criteria to miss incipient or mild cases of serotonin
syndrome.49 The Radomski criteria do not appear to be popular and
although other diagnostic criteria have been developed (i.e., the
serotonin syndrome scale) these do not appear to be in common use.50
THE HUNTER CRITERIA
Ingestion of a serotonergic drug within 5 weeks
or overdose of a serotonergic drug
↓
Spontaneous clonus → Yes → Serotonin syndrome
↓
No
↓
Inducible clonus, ocular clonus → Yes → Agitation,
↓
diaphoresis,
No
fever > 38°
↓
Tremor → Yes → Hyperreflexia → Serotonin
Syndrome
↓
No
↓
Not Serotonin Syndrome
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Dunkley, et al., (2003) made the point that the term serotonin
syndrome may contribute to the confusion surrounding this syndrome
and the under-diagnosis of serotonin syndrome.51 They suggested that
the diagnostic criteria - or perhaps the physicians using these criteria over-emphasize the more dramatic signs of serotonin syndrome. This
may result in milder forms of the syndrome being missed, and the
study by Dunkley, et al., also suggested that serotonin toxicity might
be a better term than serotonin syndrome as a syndrome is typically
thought of as a defined clinical entity. The key point for clinicians to
realize is that serotonin syndrome is a spectrum of toxicity that is
caused by an excess of serotonin; and, serotonin syndrome along the
spectrum can be diagnosed by using the Hunter criteria to look for the
characteristic autonomic, cognitive, and neuromuscular changes.
Taking a Health and Medication History
Taking an accurate health and medication history is very important. It
is fundamental to determine what medications the patient is taking
and has been taking. The clinician must be cognizant of the fact that
some drugs can cause serotonin syndrome even when the patient has
not been taking them for many weeks. Therefore, its good practice to
ask the patient whether doses have recently been changed; ask if the
patient has been taking any dietary or herbal supplements, and
determine if the medication regimen has been changed in the past five
to six weeks. Additionally, the clinician needs to determine the recent
state of the patient’s health; for example, is there any evidence of an
ongoing infectious process? What other medical problems does the
patient have? Each time a patient medication regime is reviewed by a
clinician it’s necessary to include both the existing treatment plan (i.e.,
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new medications, and how they have been taking their prescriptions)
and any new organic issues in the patient’s health state.
Clinical Conditions Resembling Serotonin Syndrome
This section covers some clinical conditions that can resemble
serotonin syndrome.52,53 Neonatal considerations for newborns with
conditions resembling serotonin syndrome have been reported,
however, this is outside the scope of this study.
Neuroleptic malignant syndrome:
Neuroleptic malignant syndrome (NMS) is an idiosyncratic drug
reaction to treatment with, or withdrawal from drugs such as levodopa
and antipsychotics that act as dopamine antagonists. Important
differences between serotonin syndrome and NMS are:

The causative agents act on a different neurotransmitter;

NMS develops slowly over several days;

The clinical findings are different than those of the serotonin
syndrome, i.e., the pupils are not mydriatic, the patient will have
normal bowel sounds, and bradyreflexia and a rigid “lead-pipe
like” muscle tone will be noted; and,

NMS is not caused by an overdose.
Anticholinergic syndrome:
The anticholinergic toxidrome is caused by overdose of drugs that act
as antagonists of acetylcholine at peripheral and central muscarinic
receptors: antihistamines, benztropine, and phenothiazines are
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examples. Important differences between serotonin syndrome and the
anticholinergic syndrome are:

The causative agents act on a different neurotransmitter
receptor site;

The temperature is usually 38.8°C or less; and,

The patient will have dry mucous membranes, hot, dry, and
flushed skin, decreased or absent bowel sounds, normal
muscular tone and reflexes, and urinary retention.
Malignant hyperthermia:
Malignant hyperthermia is an idiosyncratic response to inhalational
anesthesia. Important differences between the serotonin syndrome
and malignant hyperthermia are:

The causative agent;

Malignant hyperthermia is an idiosyncratic response, but the
serotonin syndrome is a normal physiological response to an
excess of a neurotransmitter; and,

The patient will have hyporeflexia and the temperature is
extremely high, as high as 46°C.
Other clinical conditions that could be mistaken for serotonin syndrome
include acute baclofen overdose, cocaine or ecstasy intoxication, drug
withdrawal, dystonic reactions, encephalitis, meningitis, nonconvulsive seizures, sympathomimetic syndrome caused by a large
dose or an overdose of sympathomimetic drugs), sepsis, serotonin
discontinuation syndrome, thyroid storm, and tetanus.54-56
There are many clinical conditions that can be mistaken for serotonin
syndrome, and trying to remember them all and their distinguishing
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features can be difficult for clinicians. However, by far the most
commonly occurring are NMS and the anticholinergic syndrome. To
distinguish between NMS and the anticholinergic syndrome and
serotonin syndrome, the clinician needs to pay special attention to:

The drug ingested.

Body temperature.

Onset and development of the signs and symptoms.

Bowel sounds.

Presence or absence of hyperreflexia.

Presence or absence of clonus.
Serotonin Discontinuation Syndrome
When checking for the presence of the serotonin syndrome, it is
important to know what medications the patient has been taking; this
was previously discussed. However, if a symptomatic patient had been
taking an SSRI or another drug that affects the serotonergic system,
this can confuse the issue of assessment because if these drugs are
not tapered correctly the patient may develop serotonin
discontinuation syndrome. The syndrome occurs in approximately
20%-25% of all patients who stop taking a serotonergic drug.57
The signs and symptoms of serotonin discontinuation syndrome
usually start within one to seven days of decreasing the dose or
discontinuing the drug and they last approximately two weeks.
Somatic signs and symptoms of the serotonin discontinuation
syndrome include: chills, diarrhea, dizziness, fatigue, fever, nausea,
paresthesias, unsteady gait, and vomiting. Mood disturbances such as
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agitation, anxiety, insomnia, irritation, and lethargy are common, as
well.58,59 Most cases are mild, but severe effects have been reported.60
Treatment
Most cases of serotonin syndrome will improve dramatically or resolve
with 24 hours61 but if the patient has taken a drug with a long half-life,
a drug with pharmacologically active metabolites, or an extended
release form of a drug, the signs and symptoms can last for
weeks.62.63 Mild cases can be observed for six hours and if the patient
responds well to treatment or improves spontaneously, he/she can be
discharged. Moderate and severe cases should be admitted, and
patients who have ingested an extended release preparation should be
admitted or observed for longer than six hours.
Serotonin syndrome can be caused by an overdose of serotonergic
medications, but what is considered to be an overdose? The amount of
medication that could cause serotonin syndrome cannot be precisely
quantified, but an evidence-based expert consensus published in 2007
provides the following guidelines for the SSRIs:
“Asymptomatic patients or those with mild effects . . . following
isolated unintentional acute SSRI ingestions of up to five times
an initial adult therapeutic dose (i.e., citalopram 100 mg,
escitalopram 50 mg, fluoxetine 100 mg, fluvoxamine 250 mg,
paroxetine 100 mg, sertraline 250 mg) can be observed at home
with instructions to call the poison center back if symptoms
develop. For patients already on an SSRI, those with ingestion of
up to five times their own single therapeutic dose can be
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observed at home with instructions to call the poison center back
if symptoms develop.”64
Death from serotonin syndrome is unusual, but severe cases do occur
and the condition of patients who have severe serotonin syndrome
deteriorates very quickly. Patients who have severe serotonin
syndrome should be admitted to intensive care. The use of the drugs
suspected of causing the serotonin syndrome must be immediately
stopped: in mild cases this may be enough to allow the patient to
recover.
In order to avoid serious harm and to successfully treat serotonin
syndrome, it is critical to quickly identify serotonin syndrome and
aggressively provide supportive care. Antidotal therapies have been
tried, but supportive care is the keystone of caring for a patient who
has serotonin syndrome.65-66
Supportive Care
The mainstay of treatment for serotonin syndrome is supportive care.
It includes the following diagnostic tests and therapy.

Laboratory tests:
If the diagnosis of serotonin syndrome is thought to be likely or
the diagnosis seems certain, BUN and creatinine, coagulation
studies, complete blood count, creatine phosphokinase, and
serum transaminases should be obtained.
Other tests that may be needed for making the diagnosis of
serotonin syndrome would be blood cultures, urinalysis and urine
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culture, cerebrospinal fluid analysis and culture, chest x-ray, and
CT of the head.

Aggressive cooling:
Aggressive cooling should be used for patients who are
hyperthermic. Acetaminophen will not help because
hyperthermia in serotonin syndrome is caused by excessive
muscular activity, not by a change in central thermoregulation.

Intubation and neuromuscular paralysis:
This will treat the hyperthermia and also treat the basic cause of
hyperthermia. Do not use the neuromuscular blocker
succinylcholine during the intubation process. Use a
nondepolarzing drug such as vercuronium.
Patients who are hyperthermic often have rhabdomyolysis.
Rhabdomyolysis increases serum potassium and increases the
risk of arrhythmias, and succinylcholine can cause hyperkalemia.

Benzodiazepines:
Benzodiazpines are one of the mainstays of treatment for
serotonin syndrome, and in animal models they have been
shown to increase survival rates.67-69 They decrease muscular
rigidity, provide sedation and their use alone may be all that is
needed for a mild to moderate case of serotonin syndrome.

Direct-acting sympathomimetics:
If the patient is hypotensive, use the direct-acting
sympathomimetics epinephrine, norepinephrine, or
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phenylephrine. Dopamine acts indirectly. It must be metabolized
to epinephrine and norepinephrine before it can work and in
cases of serotonin syndrome the metabolizing enzyme
(monoamine oxidase) may be inhibited.

Nitroprusside:
Nitroprusside is a good drug to use for treating hypertension
caused by serotonin syndrome because its effects are very
short-acting: the half-life of nitroprusside is two to three
minutes. The autonomic instability in severe cases of serotonin
syndrome means that blood pressure can be very unstable and
unpredictable so using a drug that can tightly controlled is a big
advantage.70

Fluids:
Hydration is a very important treatment for serotonin syndrome.
Intravenous infusion for severe volume depletion is
recommended.

Monitor for complications:
The complications of serotonin syndrome are coma, DIC,
metabolic acidosis, renal failure, and rhabomyolysis.
Special Therapies
There is no antidote for serotonin syndrome that has been proven to
be effective and safe or for which there is extensive clinical
experience. Bromocriptine, chlorpromazine, cyproheptadine,
dantrolene, intravenous lipid, olanzapine, propranolol, and other
drugs/therapies have been used. However, the evidence that supports
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or does not support the use of these drugs can be categorized as Level
II, and there are no controlled studies that compare these drugs or
truly determine how effective they are. For example, there are case
reports that suggest use of chlorpromazine, cyproheptadine, and
olanzapine helped control and shorten the duration of the signs and
symptoms of serotonin syndrome, but it may simply be that these
cases represented a natural process of recovery and the drugs had no
effect.
The drugs used in the treatment of serotonin syndrome are discussed
in greater detail below:

Chlorpromazine:
Chlorpromazine (commonly known as Thorazine®) is an
antipsychotic. The therapeutic effect of chlorpromazine is due to
its action as a centrally acting dopamine antagonist. But
chlorpromazine also blocks serotonin binding to 5-HT2A receptors
and there are several case reports of chlorpromazine being an
effective drug for treating serotonin syndrome.70-72 However,
chlorpromazine can cause hypotension, it can cause dystonias,
and it may aggravate hyperthermia, so it should be used
cautiously when treating serotonin syndrome. Chlorpomazine is
contraindicated for treating NMS because it is a dopamine
antagonist.

Cyproheptadine:
Cyproheptadine (Periactin®) is an antihistamine that acts as a
5-HT2A antagonist, and it has been successfully used to treat
cases of serotonin syndrome,73-79 and, in some of these case
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reports, the resolution of the signs and symptoms was rapid and
considerable. However, treatment failures have been noted,80
and several authors point out that although cyproheptadine may
be helpful it does not shorten the time course of serotonin
syndrome.81,82 Boyer, E.W. (2005) and Cooper, B.E. (2013) note
there are no controlled studies that have evaluated the use of
cyproheptadine for the treatment of serotonin syndrome, the
evidence for its efficacy is all from case reports, and these case
reports described mild to moderate cases of serotonin
syndrome.83,84 Despite these uncertainties, cyproheptadine is
still recommended as an adjunct, as it is a serotonin receptor
antagonist, and it has sedative properties, as well.
Cyproheptadine is given orally, and if the patient cannot tolerate
oral intake it can be crushed and given via a nasogastric tube.
The dose is 12 mg followed by 2 mg doses every two hours if the
symptoms persist. The maintenance dose is 8 mg every six
hours.85,86 The pediatric dosing is 0.25 mg/kg/day, every two
hours until improvement of symptoms.87

Olanzapine:
Olanzapine (Zyprexa®) is an atypical antipsychotic. One of its
actions is 5-HT2 receptor antagonism, and sublingual olanzapine
has been used successfully to treat cases of serotonin syndrome.
Although most of the patients in these studies had a very quick
and complete resolution of the signs and symptoms, the clinical
experience with using olanzapine to treat these cases so far
consists of eight patients.88,89
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
Bromocriptine:
Bromocriptine has been used to treat serotonin syndrome.
However, it has serotonergic effects and its use has caused one
fatality.90,91 The drug should not be used to treat serotonin
syndrome.

Dantrolene:
Dantrolene is a skeletal muscle relaxant that is used to treat
malignant hyperthermia. It should not be used to treat serotonin
syndrome. There is no clinical evidence that it is effective, and,
animal studies showed that it is not effective. Dantrolene may
actually cause serotonin syndrome, and its use in a suspected
case of serotonin syndrome was associated with a fatality.92-94

Propranolol:
Propranolol acts as a 5-HT1A antagonist but it can cause
hypotension. It also decreases heart rate, making it difficult to
assess the patient’s condition. It should not be used to treat
serotonin syndrome.95

Intravenous lipid:
There is one case report of intravenous lipid being used for the
treatment of serotonin syndrome. The authors noted that there
was a temporal association between administration of the lipid
therapy and a decrease in hyperreflexia and rigidity.96
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Summary
Serotonin syndrome is a group of signs and symptoms caused by
excessive stimulation of serotonin receptors. Serotonin syndrome is
caused by therapeutic doses, overdoses, or drug interactions between
medications that directly or indirectly affect the serotonergic system.
Direct stimulation of serotonin receptors, decreased breakdown of
serotonin, increased inhibition of serotonin reuptake, an increase in
serotonin precursors, or an excessive release of serotonin cause
serotonin syndrome.
Medications that can cause serotonin syndrome include SSRIS, MAOIs,
illicit drugs such as cocaine and amphetamines, atypical
antipsychotics, and analgesics such as fentanyl, meperidine, and
tramadol, and dextromethorphan. The incidence and severity of
serotonin syndrome are greatest when multiple drugs have been
ingested. A particularly dangerous drug combination is the MAOIs
combined with SSRIs, dextromethorphan, ecstasy, or meperidine.
The syndrome is characterized by autonomic, cognitive, and
neuromuscular derangements. Agitation, tachycardia, hypertension,
hyperthermia, muscle rigidity, clonus, hyperreflexia, diaphoresis,
diarrhea are commonly seen. Signs and symptoms usually start within
six hours, and typically last 24 hours. Clonus, inducible, spontaneous
or ocular, is the most reliable clinical finding for diagnosing serotonin
syndrome. Other clinical conditions resemble serotonin syndrome. To
distinguish serotonin syndrome, determine what drug was ingested,
determine when the signs and symptom started, the clinician should
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observe for clonus and hyperreflexia, and check body temperature and
bowel sounds. The findings will be specific for serotonin syndrome.
A severe case of serotonin syndrome is a medical emergency: patients
who have severe serotonin syndrome should be admitted to intensive
care. The patient’s condition can deteriorate rapidly and dramatically.
The complications of serotonin syndrome are coma, DIC, metabolic
acidosis, renal failure, and rhabodomyolysis. Medications used to treat
serotonin syndrome, such as, chlorpromazine, cyproheptadine, and
olanzapine may be effective, but there is no conclusive evidence that
these drugs are useful therapies for treating serotonin syndrome. In
particular, drugs that should not be used to treat serotonin syndrome
include Bromocriptine, dantrolene, propranolol, and succinylcholine.
The best treatment for serotonin syndrome is supportive care.
Considerations covered in this study included the use of activated
charcoal if the patient arrives within an hour of the ingestion.
Epinephrine, norepinephrine, or phenylephrine is recommended to
treat hypotension; alternatively, nitroprusside is recommended to
control hypertension. Additionally, aggressive cooling, neuromuscular
paralysis and intubation, benzodiazepines, and IV hydration were
raised as the most important and effective therapies.
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1. Which of the following is the correct definition of serotonin
syndrome?
a. Signs and symptoms caused by excessive stimulation of the
serotonergic system.
b. Signs and symptoms caused by an overdose of serotonergic
drugs.
c. A clinical condition that closely resembles neuroleptic malignant
syndrome.
d. A clinical condition characterized hyperthermia, clonus, and
agitation.
2. The causes of serotonin syndrome are:
a. Prolonged use of drugs that affect the serotonergic system.
b. Therapeutic use, overdose, or drug interaction
c. Improper tapering of medications that affect the serotonergic
system.
d. It is an inevitable consequence for some people who take
serotonergic drugs.
3. Which of these classes of drugs that inhibits the reuptake of
serotonin?
a. Common analgesics
b. Illicit drugs
c. Sympathomimetics
d. SSRIs
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4. Three illicit drugs that may cause serotonin syndrome are:
a. Methamphetamine, heroin, marijuana
b. Cocaine, LSD, ecstasy
c. Marijuana, ecstasy, cocaine
d. Dextromethorphan, LSD, methamphetamine
5. The three categories of signs/symptoms that are diagnostic
of serotonin syndrome are:
a. Cardiovascular, autonomic, cognitive
a. Metabolic, neuromuscular, cognitive
b. Cognitive, neuromuscular, autonomic
c. Psychiatric, metabolic, cardiovascular
6. The diagnostic signs that is most reliably noted in cases of
serotonin syndrome is:
a. Hyperthermia
b. Hallucinations
c. Tremor
d. Clonus
7. The criteria used to diagnose serotonin syndrome are:
a. Sternbach’s criteria
b. Hunter’s criteria
c. Modified Glasgow scale
d. Romberg criteria
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8. Two clinical conditions that may be mistaken for serotonin
syndrome are:
a. Cholinergic syndrome, syndrome, malignant hyperthermia
b. Anticholinergic syndrome, Stevens-Johnson syndrome
c. Neuroleptic malignant syndrome, anticholinergic syndrome
d. Sympathomimetic syndrome, drug-induced hypothermia
9. The best therapy for serotonin syndrome and three specific
treatments include:
a. Supportive care: intubation, fluids, dantrolene
b. Supportive care: aggressive cooling, benzodiazepines,
cyproheptadine
c. Antidotal therapy: cyproheptadine, chlorpromazine
d. Discontinuation of the drug: supportive care
10. Drugs that should not be used to treat serotonin
syndrome are:
a. Cyproheptadine, bromocriptine, acetaminophen, propranolol
b. Dopamine, succinylcholine, epinephrine, chlorpromazine
c. Olanzapine, tramadol, phenylephrine
d. Bromocriptine, dantrolene, propranolol, succinylcholine
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Correct Answers:
1) Which of the following is the correct definition of serotonin
syndrome?
*Signs and symptoms caused by excessive stimulation of the
serotonergic system
2) The causes of serotonin syndrome are:
*Therapeutic use, overdose, or drug interaction
3) Which of these classes of drugs inhibits the reuptake of serotonin?
*SSRIs.
4)
Three illicit drugs that may cause serotonin syndrome are:
*Cocaine, LSD, ecstasy.
5) The three categories of signs/symptoms that are diagnostic of
serotonin syndrome are:
*Cognitive, neuromuscular, autonomic,
6) The diagnostic signs that is most reliably noted in cases of
serotonin syndrome is:
*Clonus.
7) The criteria used to diagnose serotonin syndrome are:
*Hunter’s criteria.
8) Two clinical conditions that may be mistaken for serotonin
syndrome are:
*Neuroleptic malignant syndrome, anticholinergic syndrome.
9) The best therapy for serotonin syndrome and three specific
treatments include:
*Supportive care: aggressive cooling, benzodiazepines,
cyproheptadine.
10) Drugs that should not be used to treat serotonin syndrome are:
*Bromocriptine, dantrolene, propranolol, succinylcholine
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References Section
The reference section of in-text citations include published works
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and personal communications are not included in this section, although
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