Review

Drug-induced serotonin
syndrome: a review
Christina Sun-Edelstein, Stewart J Tepper & Robert E Shapiro†
†University
of Vermont College of Medicine, Department of Neurology, Given C219B,
1. Introduction 89 Beaumont Ave, Burlington, VT, USA
2. Epidemiology
Serotonin syndrome, or serotonin toxicity (ST), is a clinical condition that
3. The spectrum concept of
serotonin toxicity
occurs as a result of an iatrogenic drug-induced increase in intrasynaptic
serotonin levels primarily resulting in activation of serotonin2A receptors in
4. Pathophysiology
the central nervous system. The severity of symptoms spans a spectrum of
5. Clinical features toxicity that correlates with the intrasynaptic serotonin concentration.
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6. Diagnostic criteria Although numerous drugs have been implicated in ST, life-threatening
7. Drugs associated with cases generally occur only when monoamine oxidase inhibitors are
serotonin toxicity combined with either selective or nonselective serotonin re-uptake inhibitors.
8. Treatment The triad of clinical features consists of neuromuscular hyperactivity, autonomic
hyperactivity and altered mental status, which may present abruptly and
9. Conclusion
progress rapidly. The awareness of ST is crucial not only in avoiding the
10. Expert opinion unintentional lethal combination of therapeutic drugs but also in recognizing
the clinical picture when it occurs so that treatment can be promptly
initiated. In this review, the pathophysiology, clinical features, implicated
drugs, diagnosis and treatment of ST are discussed.
For personal use only.

Keywords: serotonin syndrome, serotonin toxicity

Expert Opin. Drug Saf. (2008) 7(5):587-596

1. Introduction

Serotonin syndrome (SS) is a drug-induced condition resulting from medications

that increase the level of intrasynaptic serotonin, acting at serotonin2A receptors.
Oates and Sjostrand [1] first described the syndrome in 1960 in patients on
monoamine oxidase inhibitors (MAOIs) who developed symptoms when given
tryptophan, the serotonin precursor. Although the classic triad consists of mental
status changes, autonomic hyperactivity and neuromuscular abnormalities, not all
patients with the syndrome manifest signs and symptoms of all three features [2].
Some authors prefer the term serotonin toxicity (ST) to SS because it is more
descriptive and informative [3]. The term SS is thought to suggest an idiosyncratic
reaction such as neuroleptic malignant syndrome. However, the SS symptom
complex is now understood to reflect a concentration-dependent action of
serotonin specifically at postsynaptic serotonin2A (5-hydroxytryptamine 2A
or 5-HT2A) receptors [4,5]. As such, ST will be used throughout this paper
to describe the range of clinical findings associated with serotonin excess.
ST has been associated with numerous medications, either alone or in
combination. Monoamine oxidase inhibitors, tricyclic antidepressants, selective
serotonin re-uptake inhibitors (SSRIs), opioids, antibiotics, over-the-counter
cough medications, weight-loss drugs, antiemetics, drugs of abuse and herbal
products have all been implicated, and some other medications such as triptans
have been called into question on the basis of controversial evidence.
ST remains difficult to diagnose for numerous reasons. The variability of
clinical manifestations, lack of awareness of the syndrome and limitations with
available diagnostic criteria may contribute to lack of recognition of ST [2,5,6].
Furthermore, misunderstandings about ST have led to inaccurate diagnoses and

10.1517/14740330802354785 © 2008 Informa UK Ltd ISSN 1474-0338 587

All rights reserved: reproduction in whole or in part not permitted
 Drug-induced serotonin syndrome: a review
greater confusion about which medications can precipitate
ST, resulting in case reports that mistakenly attribute ST to
unlikely drugs [3,5,7-9].
In this review we discuss the current concepts and
pathophysiology of SS, as well as its epidemiology, clinical
manifestations, diagnostic challenges and treatment. We
hope to raise the awareness of the condition amongst
physicians, assist in the often-challenging task of diagnosing
ST, and provide guidance in the usage of implicated drugs.
2. Epidemiology
An accurate epidemiological estimation of ST is difficult
as > 85% of clinicians are unaware of the diagnosis
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itself [10]. However, in 2002, the Toxic Exposure Surveillance
system published data showing that of 26,733 exposures
to SSRIs, 7349 people experienced toxic side effects,
93 of which resulted in death. These numbers were based
on case descriptions from office practices, in-patient hospital
settings and emergency departments [11]. ST is seen in
about 14 – 16% of people who overdose on SSRIs [12]. One
study from the British National Health Service estimated
the incidence of serotonin syndrome in patients on SSRI
monotherapy at 0.5 – 0.9 cases per 1000 patient-months
For personal use only.
of treatment [13].
3. The spectrum concept of serotonin toxicity
The clinical features seen with serotonin excess represent
a concentration-dependent spectrum of toxicity resulting
from an increase in the intrasynaptic concentration of
serotonin in the central nervous system [5], although likely
at specific serotonin (2A) receptors, and with some individual
susceptibility. This dose–effect concept has been confirmed
in animal research showing that serotonin levels have
been higher, producing more severe ST, in cases involving
combinations of serotonergic drugs as compared to single
agents [3,14-20]. Clinically relevant serotonergic drugs used
in combination produce a cumulative effect in which the
additive result is greater than that which either drug
could produce alone [21]. Depending on the degree to
which intrasynaptic serotonin is elevated, the range of
symptoms can range from mild serotonin-induced side
effects seen at therapeutic doses to severe, life-threatening
toxicity. Furthermore, the above-referenced research has shown
a greater increase in 5-HT levels, and a higher incidence of
ST-related fatalities, when combining MAOI + paroxetine
(most potent serotonin re-uptake inhibitor (SRI)) as compared
to MAOI + fluoxetine (weaker SRI).
Although the serotonergic toxicity of SSRIs increases with
dose, SSRIs alone generally do not precipitate life-threatening
ST in healthy adults, even when taken in overdose [12].
Severe toxicity resulting in death occurs most commonly
with combinations of MAOIs and SSRIs or MAOIs and
serotonin-releasers such as amfetamine [4].
588 Expert Opin. Drug Saf. (2008) 7(5)
4. Pathophysiology
5-HT is a monoamine neurotransmitter that is
synthesized by serotonergic neurons in the CNS
and the enterochromaffin cells of the gastro-
intestinal tract. It is derived from dietary tryptophan, which
undergoes several enzymatic conversions to form 5-HT.
5-HT is transported into cells by a specific transport system,
and then degraded by monoamine oxidase (MAO). The
breakdown product, 5-hydroxyindole acetic acid is excreted
in the urine. In the central nervous system, serotonergic
neurons are found in the midline raphe nuclei, which span
the brainstem from the midbrain to the medulla [22].
Serotonin plays a role in numerous functions and clinical
problems, including sleep and wakefulness, mood disorders,
pain, migraine, Alzheimer’s disease, epilepsy, emesis, myoclonus
and cerebrospinal fluid synthesis [23]. Outside of the CNS
the neurotransmitter is involved in the regulation of vascular
tone and gastrointestinal motility [24].
There are seven types of serotonin receptors (5-HT1 – 5-HT7),
several of which have many subtypes. As noted earlier,
evidence suggests that the 5-HT2A receptors mediate the
most important consequences of ST [24-28]. The use of 5-HT2A
postsynaptic receptor antagonists such as cyproheptadine in
the prevention of death from ST-related hyperpyrexia in
animals and probably humans [2,3,12,23,29-32] further supports
that conclusion. Some have proposed that other subtypes
of serotonin receptors, such as 5-HT1A, may play a role
in the development of ST through a pharmacodynamic
interaction in which elevated synaptic concentrations of
serotonin agonists saturate all receptor subtypes [2]. However,
with regard to the 5-HT1A receptor, antagonists have either
been ineffective in treating the condition, or resulted in
worsening of symptoms [3,33], and so the participation of
the 5-HT1A receptor is now no longer considered tenable.
Bromocriptine, which has both dopaminergic and 5-HT1A
agonist activity, has been suspected in the development of
ST, and its use as a dopaminergic agonist to attempt to reverse
misdiagnosed neuroleptic malignant syndrome patients who
actually had ST has precipitated a worsening of serotonergic
signs and symptoms [34,35]. But because ergots such as
bromocriptine also have 5-HT2 antagonist activity [36],
the interpretation of the genesis of bromocriptine-induced
symptoms is problematic.
5. Clinical features
Autonomic signs (fever, diaphoresis, tachypnea and tachycardia),
neuromuscular changes (tremor, clonus, myoclonus, hyper-
reflexia and rigidity) and altered mental status (agitation and
confusion) comprise the triad of clinical features seen in
ST (Table 1) [21,37,38]. The presentation can range from mild
to life-threatening.
ST generally presents abruptly and can progress quickly,
especially in patients taking a combination of serotonergic

Table 1. Clinical features associated with ST.
Neuromuscular hyperactivity Akathisia
Tremor
Clonus
Myoclonus
Hyperreflexia
Rigidity
Nystagmus
Autonomic hyperactivity Diaphoresis
Fever
Tachycardia
Tachypnea
Altered mental status Agitation
Excitement
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Confusion
ST: Serotonin toxicity.
agents. Approximately 60% of patients with ST develop
clinical manifestations within 6 h of the initial medication
use, an overdose or a change in dosing [39]. In patients on a
combination of serotonergic drugs, signs and symptoms
begin to manifest themselves when the second drug reaches
effective blood levels, usually after one or two doses [21].
For personal use only.
Initially the patient is alert, with neuromuscular signs that
are more pronounced in the lower limbs. In mild-to-moderate
cases, tachycardia, mydriasis, hyperactive bowel sounds and
diaphoresis may be present. As ST progresses, the neuro-
muscular findings become more generalized, and shaking,
shivering and teeth chattering may occur. Mental status
changes such as agitation or hypervigilence with pressured
speech may become apparent. Repetitive head turning with
the neck held in partial extension may also be noted [2,21].
Severe, life-threatening cases are characterized by rigidity,
decreasing PaCO2 and fever > 38.5°C, although core
temperature may be higher than 41.1°C in some cases.
Mental status deteriorates into an agitated delirium.
Respiratory compromise occurs when rigidity affects the
truncal musculature, and patients may develop shock [2,21].
Metabolic acidosis, rhabdomyolysis, seizures, renal failure
and disseminated intravascular coagulation can subsequently
occur, generally as a result of hyperthermia [2].
The length of an episode of ST depends on the duration
of action or the elimination half-life of the implicated drugs.
The prognosis after an ST event is generally good. There
is no evidence that ST results in permanent or long-term
neurological damage, unless secondary complications have
occurred [21].
6. Diagnostic criteria
Diagnostic criteria that are frequently used in diagnosing SS
were devised by Sternbach in 1991 [6]. These criteria were
based on his review of 38 cases from 10 case reports and
2 case series. The criteria are as follows:
Expert Opin. Drug Saf. (2008) 7(5)
Sun-Edelstein, Tepper & Shapiro
• recent addition or increase in a known serotonergic agent
• absence of other possible etiologies (infection, substance
abuse, withdrawal etc.)
• no recent addition or increase of a neuroleptic agent
• at least three of the following symptoms:
• mental status changes (confusion, hypomania)
• agitation
• myoclonus
• hyperreflexia
• diaphoresis
• shivering
• tremor
• diarrhea
• ataxia/incoordination
• fever.
The usage of these diagnostic criteria is limited by several
factors. First, a strict application of the criteria can lead
to missed diagnoses in that patients with mild, early or
subacute cases will not be identified [6,40]. Second, the
criteria include confusion, restlessness and ataxia. As only
three clinical features are required for the diagnosis, a patient
with delirium resulting from anticholinergic medications
would in theory meet the criteria. Third, the inclusion
of ataxia and incoordination does not make sense in that
serotonin toxicity does not cause cerebellar features, and
any patient who is agitated and confused may appear
ataxic [5]. Lastly, because the criteria were based on the
presence of signs and symptoms reported in the published
cases, clinical features that may have been present but
unrecognized as related to ST could have failed to be
included [5].
Dunkley et al. [5] developed another diagnostic approach
to SS, called the Hunter Serotonin Toxicity Criteria, based
on their retrospective study of 2222 patients admitted to the
Hunter Area Toxicology Service (HATS) after overdose of a
serotonergic drug from January 1987 to November 2002.
They found that many clinical features were associated with
serotonin toxicity but only five of these features (clonus,
agitation, diaphoresis, tremor and hyperreflexia) were needed
for a clinical toxicologist to make an accurate diagnosis.
Although the initial learning data set did not include cases
of life-threatening serotonin toxicity, hypertonicity and
hyperpyrexia were present in all those cases, and those
features were therefore included in the criteria.
The Hunter Serotonin Toxicity Criteria (see Table 2), a set
of decision rules, were subsequently devised based on the
presence or absence of the seven clinical features. These
criteria were found to be simpler, more sensitive (84 versus
75%) and more specific (97 versus 96%) than Sternbach’s
criteria. Of the clinical features, clonus was considered the
most important sign. All forms of clonus (spontaneous,
inducible and ocular) were common and significantly associated
with serotonin toxicity. Sensitivity was also increased by less
of a reliance on mental status criteria for diagnosis, thus
589
 Drug-induced serotonin syndrome: a review
Table 2. Hunter Serotonin Toxicity Criteria:
decision rules [11].
In the presence of a serotonergic agent
IF (spontaneous clonus = yes) THEN serotonin toxicity = YES
ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR
(diaphoresis = yes)] THEN serotonin toxicity = YES
ELSE IF (ocular clonus = yes) AND [(agitation = yes) OR
(diaphoresis = yes)] THEN serotonin toxicity = YES
ELSE IF (tremor = yes) AND (hyperreflexia = yes)
THEN serotonin toxicity = YES
ELSE IF (hypertonic = yes) AND (temperature > 38°C) AND
[(ocular clonus = yes) OR (inducible clonus = yes)]
then serotonin toxicity = YES
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ELSE serotonin toxicity = NO
decreasing the likelihood that other drug-induced deliria can
be mistaken for serotonin toxicity.
7. Drugs associated with serotonin toxicity
(Table 3)
7.1 Selective serotonin re-uptake inhibitors
For personal use only.
Although ∼ 15% of overdoses of an SSRI alone manifest
signs of ST [5], SSRI overdoses have not been associated
with life-threatening toxicity [5,41-45]. SSRIs with clinically
relevant serotonergic potency include paroxetine, fluvoxamine,
fluoxetine, sertraline and citalopram [21].
7.2 Serotonin–norepinephrine re-uptake inhibitors
Venlafaxine, a serotonin–norepinephrine re-uptake inhibitor
(SNRI) is unusual in that given its estimated SRI potency
there should be a relatively low risk for ST [5]. However, it
has been associated with ST even more frequently than
SSRIs (30 versus 15%) [46]. Evidence suggests that it may
act other than as a re-uptake inhibitor [47,48], possibly as
a serotonin releaser [49]. Duloxetine and sibutramine are
other SNRIs that have clinically significant SRI potency.
Sibutramine is a weight reduction drug [33].
7.3 Tricyclic antidepressants
Depending on their SRI potency, tricyclic antidepressants
(TCAs) combined with MAOIs can precipitate life-
threatening ST. As a group, they show affinities at the
human cloned serotonin transporter that vary 1000-fold [4].
Clomipramine seems to be one of the more potent
TCAs, and has serotonergic effects at both therapeutic
levels and in overdose [50]. It can cause pronounced
serotonergic side effects and ST, and death from ST
when combined with MAOIs [3,51,52]. Imipramine also has
clinically relevant serotonergic potency [21]. Amitriptyline,
a less potent SRI, does not cause symptoms of ST if taken
in overdose [53]. Furthermore, it can be safely combined
with an MAOI without risk of precipitating serotonergic
590 Expert Opin. Drug Saf. (2008) 7(5)
side effects or ST [3]. TCAs with less SRI potency than
amitriptyline do not cause ST alone or in combination
with MAOIs [3,54,55].
7.4 Monoamine oxidase inhibitors
Older, irreversible MAOIs, such as tranylcypromine can
cause severe ST in overdose alone [56], reflecting their
ability to elevate serotonin levels as demonstrated in animal
studies [3]. Other clinically relevant MAOIs are used in
the treatment of a wide range of disorders including
depression (phenelzine, nialamid, iproniazid, isocarboxazid,
pargyline and clorgiline), Parkinson’s disease (selegilene),
cancer (procarbazine), and infection (furazolidone, linezolid) [21].
Fatal ST can be precipitated by combining MAOIs with
SRIs (selective or nonselective) or serotonin releasers [33].
Moclobemide (not available in the US), a reversible
inhibitor of monoamine oxidase A, does not require a
tyramine-restricted diet. Its duration of action, ∼ 2 – 4 h, is
much shorter than that of the irreversible MAOIs, which
may take 2 – 4 weeks to lose their effect [21]. Moclobemide’s
short duration of action is advantageous in that side effects
take less time to subside. Nonetheless, it has been associated
with many cases of ST when used at therapeutic doses in
combination with a drug that has significant SRI or releaser
potency [39,57,58]. Data from the HATS database showed that
50% of 21 patients who used moclobemide in combination
with a serotonergic drug experienced ST, even if the seroton-
ergic drug was used in therapeutic doses. Of these 21 patients,
6 had severe ST that required intubation, paralysis and
5-HT2A antagonists [41]. Although some reviews have sug-
gested that moclobemide and SSRIs can be safely used in
combination [59,60], the risks of this combination have been
documented [49]. In contrast to the older, irreversible MAOIs,
moclobemide is safe when used alone, even in overdoses [21].
Toloxatone is another clinically relevant reversible selective
MAO-A inhibitor [21].
7.5 Opioids
The phenylpiperidine series opioids, which comprise
meperidine (also known as pethidine), tramadol, methadone,
fentanyl, dextromethorphan and propoxyphene, appear to
act as weak serotonin re-uptake inhibitors and can precipitate
life-threatening serotonin toxicity reactions when combined
with MAOIs [33,61-64]. However, in the case of fentanyl,
there is insufficient evidence to provide an accurate
assessment of risk [32]. Although authors of previous
reviews [65-67] have deemed it safe, two case reports suggest
otherwise. The first [68] describes a patient on an MAOI
before cardiac surgery who was given fentanyl in the
postoperative period and subsequently developed shivering
and hyperpyrexia, which progressed to death. The authors
and others [33] concluded that the likely cause was ST, and
that therefore fentanyl could not be assumed to be safe. The
second report [69] was not considered by the authors to be
ST, although others disagree [33]. Fentanyl congeners are
 Sun-Edelstein, Tepper & Shapiro

Table 3. Drugs associated with ST. with SRI activity are prescription drugs used for pain
management, dextromethorphan is an antitussive used in
SSRIs Paroxetine many over-the-counter cough medications. Physicians need
Sertraline
to be aware of its potential to cause ST in patients on
Fluoxetine
Fluvoxamine MAOIs, and must caution those patients about this risk.
Citalopram
SNRIs Venlafaxine 7.6 Serotonin releasers
Milnacipran Amfetamine and illicit CNS stimulant drugs such as
Duloxetine ecstasy (3,4-methylenedioxymethamfetamine) act as serotonin
Sibutramine releasers and therefore can cause life-threatening ST when
Tricyclic antidepressants Clomipramine combined with MAOIs [33]. Of note, methylphenidate does
Imipramine not seem to have enough serotonin releaser potency to trig-
MAOIs Trancylcypromine ger ST [21,71,72]. In addition to their action as serotonin
For depression Phenelzine re-uptake inhibitors, venlafaxine and tramadol may also have
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Nialamid some activity as serotonin releasers [49]. This may also be the
Iproniazid
case for meperidine, which has weak SRI activity but is still
Isocarboxazid
Pargyline associated with ST [33]. The serotonergic effect of serotonin
Clorgiline releasers is diminished when combined with SRIs, which
Moclobemide (reversible) impede their uptake into the presynaptic terminal, thus
Toloxatone (reversible) preventing the releaser effect [4].
For Parkinson’s disease Selegilene
For cancer Procarbazine
For infection Linezolid 7.7 Serotonin precursors
Furazolidone The appearance of serotonergic symptoms in depressed
Opiates Meperidine patients treated with L-tryptophan while on MAOIs
For personal use only.

Fentanyl prompted the first description of serotonin toxicity by Oates

Methadone and Sjostrand in 1960 [1]. L-tryptophan is not particularly
Tramadol effective for depression and therefore it is not generally used
Dextromethorphan (found in clinical practice anymore. It has, however, been shown to
in antitussives)
Dextropropoxyphene be helpful for sleep. In animal models, when combined with
Pentazocine MAOIs, a greater increase in brain 5-HT is seen than with
Antihistamines Chlorphenamine
MAOIs alone [21].
Brompheniramine
7.8 Triptans
Serotonin releasers Amfetamine
MDMA (ecstasy) Triptans are agonists at 5-HT1B, 5-HT1D and 5-HT1F
receptors and are approved by the FDA for the indication of
Serotonin precursors L-tryptophan
5-hydroxytryptophan acute therapy for the symptoms of migraine. Triptans do
not have activity at 5-HT2A receptors implicated in the
Triptans (controversial) Sumatriptan
Zolmitriptan
pathogenesis of ST.
Rizatriptan In 2006, the FDA issued an alert that triptans combined
Naratriptan with SSRIs or SNRIs increase the risk of SS. The alert was
Almotriptan based on a total of 29 cases (27 in the initial report and
Frovatriptan 2 subsequent cases), reported to the FDA or derived from
Eletriptan
the published literature, of presumptive ST occurring in
Miscellaneous Lithium association with the combination of triptans and SSRIs.
This FDA alert prompted a review by us of relevant
MAOI: Monoamine oxidase inhibitor; MDMA: 3,4-methylenedioxymethamfetamine;
SNRI: Serotonin–norepinephrine re-uptake inhibitor; SSRI: Selective serotonin published data [73] and an analysis by Evans of the
re-uptake inhibitor; ST: Serotonin toxicity. FDA-cited case reports, obtained through the US Freedom
of Information Act [9]. Assuming that the FDA cases were
more likely to be safe because they have short half-lifes and accurately diagnosed and that 10% of all US cases of SS
are rapidly reversible [33]. For example, remifentanyl’s safety resulting from triptans combined with SSRIs were reported,
in combination with MAOIs has been documented [70]. we estimated the annual incidence of ST to be < 0.03% of
Morphine and its analogues such as codeine, oxycodone patients exposed to both SSRIs and triptans, and the annual
and buprenorphine do not have any known action as SRIs incidence of life-threatening events to be < 0.002% in that
and therefore are not associated with ST, either alone or in population [73]. Evans’ analysis of the FDA-cited case reports
combination with MAOIs [33]. Whereas most of the opioids revealed omission of critical clinical information thus calling

Expert Opin. Drug Saf. (2008) 7(5) 591

 Drug-induced serotonin syndrome: a review
into question the accuracy of most assignments of the
diagnosis of ST [9].
Evans concluded, “The evidence does not support any
change in the use of triptans with SSRIs or SNRIs” [9]. We
concluded that insufficient data were available to determine
whether the addition of triptans to the use of SSRIs or
SNRIs increases the risk of serotonin syndrome [73].
A recent letter [74], co-authored by an FDA physician,
discusses 27 cases of presumptive SS in the setting of
co-prescription of triptans and SSRIs. It is unclear whether
these cases are the same 27 cases discussed in the original
2006 FDA alert but omitting the extra two cases reported
by Evans [9].
The recent letter [74] further describes 11 patients with
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symptoms suggestive of SS following triptan monotherapy.
Four of these cases developed symptoms within 1 h of
administration, five resulted in hospitalization, and two were
deemed ‘life-threatening’. Unfortunately, the letter provides
scant further clinical details of these cases, their provenance,
the numerator and denominator of the total numbers of
reports, or what validated SS diagnostic criteria (if any) were
applied. Moreover, intravenous diphenhydramine was reported
as an effective treatment for an unspecified number of these
cases. Diphenhydramine, an anticholinergic antihistamine
For personal use only.
that can also inhibit serotonin re-uptake [75], may be
expected to exacerbate rather than remedy serotonin toxicity.
This fact raises further questions about the accuracy of the
diagnoses for these cases.
7.9 Miscellaneous drugs
The antihistamine chorpheniramine has SRI activity and
can potentially precipitate ST [33]. Lithium, in combination
with venlafaxine, has been implicated in the precipitation of
ST in two case reports [76,77]. In both cases, moderate doses
of lithium and venlafaxine were used, thus raising the
question of whether the lithium acted to pharmaco-
dyamically augment the serotonergic effect of venlafaxine,
or diminish its renal excretion. Despite reports [78,79],
mirtazepine, a tetracyclic antidepressant, which also acts as
an antihistamine, is not associated with ST or serotonergic
symptoms [80,81].
8. Treatment
When assessing a patient with ST, the key elements of the
history are the quantity and type of drugs ingested, and the
evolution and rate of progression of symptoms [21]. Although
many cases of ST resolve within 24 h after cessation of
the offending drugs and initiation of treatment, clinical
signs and symptoms may be present for longer periods
in cases involving serotonergic drugs with long duration
of action, active metabolites or long half-lifes [2]. The
foundation of ST management comprises the removal of the
offending drugs, the initiation of supportive care, the use of
5-HT2A antagonists, and the control of agitation, autonomic
592 Expert Opin. Drug Saf. (2008) 7(5)
instability and hyperthermia [2,32]. The aggressiveness of the
treatment regimen depends on the severity and rapidity
of symptoms.
Life-threatening ST may occur in 50% of patients who
have ingested a combination of MAOI and an SRI [41,49]. In
those cases, rapid deterioration generally occurs, and patients
must be transferred to intensive care settings. Neuromuscular
paralysis, active cooling, orotracheal intubation, control of
autonomic instability and consideration of 5-HT2A antagonism
with medications such as cyproheptadine are required. Paralysis
should be undertaken with nondepolarizing agents such as
vecuronium. Succinylcholine should be avoided owing to
the risk of arrhythmia from hyperkalemia resulting from
rhabdomyolysis [2]. Neuromuscular paralysis is the appropriate
treatment for hyperthermia as hyperthermia results from
excess muscle activity, not an alteration in the hypothalamic
temperature set point. As such, there is no need for
antipyretic drugs in the treatment of fever in the setting
of ST. Physical restraints should not be used as they
may increase the isometric muscle contractions associated
with lactic acidosis and hyperthermia, thus exacerbating
the clinical picture [82]. Toxicology consults are strongly
recommended [21].
In mild cases, supportive therapy, discontinuation of the
serotonergic drugs, and the administration of benzodiazepines
generally suffices in managing the condition [2]. Benzodiazepines
play a critical role in the treatment of mild-to-moderate
cases, and are used to control agitation and dampen the
hyperadrenergic aspect of ST [2]. They have also been shown
to improve survival in animal models [32,83].
Patients who develop moderate ST demonstrate cardio-
respiratory abnormalities and fever, which should be
aggressively corrected. Those patients also benefit from
5-HT2A antagonists such as cyproheptadine, which is
available only in tablet and liquid form. The dose, which
binds 85 – 95% of serotonin receptors [84], is 12 mg orally
(or crushed and administered through nasogastric tube)
initially, followed by 4 – 8 mg every 6 h. However, if
charcoal has already been given, i.v. chlorpromazine must be
given. At present chlorpromazine, which shows nanomolar
affinity for cloned human 5-HT2A receptors [85] is the
only intravenous 5-HT2A antagonist that is effective in
the treatment of ST [3,28,32,86]. Although the atypical
antipsychotics olanzapine and ziprasidone are available in
some countries in short-acting intramuscular form, their
efficacy in ST management has not been established [21].
Olanzapine is also available in sublingual form, which
has been used successfully in treating ST but its efficacy
has yet to be determined as well [87]. The initial dose of
chlorpromazine is 12.5 – 25 mg intravenously, followed by
25 mg orally or intravenously every 6 h, although higher
doses have been used with apparent safety and effectiveness.
Chlorpromazine treatment should be preceded by fluid loading
as it can precipitate hypotension through α-2 adrenoceptor
antagonism. Chlorpromazine should be avoided if the

drugs that precipitated ST have pronounced cardiotoxic or
epileptogenic properties (i.e., venlafaxine), as it may aggravate
those symptoms [33].
9. Conclusion
Although ST is a potentially life-threatening condition, it is
also a preventable one. The implicated drugs are used in a
wide range of clinical situations, and therefore a familiarity
of the agents associated with ST is essential for physicians of
all specialties. Clinicians should also warn their patients
on serotonergic therapy that illicit drugs such as ecstasy
and over-the-counter medications such as dextromethorphan
are associated with ST. Furthermore, awareness of ST and
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Kainan University on 04/25/15
its heralding signs and symptoms are crucial in early
recognition of the condition, so that treatment can be
promptly initiated.
10. Expert opinion
• The term ‘serotonin toxicity’ has been advocated over
‘serotonin syndrome’ because it describes the clinical
picture of serotonin excess more accurately. The term
SS implies an idiosyncratic reaction, as with neuroleptic
For personal use only.
malignant syndrome.
• The clinical features seen in ST represent a concentration-
dependent range of toxicity resulting from an increase in
the intrasynaptic concentration of serotonin in the central
nervous system [5]. This dose–effect relationship is referred
to as the spectrum concept. The critical serotonin receptor
required for activation of ST is the 5-HT2A receptor.
• Overdoses of SSRIs alone rarely or never cause fatal ST.
Life-threatening ST generally occurs only when MAOIs are
combined with either SRIs (selective or nonselective) or
serotonin releasers such as amfetamine or the recreational
drug ecstasy. Death can also occur from a large overdose of
an older irreversible MAOI (i.e., tranylcypromine) alone.
The newer reversible MAOIs (i.e., moclobemide) do not
cause ST alone in overdose.
• The triad of ST signs and symptoms comprise
neuromuscular hyperactivitiy, altered mental status and
autonomic hyperactivity.
• Some clinical features are more predictive of ST than
others. For example, mydriasis may be typical of ST but
also present in other toxic syndromes. The Hunter
Expert Opin. Drug Saf. (2008) 7(5)
Sun-Edelstein, Tepper & Shapiro
Serotonin Toxicity Criteria, in which only clonus, agitation,
diaphoresis, tremor and hyperreflexia are needed for
the accurate prediction of ST as diagnosed by a clinical
toxicologist are the most sensitive and specific criteria.
• The management of ST involves the removal of the
offending drugs, the initiation of supportive care, the use
of 5-HT2A antagonists such as cyproheptadine, and
the control of agitation, autonomic instability and
hyperthermia. The aggressiveness of the treatment regimen
depends on the severity and rapidity of symptoms.
• Cases of severe ST must be recognized early, and
symptoms can progress quickly. These cases must be
managed in an intensive care setting, and a toxicologist
should be consulted.
• Cyproheptadine is an effective 5-HT2A antagonist, and
should be used in cases of (moderate) ST. If activated
charcoal has already been given, or if intravenous therapy
is required, chlorpromazine can also be used.
• The length of an episode of ST correlates with the
duration or action or the elimination half-life of the
offending drug(s).
• The prognosis after ST is good. ST does not result in
permanent or long-term neurological damage, unless
secondary complications have occurred.
Declaration of interest
C Sun-Edelstein has no interests to declare.
SJ Tepper has received grants/research support (at The
New England Center for Headache) from Allergan, Alexza,
ANS/Advanced Bionics, AstraZeneca, Eisai, Endo, Forrest,
GlaxoSmithKline, King, Merck, Medtronix, Minster,
Neurochem, NMT, Novartis, Ortho-McNeil, Pfizer, Pozen,
Proethic, Takeda, Winston, Vernalis. He has been a
consultant (since 2007) for Allergan, AstraZeneca, Coherex,
Elan, Endo, Forrest, GlaxoSmithKline, Merck, NMT,
Ortho-McNeil, Vernalis. Since 2007, he has been on
the speakers bureau of Allergan, AstraZeneca, Endo,
GlaxoSmithKline, Merck, NMT, Ortho-McNeil, Pfizer,
Valeant. Since 2007, he has been on the advisory board
of GlaxoSmithKline, Merck and Nupathe.
RE Shapiro has received grants/research support (since 2007)
from Merck. Since 2007, he has been on the advisory board
of MAP Pharma, Merck, NuPathe.
593
 Drug-induced serotonin syndrome: a review
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Affiliation
Christina Sun-Edelstein1 MD,
Stewart J Tepper2 MD &
Robert E Shapiro†3 MD PhD
†Author for correspondence
1New York Headache Center,
New York, NY, USA
2Center for Headache and Pain,
Neurological Institute,
Cleveland Clinic Foundation,
Cleveland, OH, USA
3University of Vermont College of Medicine,
Department of Neurology,
Given C219B, 89 Beaumont Ave,
Burlington, VT, USA
Tel: +1 802 656 1480; Fax: +1 802 656 5844;
E-mail: robert.shapiro@uvm.edu