Download Report

OVERVIEW OF SEROTONIN SYNDROME
REVIEW ARTICLE
ANNALS OF CLINICAL PSYCHIATRY 2012;24(4):310-318
Overview of serotonin syndrome
Mohammad M. Iqbal, MD, MPH, MSPH
Auburn Mental Health Unit
Central New York Psychiatric Center
Marcy, NY, USA
Department of Psychiatry
State University of New York (SUNY)
Upstate Medical University
Syracuse, NY, USA
Miles J. Basil, BSc
School of Medicine and Biomedical Sciences
SUNY Buffalo
Buffalo, NY, USA
Jonathan Kaplan, MD
Central New York Psychiatric Center
Marcy, NY, USA
MD Touhid Iqbal, BA
Central New York Master
of Public Health Program
SUNY Upstate Medical University
Syracuse, NY, USA
Syracuse University
Syracuse, NY, USA
CORRESPONDENCE
Mohammad M. Iqbal, MD, MPH, MSPH
Auburn Mental Health Unit
Central New York Psychiatric Center
PO Box 300
Marcy, NY 13403 USA
E-MAIL
iqbalmo@upstate.edu
310
Serotonin syndrome (SS) is a rare and potentially lifethreatening toxic state caused by an adverse drug reaction that leads to
excessive central and peripheral serotonergic activity. This excessive serotonin hyperstimulation may be secondary to 1 standard therapeutic dose
of a single agent, inadvertent interactions between various drugs, intentionally or unintentionally excessive use of particular drugs, deliberate
self-harm, or recreational use of certain drugs. This review article serves as
an overview of the epidemiology, pathophysiology, clinical features, diagnosis, differential diagnosis, management, and prevention of SS.
BACKGROUND:
The authors conducted a MEDLINE search for the period covering 1955 to 2011.
METHODS:
SS commonly occurs after the use of serotonergic agents alone
or in combination with monoamine oxidase inhibitors. SS classically consists of a triad of signs and symptoms broadly characterized as alteration
of mental status, abnormalities of neuromuscular tone, and autonomic
hyperactivity. However, all 3 triads of SS may not occur simultaneously.
Clinical manifestations are diverse and nonspecific, which may lead to
misdiagnosis. SS can range in severity from mild to life-threatening. Most
cases of SS are mild and resolve with prompt recognition and supportive
care. Management of SS involves withdrawal of the offending agent(s),
aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists—
cyproheptadine or chlorpromazine. Patients with moderate and severe
cases of SS require inpatient hospitalization.
RESULTS:
Psychiatrists, clinicians, and general practitioners must
develop increased awareness of SS due to the current increase in the use of
serotonergic agents in clinical practice. As SS is a manifestation of adverse
CONCLUSIONS:
November 2012 | Vol. 24 No. 4 | Annals of Clinical Psychiatry
ANNALS OF CLINICAL PSYCHIATRY
pharmacology, it is not considered an idiosyncratic drug
reaction, making it predictable and highly preventable.
Most cases of SS are mild and easily managed. With
prompt recognition and supportive care, more severe
cases of SS have a favorable prognosis.
TABLE 1
Drug combinations associated with SS
Antidepressants
MAO-A irreversible: Isocarboxazid,
phenelzine, tranylcypromine
MAO-A reversible: Moclobemide
MAO-B: Selegiline
SNRIs: Duloxetine, venlafaxine
SSRIs: Citalopram, escitalopram, fluoxetine,
paroxetine, sertraline
TCAs: Amitriptyline, clomipramine,
desipramine, doxepin, imipramine,
nortriptyline, protriptyline
Other: Bupropion, mirtazapine, nefazodone,
trazodone
Opiate
analgesics/pain
medications
Buprenorphine, cyclobenzaprine, fentanyl,
hydrocodone, meperidine, morphine,
oxycodone, pentazocine, tramadol
OTC cough
medication
Dextromethorphan
Antimigraine
agents/triptans
(5-HT1 agonists)
Triptans: Almotriptan, dihydroergotamine,
eletriptan, frovatriptan, naratriptan,
rizatriptan, sumatriptan, zolmitriptan
Others: Carbamazepine, valproic acid
Psychedelics
Amphetamine, cocaine, LSD, MDA, MDMA
(“ecstasy”), 5-MeO-DiPT (“foxy methoxy”),
Syrian rue (Peganum harmala) seeds
Bariatric
medications
Sibutramine, phenylpropanolamine
Herbal products
Ginseng, nutmeg, Panax, St John’s wort,
Syrian rue (Peganum harmala) seeds,
yohimbe
Antibiotics
Linezolid
Antiemetics
Droperidol, granisetron, metoclopramide,
ondansetron
Tryptophan
(others)
5-HTP, buspirone, certain foods (eg,
cheese, red wine), dextromethorphan,
L-dopa, lithium, valproate
CNS stimulants
Amphetamine, cocaine, diethylpropion,
methamphetamine, methylphenidate,
phentermine, sibutramine
Anticonvulsants
Carbamazepine, valproic acid
Antiviral
Ritonavir
Others
Chlorpheniramine, olanzapine, reserpine
KEYWORDS: serotonin syndrome, antidepressants, seroto-
nergic agents, 5-hydroxytryptamine, selective serotonin
reuptake inhibitors, neuroleptic malignant syndrome
I N T RO D U C T I O N
Serotonin syndrome (SS), previously known as serotonin toxicity,1,2 has become an increasingly common
and important clinical problem with the introduction of
many new antidepressants.
Typically, SS develops soon after initiation or dosage increase of the offending serotomimetic/serotonergic agents. A striking number of drugs and drug combinations have been associated with SS.1,3-9 These include
monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), opiate analgesics/pain medications, over-thecounter (OTC) cough medications, muscle relaxants,
antimigraine medications, weight-reducing drugs, antiemetics, street drugs/drugs of abuse, herbal products,
certain foods—cheese and red wine are known for their
serotonergic activity because they contain the serotonin
(5-hydroxytryptamine, 5-HT) precursor tryptophan—
mood-stabilizing drugs, antiviral drugs, antibiotics, and
antihypertensive agents1,3-16 (TABLE 1).1,3-12,14-17
Norepinephrine-dopamine reuptake inhibitors
(NDRIs), such as bupropion, and other antidepressant
drugs such as trazodone, nefazodone, and mirtazapine
also have been associated with SS in some cases.1,4-9,18
There have been several case reports showing that a single therapeutic dose of an SSRI caused SS.19
Severe cases of SS have been documented from
use of dextromethorphan, meperidine, tramadol, SSRIs
(fluoxetine, citalopram), ecstasy, imipramine, and
MAOIs10,20 and typically result from the combined use
of antidepressants of the MAOI, SSRI, or SNRI classes.21
Other medications also may induce less severe forms of
SS when compared with the extremely severe forms associated with MAOIs in combination with selective and
nonselective SSRIs.
AACP.com
5-HTP: 5-hydroxytryptophan; 5-MeO-DiPT: 5-methoxy-diisopropyltryptamine;
L-dopa: L-3,4-dihydroxyphenylalanine; LSD: lysergic acid diethylamide;
MAO-A: monoamine oxidase A; MAO-B: monoamine oxidase B; MDA:
methylenedioxyamphetamine; MDMA: 3,4-methylenedioxymethamphetamine;
OTC: over the counter; SNRI: serotonin-norepinephrine reuptake inhibitor; SS:
serotonin syndrome; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic
antidepressant.
Source: References 1,3-12,14-17.
Annals of Clinical Psychiatry | Vol. 24 No. 4 | November 2012
311
OVERVIEW OF SEROTONIN SYNDROME
Newer antidepressants, including SSRIs, SNRIs such
as venlafaxine and duloxetine, and NDRIs such as bupropion, have shown far fewer side effects than their precursors, the MAOIs and TCAs. This is due to their narrower
range of targets within the CNS. This added safety and efficacy have allowed these newer drugs to be used widely.22
Symptom onset typically develops within hours or
days after the addition of new serotonergic agents to a
medication regimen that already includes serotoninenhancing drugs.10-12,23-29 Increasing the dosage of current
serotonergic therapy, either after overdose or premature
initiation of serotonergic agents, also can precipitate
symptoms, with up to 60% of patients presenting to a hospital within 6 hours.3,17,27,30-32
Epidemiology/the discovery of SS
SS was first described in 1959 in a patient with tuberculosis who received meperidine along with iproniazid
and died of a “fatal toxic encephalitis.”14,33-36 Oates and
Sjoerdsma37 first recognized SS, also known as indoleamine syndrome, in 1960 as a result of medication interactions in depressed patients with tuberculosis. The
signs and symptoms—changes in mental status, ataxia,
restlessness, lower extremity hyperreflexia, and diaphoresis—were attributed to excess 5-HT levels in the CNS
following the administration of a high dose of tryptophan
in combination with MAOIs.
Since 1959, many similar reports have been published
in various psychiatric and pharmacologic journals.11,12,17,23-32
Insel et al30 first described the constellation of symptoms
observed with administration of ≥2 proserotonergic medications, coining the term serotonin syndrome.35
Despite being a widespread and important clinical
problem, most epidemiologic research suggests that up
to 85% of general practitioners are unaware of SS.38 Boyer
and Shannon3 cited a report showing that in 2002 there
were 7,349 cases of SS, resulting in 93 deaths. It is estimated that 14% to 16% of those who overdose with SSRIs
display symptoms of SS.39 These numbers strongly indicate how important it is for physicians, especially psychiatrists, to gain greater insight and knowledge into this
potentially dangerous adverse response.
SS came to national attention after the 1984 death of
Libby Zion, age 18, the daughter of a lawyer and New York
Times writer. Ms. Zion had presented with fever, agitation, and confusion and died within 8 hours of her emergency admission.35,40,41 Her untimely death was attributed
to serotonin toxicity, resulting from the coadministration
312
of meperidine, prescribed by an intern for agitation, and
the MAOI phenelzine, which she had already been taking
for depressive symptoms.35,40
Pathophysiology
Serotonin is a neurotransmitter responsible for various
roles in the body. Serotonin is unable to cross the bloodbrain barrier and therefore is synthesized both peripherally and centrally by decarboxylation and hydroxylation
of the dietary amino acid L-tryptophan.42 Once formed,
it is stored or rapidly inactivated by monoamine oxidase
(MAO). Serotonin is 1 of 3 monoamine neurotransmitters most often associated with depressive symptoms.
Although serotonin generally is associated with clinical depression, there are >7 known serotonin receptor
(5-HT1A to 5-HT7A) subtypes found throughout the
body in many organ systems other than the CNS.
Centrally, serotonin acts as a neurotransmitter with
influences on mood, personality, sleep, nausea, vomiting,
pain perception, cognition, sexual behavior, temperature
regulation, hormone regulation, wakefulness, affective
behavior, food intake (appetite), and emesis. While correct serotonin concentrations can greatly improve quality of life, excessive amounts can have deleterious effects,
which are manifested as SS.
Serotonin is produced in presynaptic neurons within
the CNS, primarily in the pons and the upper brain stem,43
and released into the synapse. Once bound to postsynaptic serotonin receptors, it remains viable until removed
from the synapse by reuptake pumps or degraded by the
enzyme MAO-A.44-46 The cause of SS is thought to be overstimulation of postsynaptic serotonin receptors in the CNS,
mainly of the 5-HT1A—associated with overstimulation,
which may cause hyperactivity, hyperreflexia, and anxiety—and the 5-HT2A type—associated with hyperthermia,
incoordination, and neuromuscular excitement.3,14,42,47-50
Overstimulation of 5-HT1A receptors in the central
gray nuclei and the medulla are thought to be primarily responsible for major SS symptoms.42 Monoaminergic
neurotransmitters, N-methyl-d-aspartate receptor antagonists, and γ-aminobutyric acid also have been suggested
as affecting SS development, providing evidence that other
neurotransmitters also may play a role.3,6
There are at least 4 separate ways proserotonergic
drugs can interact and cause excessive serotonin activation at 5-HT1A and 5-HT2A receptors:
1) Decreasing serotonin breakdown (eg, MAOIs,
linezolid)
November 2012 | Vol. 24 No. 4 | Annals of Clinical Psychiatry
ANNALS OF CLINICAL PSYCHIATRY
2) Decreasing serotonin reuptake (eg, SSRIs,
SNRIs, TCAs, tramadol, fentanyl, cocaine, methadone,
3,4-methylenedioxymethamphetamine
[MDMA,
“ecstasy”], meperidine, St John’s wort, amphetamine,
dextromethorphan)
3) Increasing serotonin precursors or agonists (eg,
L-tryptophan, antimigraine medications, lysergic acid
diethylamide, buspirone)
4) Increasing serotonin release (eg, amphetamine,
methylphenidate, MDMA, cocaine, reserpine, buspirone, lithium).3,16,44,51
Clinical features and diagnosis of SS
SS classically is characterized by a triad of neuroexcitatory
features, including altered mental status, neuromuscular
hyperactivity, and autonomic instability.3,6,15,16,44,51-56
Alteration of mental status—ranging from agitation, excitement, irritability, hyperactivity, restlessness,
anxiety, hypomania, confusion, lethargy, disorientation,
delirium, hallucinations, and drowsiness to coma—is
present in about 40% of patients with SS.52
One-half of patients with SS have evidence of neuromuscular hyperactivity, including rigidity; hyperreflexia and hypertonia (greater in legs); teeth grinding;
myoclonus; clonus—inducible, ocular, or spontaneous
(especially in ankles); ataxia and tremor—greater in legs;
and advanced stages, nystagmus and pyramidal rigidity,
which may affect truncal muscles.52,53
Autonomic instability occurs in approximately 40%
of patients with SS and includes dilated and unreactive
pupils, tachycardia, tachypnea, fever, diarrhea, abdominal pain, flushing, profuse sweating, hypertension,
or hypotension.6,52-55 Symptom onset is rapid, usually
developing within 6 hours of an increase or addition of a
serotonergic agent,1,3,44,57,58 and typically resolves within
24 hours.35,55 Administration of serotonergic agents
within 5 weeks after discontinuation of SSRIs also has
produced SS.18
SS encompasses a wide range of clinical findings,
ranging from barely perceptible to fatal.57,59,60 Classically,
symptoms of SS have been classified into 3 major types
based on their severity: mild, moderate, and severe—the
full-blown form.57 Mild toxicity may or may not worsen
the patient’s condition and may occur with therapeutic
use of many serotonergic drugs. Mild forms of toxicity
may show intermittent tremor or twitching, myoclonus,
diaphoresis, restlessness, shivering, mydriasis, no fever,
tachycardia, and hyperreflexia.57
AACP.com
In moderate toxicity, symptoms cause the patient
significant distress and require symptomatic treatment.
Moderate cases may show tachycardia; hypertension;
hyperthermia—up to 40°C/104°F; hyperactive bowel
sounds; diaphoresis; hyperreflexia/clonus—both greater
in lower extremities than upper; horizontal ocular clonus; sweaty skin; tremor—greater in lower extremities
than upper; and altered mental status—mild agitation,
restlessness, irritability, slight pressured speech, hypervigilance; and peculiar head turning—repetitive rotation
of head with neck hold in moderate extension.
In contrast, a patient with a severe serotonin toxicity
or serotonin crisis—full blown or toxic—may manifest as
a medical emergency, with symptoms such as the following: elevated mood; shivering; generalized tonic-clonic
seizures; shock; unstable blood pressure—either marked
hypertension or hypotension; tachycardia; tachypnea;
hypertonicity; increase rigidity and muscle tone—greater
in lower extremities; multiple organ failure; and mental
status changes, such as confusion and agitated delirium
that may ultimately lead to coma.10,47,57
Other findings include rapid onset of severe hyperthermia secondary to increased muscular hyperactivity
that can exceed 40°C/104°F; rhabdomyolysis; seizures;
elevated creatine phosphokinase (CPK) and transaminase activity; metabolic acidosis; renal failure; and
rarely, disseminated intravascular coagulopathy (DIC).57
However, many of these abnormalities, such as metabolic
acidosis, rhabdomyolysis, seizures, renal failure, and DIC,
arise as a consequence of poorly treated hyperthermia.
The presence of muscular hypertonicity, sustained
clonus, and hyperthermia—which may rise as high as
41°C/106°F—indicate severe, life-threatening, or fullblown SS, and if not treated within hours, can progress to
multiple organ failure. This is a medical emergency and
is almost exclusively associated with a combination of
drugs acting at different sites, most commonly including
an MAOI and an SSRI.10
Diagnosis
There is no laboratory test for diagnosing SS; therefore,
diagnosis is purely clinical and relies on patient presentation, symptom observation, medication history, physical examination, patient history, and the ruling out of
other neurologic disorders such as meningoencephalitis,
severe sepsis, delirium tremens, heat stroke, neuroleptic
malignant syndrome (NMS), malignant hyperthermia,
sympathomimetic toxicity, and anticholinergic poison-
Annals of Clinical Psychiatry | Vol. 24 No. 4 | November 2012
313
OVERVIEW OF SEROTONIN SYNDROME
TABLE 2
Sternbach’s clinical criteria for SS diagnosis
• Recent addition or increase in dosage of all agents that
increases serotonin activity or are available in the central
nervous system
• The presence of ≥3 of the following clinical signs or symptoms:
– Agitation
– Altered mental status (confusion, hypomania)
– Ataxia/incoordination
– Diaphoresis
– Diarrhea
– Fever
– Hyperreflexia
– Myoclonus
– Shivering
– Tremor
• Absence of other possible etiologies (eg, infection,
metabolic disorder, endocrine disorder, substance abuse,
withdrawal, etc.)
• No recent addition or increase in the dose of a neuroleptic
drug
SS: serotonin syndrome.
Source: References 1,52,64,65.
ing.61,62 The diagnosis should not be made without identifying a cause. Before an SS diagnosis can be made, other
toxidromes that may mimic SS must be excluded.
Although specific tests for SS have not been developed, diagnostic decision tools designed to aid physicians
exist. In 1991, Harvey Sternbach, a psychiatry professor at
the University of California, Los Angeles first defined SS in
his published article, inciting heightened clinical awareness and research interest in this syndrome.1,3,63 Since then,
Sternbach’s criteria have been used to define the majority
of subsequent human cases of serotonin toxicity in the literature (TABLE 2).1,52,64,65 As of 2007, Sternbach’s criteria were
still the most commonly used.64
Subsequently, several other diagnostic criteria have
been developed to aid diagnosis, such as the Hunter
Serotonin Toxicity Criteria (TABLE 3)3,52,65-67 and the
Serotonin Syndrome Scale1,52 to assist with the difficulties
surrounding SS diagnosis.1,58,65 Although Sternbach’s criteria exist, the gold standard of diagnosis is examination
by a medical toxicologist.52
No specific laboratory abnormalities have been
identified in association with SS. Those that have been
reported have been either nonspecific (eg, leukocytosis) or secondary to complications of the syndrome (eg,
azotemia). However, a thorough laboratory evaluation is
often needed to rule out other causes of the clinical fea-
314
tures associated with SS, especially in moderate to severe
cases. These evaluations may include CPK, transaminase, myoglobin, and electrolyte levels—mainly sodium,
magnesium, and calcium—and also may include drug
screens.
Increases in CPK found in rhabdomyolysis, myoglobin secondary to muscle breakdown from muscular
activity or rigidity, and decreases in sodium, magnesium,
and calcium also have been reported in isolated cases
secondary to fluid and electrolyte disturbances resulting
from severe SS. Measurement of serum serotonin levels
has not been shown to be helpful.35
Differential diagnosis
The differential diagnosis of SS is extensive and should
include cognitive, behavioral, neuromuscular, and
autonomic nervous system dysfunction with or without
hyperthermia.62,68,69 Other toxidromes to be considered
are anticholinergic syndrome, sympathomimetic syndrome/toxicity from poisoning with OTC cold remedies
containing ephedrine, illegal drug use, dietary supplement use, malignant hyperthermia, NMS from the use of
antipsychotic agents, abrupt discontinuation of neuroleptic or antiparkinsonian agents, and the use of dopamine-depleting agents.70
Patients with anticholinergic syndrome or anticholinergic toxicity have normal reflexes; hot, red, dry,
blotchy, and flushed skin; decreased mucus production
resulting in dry mouth, nose, and throat; sore throat; urinary retention; dilated pupils with photophobia; altered
consciousness—agitation, confusion, disorientation,
delirium, and loss of coordination; auditory or sensory
hallucination; increased vital signs—tachycardia, tachypnea, and hyperthermia; shaking; and a decrease or
absence of bowel sounds. Patients with anticholinergic
syndrome do not develop neuromuscular abnormalities.
Treatment involves symptomatic and supportive care
with the use of physostigmine as an antidote.
Patients with sympathomimetic syndrome or toxicity present signs and symptoms that include tachycardia,
hypertension, diaphoresis, hyperthermia, and altered
consciousness. Treatment involves physical, and more
importantly, pharmacologic control of their agitation and
combativeness.
Malignant hyperthermia (MH), also known as
malignant hyperthermia syndrome or malignant hyperpyrexia,71 is a rare, life-threatening condition usually triggered by exposure to certain volatile drugs (eg, halothane,
November 2012 | Vol. 24 No. 4 | Annals of Clinical Psychiatry
ANNALS OF CLINICAL PSYCHIATRY
desflurane, sevoflurane) and neuromuscular blocking
agents (succinylcholine) used for general anesthesia.72
Patients with MH present signs and symptoms
including sweaty and mottled skin, generalized rigor
mortis like rigidity and stiffness of the extremities, hyporeflexia, decreased bowel sounds, fluctuation of blood
pressure, and increased vital signs—most importantly,
very high body temperature: up to 46°C/114.8°F.
Patients with MH also present with metabolic and
respiratory acidosis, hyperkalemia, and rhabdomyolysis; and dark, bloody urine, which if left untreated
can lead to circulatory collapse and death. Symptoms
usually develop within 1 hour after exposure to trigger
substances, but may even occur several hours later in
rare instances. Treatment involves reduction of temperature by using cooling blankets as well as supportive
care with administration of IV dantrolene, lidocaine, or
a beta blocker.
The development of NMS appears to be an idiosyncratic adverse drug reaction73,74 that has a more gradual
onset.62 All antipsychotic medications are D2 dopamine
receptor antagonists, which may cause many of the symptoms associated with NMS.73,74 Patients with NMS may
have extremely high fever; diffuse “lead-type” rigidity
throughout all extremities (catatonia); pale, sweaty skin;
bradyreflexia; difficulty swallowing and speaking; sialorrhea; profuse sweating; incontinence; seizure; tremor;
autonomic dysfunction—tachycardia, rapid heart beat,
rapid breathing, or fluctuation of blood pressure; normal or dilated pupils; altered mental status; hypoxia with
respiratory failure; metabolic acidosis; and acute renal
failure.
Patients with NMS also have abnormal laboratory
findings—myoglobin in urine and increased levels of
serum transaminase, CPK, and white blood cells.62 Signs
and symptoms of NMS usually resolve within 5 to 14
days after discontinuation of causative agents. Treatment
involves symptomatic and supportive care (hydration,
nutrition, and reduction of fever) with administration of
dantrolene or bromocriptine to decrease muscular rigidity and body temperature.
There have been no gastrointestinal abnormalities,
muscular rigidity, or hyperreflexia observed with NMS
compared with SS. Catatonia, transaminase and CPK elevation, and leukocytosis are all abnormalities reported in
both SS and NMS, although frequently noticed in NMS.75
In sum, there are many overlapping aspects in the clinical
presentation of SS and NMS.
AACP.com
TABLE 3
Hunter serotonin toxicity criteria
• In the presence of a serotonergic agent
• Any of following clinical signs and symptoms:
– Hypertonia, temperature >38°C/100.4°F
– Inducible clonus and agitation or diaphoresis
– Ocular clonus and agitation or diaphoresis
– Ocular or inducible clonus
– Spontaneous clonus
– Tremor and hyperreflexia
Source: References 3,52,65-67.
Management of SS
There are no prospective, randomized controlled trials
for the management of SS.1 Management principles are
largely based on case series, and include supportive measures, such as the control of agitation, autonomic instability, and hyperthermia, and specific antiserotonergic
therapies and therapies directed toward neuromuscular
excitability.76 Additionally, those who ingest large doses
of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be
administered within 1 hour of overdose.64
The initial management and treatment for all forms
of SS is supportive care and cessation of any serotonergic medications. Initiation of supportive measures in the
emergency department is imperative. Initial management must focus on the removal of the offending agents;
focus on airway, breathing, circulation, and supportive
care, including passive and active cooling of the patient;
sedation, intubation; and controlling agitation, hyperthermia, muscle paralysis, and autonomic instability.77
Mild SS cases may not require hospital admission
and may only require cessation of offending agents and
supportive care. Supportive care can prevent secondary
complications, such as rhabdomyolysis, renal failure, and
DIC. Patients should be observed for at least 6 to 12 hours
to monitor vital signs, electrolytes, and kidney function.
Most patients will improve within 24 to 36 hours with
treatment focused on decreasing muscle rigidity and
controlling hyperthermia.58
Patients with moderate SS may show progressively
increasing toxicity a number of hours after ingestion of
serotonergic drugs and should be observed for 6 hours.
However, if a slow-release formulation has been ingested,
observation should be continued for 12 hours.64
Patients presenting with severe SS should be admitted on an urgent basis and referred to the intensive care
Annals of Clinical Psychiatry | Vol. 24 No. 4 | November 2012
315
OVERVIEW OF SEROTONIN SYNDROME
unit, where neuromuscular complications can be treated
with pharmacotherapy and artificial ventilation. Means
to control muscular rigidity and possible hyperthermia
also should be used and include benzodiazepine sedation, external cooling, and other methods seen in the
treatment of MH.3,64,78
Aggressive fluid replacement is a mainstay of therapy. Therefore, it is recommended to rapidly correct any
fluid deficits with crystalloids to maintain a high urine
output (200 to 300 mL/h).79,80 Numerous studies indicate
there may be a role for specific serotonin antagonists
in serotonin toxicity, and animal studies provide data
that nonspecific 5-HT2 antagonists and more selective
5-HT2A receptor antagonists reverse the lethal effects of
serotonin toxicity.50,56 There are numerous case reports
of patients improving after being given 5-HT2A receptor antagonists—cyproheptadine and chlorpromazine3,41,81,82—in the treatment of moderate to severe SS.3,9
The use of cyproheptadine, the most widely prescribed 5-HT antagonist, for the treatment of SS in
humans is limited. Because cyproheptadine may only be
administered nasogastrically, it is unlikely to be effective
in patients administered activated charcoal and has limited use in severe cases.64 In less severe cases, cyproheptadine may produce rapid resolution of symptoms within
1 hour.81 The doses of cyproheptadine used in managing SS are an initial dose of 4 mg to 8 mg every 6 hours
because of recurrence of symptoms. The main side effect
of cyproheptadine is sedation, which usually is beneficial
for controlling agitation.
Chlorpromazine has been reported to be effective
in management of SS.3,83 Unlike cyproheptadine, chlorpromazine can be administered intramuscularly or intravenously, allowing for the treatment of severe cases of SS.
Chlorpromazine should not be routinely used to manage
SS, especially if the patient is hypotensive and/or NMS
cannot be excluded.42
Prevention
SS is highly preventable at the primary level, and
increased awareness of this adverse drug reaction can
reduce the various autonomic, somatic, and cognitive
symptoms related to SS.3
Prevention should start with increased education for
and awareness by both physicians and patients regarding the possibility of toxicity from serotonergic drugs.
Physicians should be up to date on the patient’s current medications as well as previous medication history.
316
Interactions between drugs are complex, and the risk of
serotonin toxicity rises with the use of ≥2 serotonergic
agents. Physicians should carefully monitor patients at
increased risk of SS for its related symptoms, since there
is currently no laboratory test to confirm a diagnosis.64
Physicians also should limit polypharmacy whenever
possible to further decrease the risk of SS. Along with
increased awareness, physicians should also be knowledgeable about what drugs and combinations of drugs
may manifest as a possible source of serotonin toxicity.
This will allow physicians to minimize prescribing drugs
known to have a high probability of inducing SS, as well
as creating the possibility of alternative drug options.
Physicians as well as pharmacists can use medical software to check for possible adverse interactions when
multiple drug regimens are necessary.67
Also important for primary prevention is to understand that serotonin levels can be affected by various
agents, including OTC drugs, illicit drugs, and dietary
supplements as well as general lifestyle. Patients must be
forthcoming with their physicians regarding their health,
diet, and lifestyle to avoid drug treatments that may disrupt proper serotonin activity. Physicians should encourage patients who have a history of depression or related
diseases to seek natural ways, such as exercise and stress
management, to promote healthy serotonin levels.
CONCLUSIONS
Although an uncommon adverse effect of combinations
or high dosages of serotonergic medications, SS is potentially life-threatening and warrants further attention
because the prescribing of inciting agents like SSRIs and
serotonergic agents continues to increase among psychiatrists and general practitioners. Because diagnosing
SS is based solely on patient presentation and medication history, greater awareness of the drug combinations
commonly associated with the syndrome, attention to
medication history, and patient presentation, combined with greater awareness of signs and symptoms,
should enhance early recognition and treatment. SS is a
complex but easily preventable and recognizable condition. Management varies depending on the severity of
symptoms and consists of multiple treatment options.
Such strategies include discontinuation of responsible
medications, supportive care, administration of 5-HT2A
receptor antagonists (eg, cyproheptadine or chlorprom-
November 2012 | Vol. 24 No. 4 | Annals of Clinical Psychiatry
ANNALS OF CLINICAL PSYCHIATRY
azine), control of agitation with benzodiazepines (eg,
lorazepam), and treatment of autonomic dysfunction
and hyperthermia.
The manufacturer’s advice about washout periods should be considered carefully when switching or
prescribing >1 antidepressant. By limiting drug combinations, improving compliance with “medication
holidays,” and educating patients about possible drug
interactions, avoiding self-medication (including OTC
and herbal medications), and symptoms of serotonin
toxicity and SS, its incidence may be reduced and early
diagnosis facilitated. ■
DISCLOSURE: The authors report no financial relationship
with any company whose products are mentioned in this
article or with manufacturers of competing products.
REFERENCES
1. Sternbach H. The serotonin syndrome. Am J
Psychiatry. 1991;148:705-713.
2. Buck ML. Serotonin syndrome: pediatric and
neonatal considerations. Pediatric Pharmacotherapy.
2006:12:1-5.
3. Boyer EW, Shannon M. The serotonin syndrome. N
Engl J Med. 2005;352:1112-1120.
4. Jones D, Story DA. Serotonin syndrome and the
anaesthetist. Anaesth Intensive Care. 2005;33:181-187.
5. Huang V, Gortney JS. Risk of serotonin syndrome
with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26:1784-1793.
6. Keegan MT, Brown DR, Rabinstein AA. Serotonin
syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth Analg.
2006;103:1466-1468.
7. D’Esposito M. Serotonin neurotoxicity: implications
for cognitive neuroscience and neurology. Neurology.
1998;51:1529-1530.
8. Parker V, Wong AH, Boon HS, et al. Adverse reactions to St John’s Wort. Can J Psychiatry. 2001;46:77-79.
9. Strouse TB, Kerrihard TN, Forscher CA, et al.
Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine. J Clin Psychopharmacol.
2006;26:681-683.
10. Isbister GK, Hackett LP, Dawson AH, et al.
Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol.
2003;56:441-450.
11. Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine oxidase inhibitor therapy
with isocarboxazid. N Engl J Med. 1988;319:1671.
12. Bhatara VS, Bandettini FC. Possible interaction
between sertraline and tranylcypromine. Clin Pharm.
1993;12:222-225.
13. Marley E, Wozniak KM. Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine
and nialamide, with inhibitors of 5-hydroxytryptamine,
dopamine or noradrenaline re-uptake. J Psychiatr Res.
1984;18:191-203.
14. Hall M, Buckley N. Serotonin syndrome. Australian
Prescriber. 2003;26:62-63.
15. Keck PE Jr, Arnold LM. Serotonin syndrome.
Psychiatr Ann. 2000;30:333-343.
16. Wooltorton E. Triptan migraine treatments and
antidepressants: risk of serotonin syndrome. CMAJ.
2006;175:874.
17. Westphal RJ. Serotonin syndrome. J Am Psychiatr
Nurses Assoc. 1999;5:97-102.
18. Gill M, LoVecchio F, Selden B. Serotonin syndrome
in a child after a single dose of fluvoxamine. Ann Emerg
Med. 1999;33:457-459.
19. Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication: an overlap between serotonin syndrome and
neuroleptic malignant syndrome. Clin Neuropharmacol.
1996;19:157-164.
20. Milnacipran (savella) for fibromyalgia. Med Lett
Drugs Ther. 2009;51:45-46.
21. Rajapakse S, Abeynaike L, Wickramarathne T.
Venlafaxine-associated serotonin syndrome causing severe rhabdomyolysis and acute renal failure
AACP.com
in a patient with idiopathic Parkinson disease. J Clin
Psychopharmacol. 2010;30:620-622.
22. Thomas JM, Rubin EH. Case report of a toxic reaction from a combination of tryptophan and phenelzine.
Am J Psychiatry. 1984;141:281-283.
23. Guzé BH, Baxter LR Jr. The serotonin syndrome:
case responsive to propranolol. J Clin Psychopharmacol.
1986;6:119-120.
24. Smilkstein MJ, Smolinske SC, Rumack BH. A case of
MAO inhibitor/MDMA interaction: agony after ecstasy. J
Toxicol Clin Toxicol. 1987;25:149-159.
25. Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin Psychiatry. 1990;51:126.
26. Iruela LM, Minguez L, Merino J, et al. Toxic interaction of S-adenosylmethionine and clomipramine. Am J
Psychiatry. 1993;150:522.
27. Goldberg RJ, Huk M. Serotonin syndrome
from trazodone and buspirone. Psychosomatics.
1992;33:235-236.
28. Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al.
Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet. 1993;342:1419.
29. Insel TR, Roy BF, Cohen RM, et al. Possible development of the serotonin syndrome in man. Am J
Psychiatry. 1982;139:954-955.
30. Ooi TK. The serotonin syndrome. Anaesthesia.
1991;46:507-508.
31. Brannan SK, Talley BJ, Bowden CL. Sertraline
and isocarboxazid cause a serotonin syndrome. J Clin
Psychopharmacol. 1994;14:144-145.
32. Sandyk R. L-dopa induced “serotonin syndrome”
in a parkinsonian patient on bromocriptine. J Clin
Psychopharmacol. 1986;6:194-195.
33. Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann
Intern Med. 1955;42:417-424.
34. Gillman PK. Serotonin syndrome: history and risk.
Fundam Clin Pharmacol. 1998;12:482-491.
35. Arora B, Kannikeswaran N. The serotonin syndrome—the need for physician’s awareness. Int J Emerg
Med. 2010;3:373-377.
36. Sorenson S. Serotonin syndrome. Utox Update.
2002;4:1-2.
37. Oates JA, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology. 1960;10:1076-1078.
38. Mackay FJ, Dunn NR, Mann RD. Antidepressants
and the serotonin syndrome in general practice. Br J Gen
Pract. 1999;49:871-874.
39. Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in
overdose. J Toxicol Clin Toxicol. 2004;42:277-285.
40. Asch DA, Parker RM. The Libby Zion case. One
step forward or two steps backward? N Engl J Med.
1988;318:771-775.
41. Graham PM. Successful treatment of the toxic
serotonin syndrome with chlorpromazine. Med J Aust.
1997;166:166-167.
42. Hall RCW, Hall RCW, Chapman MJ. Central serotonin syndrome: Part II—Pathophysiology, drug interac-
tions, and treatment. Clin Geriatr. 2008;16:24-28.
43. Mills KC. Serotonin syndrome. Am Fam Physician.
1995;52:1475-1482.
44. Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a brief review. CMAJ. 2003;168:1439-1442.
45. Mills KC. Serotonin syndrome. A clinical update.
Crit Care Clin. 1997;13:763-783.
46. Glennon RA, Dukat M, Westkaemper RB. Serotonin
receptor subtypes and ligands. In: Bloom FE, Kupfer
DJ, eds. Psychopharmacology: the fourth generation of
progress. New York, NY: Raven Press, Ltd; 1995.
47. Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current
Psychiatry. 2011;10:81-83.
48. Nelson LS, Erdman AR, Booze LL, et al. Selective
serotonin reuptake inhibitor poisoning: an evidencebased consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45:315-332.
49. Glennon RA. Serotonin receptors: clinical implications. Neurosci Biobehav Rev. 1990;14:35-47.
50. Nisijima K, Yoshino T, Yui K, et al. Potent serotonin
(5-HT)(2A) receptor antagonists completely prevent the
development of hyperthermia in an animal model of the
5-HT syndrome. Brain Res. 2001;890:23-31.
51. Bodner RA, Lynch T, Lewis L, et al. Serotonin syndrome. Neurology. 1995;45:219-223.
52. Walsh J. Serotonin syndrome. Anaesthesia Tutorial
of the Week. 2010;1-5.
53. Dvir Y, Smallwood P. Serotonin syndrome: a
complex but easily avoidable condition. Gen Hosp
Psychiatry. 2008;30:284-287.
54. Thanacoody RHK. Serotonin syndrome. Adverse
Drug React Bull. 2007;243:931-934.
55. Gelener P, Gorgulu U, Kutlu G, et al. Serotonin
syndrome due to duloxetine. Clin Neuropharmacol.
2011;34:127-128.
56. Isbister GK, Buckley NA. The pathophysiology of
serotonin toxicity in animals and humans: implications
for diagnosis and treatment. Clin Neuropharmacol.
2005;28:205-214.
57. Radomski JW, Dursun SM, Reveley MA, et al. An
exploratory approach to the serotonin syndrome: an
update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses. 2000;55:218-224.
58. Martin TG. Serotonin syndrome. Ann Emerg Med.
1996;28:520-526.
59. Kaneda Y, Ishimoto Y, Ohmori T. Mild serotonin syndrome on fluvoxamine. Int J Neurosci. 2001;109:165-172.
60. Lantz MS. Serotonin syndrome. A common but
often unrecognized psychiatric condition. Geriatrics.
2001;56:52-53.
61. Garside S, Rosebush PI. Serotonin syndrome: not a
benign toxidrome. CMAJ. 2003;169:543.
62. Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic
malignant syndrome. Br J Anaesth. 2000;85:129-135.
63. Hegerl U, Bottlender R, Gallinat J, et al. The serotonin syndrome scale: first results on validity. Eur Arch
Psychiatry Clin Neurosci. 1998;248:96-103.
64. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment.
Med J Aust. 2007;187:361-365.
Annals of Clinical Psychiatry | Vol. 24 No. 4 | November 2012
317
OVERVIEW OF SEROTONIN SYNDROME
65. Jacobs BL. An animal behavior model for studying
central serotonergic synapses. Life Sci. 1976;19:777-785.
66. Dunkley EJ, Isbister GK, Sibbritt D, et al. The
Hunter Serotonin Toxicity Criteria: simple and accurate
diagnostic decision rules for serotonin toxicity. QJM.
2003;96:635-642.
67. Ables AZ, Nagubilli R. Prevention, recognition,
and management of serotonin syndrome. Am Fam
Physician. 2010;81:1139-1142.
68. Wappler F. Malignant hyperthermia. Eur J
Anaesthesiol. 2001;18:632-652.
69. Frommer DA, Kulig KW, Marx JA, et al. Tricyclic antidepressant overdose. A review. JAMA. 1987;257:521-526.
70. Hasan S, Buckley P. Novel antipsychotics and the
neuroleptic malignant syndrome: a review and critique.
Am J Psychiatry. 1998;155:1113-1116.
71. Rosenberg H, Davis M, James D, et al. Malignant
318
hyperthermia. Orphanet J Rare Dis. 2007;2:21.
72. Gronert GA, Pessah IN, Muldoon SM, et al.
Malignant hyperthermia. In: Miller RD, ed. Miller’s
anesthesia. 6th ed. Philadelphia, PA: Elsevier Churchill
Livingston; 2005:1169-1190.
73. Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical
antipsychotics? Curr Drug Saf. 2009;4:84-93.
74. Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin. 2004;22:389-411.
75. Keltner NL, Folks DG. Psychotropic drugs. 4th ed. St.
Louis, MO: Elsevier; 2005.
76. Sporer KA. The serotonin syndrome. Implicated
drugs, pathophysiology and management. Drug Saf.
1995;13:94-104.
77. Gillman PK. The serotonin syndrome and its treat-
November 2012 | Vol. 24 No. 4 | Annals of Clinical Psychiatry
ment. J Psychopharmacol. 1999;13:100-109.
78. Mir S, Taylor D. Serotonin syndrome. Psychiatric
Bulletin. 1999;23:742-747.
79. Bagley WH, Yang H, Shah KH. Rhabdomyolysis.
Intern Emerg Med. 2007;2:210-218.
80. Criddle LM. Rhabdomyolysis. Pathophysiology, recognition, and management. Crit Care Nurse. 2003;23:1422, 24-26, 28.
81. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med.
1994;331:1021-1022.
82. Chan BS, Graudins A, Whyte IM, et al. Serotonin
syndrome resulting from drug interactions. Med J Aust.
1998;169:523-525.
83. Gillman PK. Successful treatment of serotonin syndrome with chlorpromazine. Med J Aust.
1996;165:345-346.