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

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All rights reserved: reproduction in whole or in part not permitted
 Drug-induced serotonin syndrome: a review

greater confusion about which medications can precipitate 4. Pathophysiology

ST, resulting in case reports that mistakenly attribute ST to
unlikely drugs [3,5,7-9]. 5-HT is a monoamine neurotransmitter that is
In this review we discuss the current concepts and synthesized by serotonergic neurons in the CNS
pathophysiology of SS, as well as its epidemiology, clinical and the enterochromaffin cells of the gastro-
manifestations, diagnostic challenges and treatment. We intestinal tract. It is derived from dietary tryptophan, which
hope to raise the awareness of the condition amongst undergoes several enzymatic conversions to form 5-HT.
physicians, assist in the often-challenging task of diagnosing 5-HT is transported into cells by a specific transport system,
ST, and provide guidance in the usage of implicated drugs. and then degraded by monoamine oxidase (MAO). The
breakdown product, 5-hydroxyindole acetic acid is excreted
2. Epidemiology in the urine. In the central nervous system, serotonergic
neurons are found in the midline raphe nuclei, which span
An accurate epidemiological estimation of ST is difficult the brainstem from the midbrain to the medulla [22].
as > 85% of clinicians are unaware of the diagnosis Serotonin plays a role in numerous functions and clinical
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itself [10]. However, in 2002, the Toxic Exposure Surveillance problems, including sleep and wakefulness, mood disorders,
system published data showing that of 26,733 exposures pain, migraine, Alzheimer’s disease, epilepsy, emesis, myoclonus
to SSRIs, 7349 people experienced toxic side effects, and cerebrospinal fluid synthesis [23]. Outside of the CNS
93 of which resulted in death. These numbers were based the neurotransmitter is involved in the regulation of vascular
on case descriptions from office practices, in-patient hospital tone and gastrointestinal motility [24].
settings and emergency departments [11]. ST is seen in There are seven types of serotonin receptors (5-HT1 – 5-HT7),
about 14 – 16% of people who overdose on SSRIs [12]. One several of which have many subtypes. As noted earlier,
study from the British National Health Service estimated evidence suggests that the 5-HT2A receptors mediate the
the incidence of serotonin syndrome in patients on SSRI most important consequences of ST [24-28]. The use of 5-HT2A
monotherapy at 0.5 – 0.9 cases per 1000 patient-months postsynaptic receptor antagonists such as cyproheptadine in
For personal use only.

of treatment [13]. the prevention of death from ST-related hyperpyrexia in

animals and probably humans [2,3,12,23,29-32] further supports
3. The spectrum concept of serotonin toxicity that conclusion. Some have proposed that other subtypes
of serotonin receptors, such as 5-HT1A, may play a role
The clinical features seen with serotonin excess represent in the development of ST through a pharmacodynamic
a concentration-dependent spectrum of toxicity resulting interaction in which elevated synaptic concentrations of
from an increase in the intrasynaptic concentration of serotonin agonists saturate all receptor subtypes [2]. However,
serotonin in the central nervous system [5], although likely with regard to the 5-HT1A receptor, antagonists have either
at specific serotonin (2A) receptors, and with some individual been ineffective in treating the condition, or resulted in
susceptibility. This dose–effect concept has been confirmed worsening of symptoms [3,33], and so the participation of
in animal research showing that serotonin levels have the 5-HT1A receptor is now no longer considered tenable.
been higher, producing more severe ST, in cases involving Bromocriptine, which has both dopaminergic and 5-HT1A
combinations of serotonergic drugs as compared to single agonist activity, has been suspected in the development of
agents [3,14-20]. Clinically relevant serotonergic drugs used ST, and its use as a dopaminergic agonist to attempt to reverse
in combination produce a cumulative effect in which the misdiagnosed neuroleptic malignant syndrome patients who
additive result is greater than that which either drug actually had ST has precipitated a worsening of serotonergic
could produce alone [21]. Depending on the degree to signs and symptoms [34,35]. But because ergots such as
which intrasynaptic serotonin is elevated, the range of bromocriptine also have 5-HT2 antagonist activity [36],
symptoms can range from mild serotonin-induced side the interpretation of the genesis of bromocriptine-induced
effects seen at therapeutic doses to severe, life-threatening symptoms is problematic.
toxicity. Furthermore, the above-referenced research has shown
a greater increase in 5-HT levels, and a higher incidence of 5. Clinical features
ST-related fatalities, when combining MAOI + paroxetine
(most potent serotonin re-uptake inhibitor (SRI)) as compared Autonomic signs (fever, diaphoresis, tachypnea and tachycardia),
to MAOI + fluoxetine (weaker SRI). neuromuscular changes (tremor, clonus, myoclonus, hyper-
Although the serotonergic toxicity of SSRIs increases with reflexia and rigidity) and altered mental status (agitation and
dose, SSRIs alone generally do not precipitate life-threatening confusion) comprise the triad of clinical features seen in
ST in healthy adults, even when taken in overdose [12]. ST (Table 1) [21,37,38]. The presentation can range from mild
Severe toxicity resulting in death occurs most commonly to life-threatening.
with combinations of MAOIs and SSRIs or MAOIs and ST generally presents abruptly and can progress quickly,
serotonin-releasers such as amfetamine [4]. especially in patients taking a combination of serotonergic

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

 Sun-Edelstein, Tepper & Shapiro

Table 1. Clinical features associated with ST. • recent addition or increase in a known serotonergic agent
• absence of other possible etiologies (infection, substance
Neuromuscular hyperactivity Akathisia abuse, withdrawal etc.)
Tremor
• no recent addition or increase of a neuroleptic agent
Clonus
Myoclonus • at least three of the following symptoms:
Hyperreflexia • mental status changes (confusion, hypomania)
Rigidity • agitation
Nystagmus • myoclonus
Autonomic hyperactivity Diaphoresis • hyperreflexia
Fever • diaphoresis
Tachycardia • shivering
Tachypnea
• tremor
Altered mental status Agitation • diarrhea
Excitement
• ataxia/incoordination
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Confusion
• fever.
ST: Serotonin toxicity.
The usage of these diagnostic criteria is limited by several
factors. First, a strict application of the criteria can lead
agents. Approximately 60% of patients with ST develop to missed diagnoses in that patients with mild, early or
clinical manifestations within 6 h of the initial medication subacute cases will not be identified [6,40]. Second, the
use, an overdose or a change in dosing [39]. In patients on a criteria include confusion, restlessness and ataxia. As only
combination of serotonergic drugs, signs and symptoms three clinical features are required for the diagnosis, a patient
begin to manifest themselves when the second drug reaches with delirium resulting from anticholinergic medications
effective blood levels, usually after one or two doses [21]. would in theory meet the criteria. Third, the inclusion
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Initially the patient is alert, with neuromuscular signs that of ataxia and incoordination does not make sense in that
are more pronounced in the lower limbs. In mild-to-moderate serotonin toxicity does not cause cerebellar features, and
cases, tachycardia, mydriasis, hyperactive bowel sounds and any patient who is agitated and confused may appear
diaphoresis may be present. As ST progresses, the neuro- ataxic [5]. Lastly, because the criteria were based on the
muscular findings become more generalized, and shaking, presence of signs and symptoms reported in the published
shivering and teeth chattering may occur. Mental status cases, clinical features that may have been present but
changes such as agitation or hypervigilence with pressured unrecognized as related to ST could have failed to be
speech may become apparent. Repetitive head turning with included [5].
the neck held in partial extension may also be noted [2,21]. Dunkley et al. [5] developed another diagnostic approach
Severe, life-threatening cases are characterized by rigidity, to SS, called the Hunter Serotonin Toxicity Criteria, based
decreasing PaCO2 and fever > 38.5°C, although core on their retrospective study of 2222 patients admitted to the
temperature may be higher than 41.1°C in some cases. Hunter Area Toxicology Service (HATS) after overdose of a
Mental status deteriorates into an agitated delirium. serotonergic drug from January 1987 to November 2002.
Respiratory compromise occurs when rigidity affects the They found that many clinical features were associated with
truncal musculature, and patients may develop shock [2,21]. serotonin toxicity but only five of these features (clonus,
Metabolic acidosis, rhabdomyolysis, seizures, renal failure agitation, diaphoresis, tremor and hyperreflexia) were needed
and disseminated intravascular coagulation can subsequently for a clinical toxicologist to make an accurate diagnosis.
occur, generally as a result of hyperthermia [2]. Although the initial learning data set did not include cases
The length of an episode of ST depends on the duration of life-threatening serotonin toxicity, hypertonicity and
of action or the elimination half-life of the implicated drugs. hyperpyrexia were present in all those cases, and those
The prognosis after an ST event is generally good. There features were therefore included in the criteria.
is no evidence that ST results in permanent or long-term The Hunter Serotonin Toxicity Criteria (see Table 2), a set
neurological damage, unless secondary complications have of decision rules, were subsequently devised based on the
occurred [21]. presence or absence of the seven clinical features. These
criteria were found to be simpler, more sensitive (84 versus
6. Diagnostic criteria 75%) and more specific (97 versus 96%) than Sternbach’s
criteria. Of the clinical features, clonus was considered the
Diagnostic criteria that are frequently used in diagnosing SS most important sign. All forms of clonus (spontaneous,
were devised by Sternbach in 1991 [6]. These criteria were inducible and ocular) were common and significantly associated
based on his review of 38 cases from 10 case reports and with serotonin toxicity. Sensitivity was also increased by less
2 case series. The criteria are as follows: of a reliance on mental status criteria for diagnosis, thus

Expert Opin. Drug Saf. (2008) 7(5) 589

 Drug-induced serotonin syndrome: a review

Table 2. Hunter Serotonin Toxicity Criteria: side effects or ST [3]. TCAs with less SRI potency than
decision rules [11]. amitriptyline do not cause ST alone or in combination
with MAOIs [3,54,55].
In the presence of a serotonergic agent
IF (spontaneous clonus = yes) THEN serotonin toxicity = YES 7.4 Monoamine oxidase inhibitors
ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR Older, irreversible MAOIs, such as tranylcypromine can
(diaphoresis = yes)] THEN serotonin toxicity = YES cause severe ST in overdose alone [56], reflecting their
ELSE IF (ocular clonus = yes) AND [(agitation = yes) OR ability to elevate serotonin levels as demonstrated in animal
(diaphoresis = yes)] THEN serotonin toxicity = YES studies [3]. Other clinically relevant MAOIs are used in
ELSE IF (tremor = yes) AND (hyperreflexia = yes) the treatment of a wide range of disorders including
THEN serotonin toxicity = YES depression (phenelzine, nialamid, iproniazid, isocarboxazid,
ELSE IF (hypertonic = yes) AND (temperature > 38°C) AND
pargyline and clorgiline), Parkinson’s disease (selegilene),
[(ocular clonus = yes) OR (inducible clonus = yes)] cancer (procarbazine), and infection (furazolidone, linezolid) [21].
then serotonin toxicity = YES Fatal ST can be precipitated by combining MAOIs with
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ELSE serotonin toxicity = NO 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
decreasing the likelihood that other drug-induced deliria can tyramine-restricted diet. Its duration of action, ∼ 2 – 4 h, is
be mistaken for serotonin toxicity. much shorter than that of the irreversible MAOIs, which
may take 2 – 4 weeks to lose their effect [21]. Moclobemide’s
7. Drugs associated with serotonin toxicity short duration of action is advantageous in that side effects
(Table 3) take less time to subside. Nonetheless, it has been associated
with many cases of ST when used at therapeutic doses in
7.1 Selective serotonin re-uptake inhibitors combination with a drug that has significant SRI or releaser
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Although ∼ 15% of overdoses of an SSRI alone manifest potency [39,57,58]. Data from the HATS database showed that
signs of ST [5], SSRI overdoses have not been associated 50% of 21 patients who used moclobemide in combination
with life-threatening toxicity [5,41-45]. SSRIs with clinically with a serotonergic drug experienced ST, even if the seroton-
relevant serotonergic potency include paroxetine, fluvoxamine, ergic drug was used in therapeutic doses. Of these 21 patients,
fluoxetine, sertraline and citalopram [21]. 6 had severe ST that required intubation, paralysis and
5-HT2A antagonists [41]. Although some reviews have sug-
7.2 Serotonin–norepinephrine re-uptake inhibitors gested that moclobemide and SSRIs can be safely used in
Venlafaxine, a serotonin–norepinephrine re-uptake inhibitor combination [59,60], the risks of this combination have been
(SNRI) is unusual in that given its estimated SRI potency documented [49]. In contrast to the older, irreversible MAOIs,
there should be a relatively low risk for ST [5]. However, it moclobemide is safe when used alone, even in overdoses [21].
has been associated with ST even more frequently than Toloxatone is another clinically relevant reversible selective
SSRIs (30 versus 15%) [46]. Evidence suggests that it may MAO-A inhibitor [21].
act other than as a re-uptake inhibitor [47,48], possibly as
a serotonin releaser [49]. Duloxetine and sibutramine are 7.5 Opioids
other SNRIs that have clinically significant SRI potency. The phenylpiperidine series opioids, which comprise
Sibutramine is a weight reduction drug [33]. meperidine (also known as pethidine), tramadol, methadone,
fentanyl, dextromethorphan and propoxyphene, appear to
7.3 Tricyclic antidepressants act as weak serotonin re-uptake inhibitors and can precipitate
Depending on their SRI potency, tricyclic antidepressants life-threatening serotonin toxicity reactions when combined
(TCAs) combined with MAOIs can precipitate life- with MAOIs [33,61-64]. However, in the case of fentanyl,
threatening ST. As a group, they show affinities at the there is insufficient evidence to provide an accurate
human cloned serotonin transporter that vary 1000-fold [4]. assessment of risk [32]. Although authors of previous
Clomipramine seems to be one of the more potent reviews [65-67] have deemed it safe, two case reports suggest
TCAs, and has serotonergic effects at both therapeutic otherwise. The first [68] describes a patient on an MAOI
levels and in overdose [50]. It can cause pronounced before cardiac surgery who was given fentanyl in the
serotonergic side effects and ST, and death from ST postoperative period and subsequently developed shivering
when combined with MAOIs [3,51,52]. Imipramine also has and hyperpyrexia, which progressed to death. The authors
clinically relevant serotonergic potency [21]. Amitriptyline, and others [33] concluded that the likely cause was ST, and
a less potent SRI, does not cause symptoms of ST if taken that therefore fentanyl could not be assumed to be safe. The
in overdose [53]. Furthermore, it can be safely combined second report [69] was not considered by the authors to be
with an MAOI without risk of precipitating serotonergic ST, although others disagree [33]. Fentanyl congeners are

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

 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
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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

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 Drug-induced serotonin syndrome: a review

into question the accuracy of most assignments of the instability and hyperthermia [2,32]. The aggressiveness of the
diagnosis of ST [9]. treatment regimen depends on the severity and rapidity
Evans concluded, “The evidence does not support any of symptoms.
change in the use of triptans with SSRIs or SNRIs” [9]. We Life-threatening ST may occur in 50% of patients who
concluded that insufficient data were available to determine have ingested a combination of MAOI and an SRI [41,49]. In
whether the addition of triptans to the use of SSRIs or those cases, rapid deterioration generally occurs, and patients
SNRIs increases the risk of serotonin syndrome [73]. must be transferred to intensive care settings. Neuromuscular
A recent letter [74], co-authored by an FDA physician, paralysis, active cooling, orotracheal intubation, control of
discusses 27 cases of presumptive SS in the setting of autonomic instability and consideration of 5-HT2A antagonism
co-prescription of triptans and SSRIs. It is unclear whether with medications such as cyproheptadine are required. Paralysis
these cases are the same 27 cases discussed in the original should be undertaken with nondepolarizing agents such as
2006 FDA alert but omitting the extra two cases reported vecuronium. Succinylcholine should be avoided owing to
by Evans [9]. the risk of arrhythmia from hyperkalemia resulting from
The recent letter [74] further describes 11 patients with rhabdomyolysis [2]. Neuromuscular paralysis is the appropriate
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symptoms suggestive of SS following triptan monotherapy. treatment for hyperthermia as hyperthermia results from
Four of these cases developed symptoms within 1 h of excess muscle activity, not an alteration in the hypothalamic
administration, five resulted in hospitalization, and two were temperature set point. As such, there is no need for
deemed ‘life-threatening’. Unfortunately, the letter provides antipyretic drugs in the treatment of fever in the setting
scant further clinical details of these cases, their provenance, of ST. Physical restraints should not be used as they
the numerator and denominator of the total numbers of may increase the isometric muscle contractions associated
reports, or what validated SS diagnostic criteria (if any) were with lactic acidosis and hyperthermia, thus exacerbating
applied. Moreover, intravenous diphenhydramine was reported the clinical picture [82]. Toxicology consults are strongly
as an effective treatment for an unspecified number of these recommended [21].
cases. Diphenhydramine, an anticholinergic antihistamine In mild cases, supportive therapy, discontinuation of the
For personal use only.

that can also inhibit serotonin re-uptake [75], may be serotonergic drugs, and the administration of benzodiazepines
expected to exacerbate rather than remedy serotonin toxicity. generally suffices in managing the condition [2]. Benzodiazepines
This fact raises further questions about the accuracy of the play a critical role in the treatment of mild-to-moderate
diagnoses for these cases. cases, and are used to control agitation and dampen the
hyperadrenergic aspect of ST [2]. They have also been shown
7.9 Miscellaneous drugs to improve survival in animal models [32,83].
The antihistamine chorpheniramine has SRI activity and Patients who develop moderate ST demonstrate cardio-
can potentially precipitate ST [33]. Lithium, in combination respiratory abnormalities and fever, which should be
with venlafaxine, has been implicated in the precipitation of aggressively corrected. Those patients also benefit from
ST in two case reports [76,77]. In both cases, moderate doses 5-HT2A antagonists such as cyproheptadine, which is
of lithium and venlafaxine were used, thus raising the available only in tablet and liquid form. The dose, which
question of whether the lithium acted to pharmaco- binds 85 – 95% of serotonin receptors [84], is 12 mg orally
dyamically augment the serotonergic effect of venlafaxine, (or crushed and administered through nasogastric tube)
or diminish its renal excretion. Despite reports [78,79], initially, followed by 4 – 8 mg every 6 h. However, if
mirtazepine, a tetracyclic antidepressant, which also acts as charcoal has already been given, i.v. chlorpromazine must be
an antihistamine, is not associated with ST or serotonergic given. At present chlorpromazine, which shows nanomolar
symptoms [80,81]. affinity for cloned human 5-HT2A receptors [85] is the
only intravenous 5-HT2A antagonist that is effective in
8. Treatment the treatment of ST [3,28,32,86]. Although the atypical
antipsychotics olanzapine and ziprasidone are available in
When assessing a patient with ST, the key elements of the some countries in short-acting intramuscular form, their
history are the quantity and type of drugs ingested, and the efficacy in ST management has not been established [21].
evolution and rate of progression of symptoms [21]. Although Olanzapine is also available in sublingual form, which
many cases of ST resolve within 24 h after cessation of has been used successfully in treating ST but its efficacy
the offending drugs and initiation of treatment, clinical has yet to be determined as well [87]. The initial dose of
signs and symptoms may be present for longer periods chlorpromazine is 12.5 – 25 mg intravenously, followed by
in cases involving serotonergic drugs with long duration 25 mg orally or intravenously every 6 h, although higher
of action, active metabolites or long half-lifes [2]. The doses have been used with apparent safety and effectiveness.
foundation of ST management comprises the removal of the Chlorpromazine treatment should be preceded by fluid loading
offending drugs, the initiation of supportive care, the use of as it can precipitate hypotension through α-2 adrenoceptor
5-HT2A antagonists, and the control of agitation, autonomic antagonism. Chlorpromazine should be avoided if the

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

 Sun-Edelstein, Tepper & Shapiro

drugs that precipitated ST have pronounced cardiotoxic or Serotonin Toxicity Criteria, in which only clonus, agitation,
epileptogenic properties (i.e., venlafaxine), as it may aggravate diaphoresis, tremor and hyperreflexia are needed for
those symptoms [33]. the accurate prediction of ST as diagnosed by a clinical
toxicologist are the most sensitive and specific criteria.
9. Conclusion • The management of ST involves the removal of the
offending drugs, the initiation of supportive care, the use
Although ST is a potentially life-threatening condition, it is of 5-HT2A antagonists such as cyproheptadine, and
also a preventable one. The implicated drugs are used in a the control of agitation, autonomic instability and
wide range of clinical situations, and therefore a familiarity hyperthermia. The aggressiveness of the treatment regimen
of the agents associated with ST is essential for physicians of depends on the severity and rapidity of symptoms.
all specialties. Clinicians should also warn their patients • Cases of severe ST must be recognized early, and
on serotonergic therapy that illicit drugs such as ecstasy symptoms can progress quickly. These cases must be
and over-the-counter medications such as dextromethorphan managed in an intensive care setting, and a toxicologist
are associated with ST. Furthermore, awareness of ST and should be consulted.
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its heralding signs and symptoms are crucial in early • Cyproheptadine is an effective 5-HT2A antagonist, and
recognition of the condition, so that treatment can be should be used in cases of (moderate) ST. If activated
promptly initiated. charcoal has already been given, or if intravenous therapy
is required, chlorpromazine can also be used.
10. Expert opinion • The length of an episode of ST correlates with the
duration or action or the elimination half-life of the
• The term ‘serotonin toxicity’ has been advocated over offending drug(s).
‘serotonin syndrome’ because it describes the clinical • The prognosis after ST is good. ST does not result in
picture of serotonin excess more accurately. The term permanent or long-term neurological damage, unless
SS implies an idiosyncratic reaction, as with neuroleptic secondary complications have occurred.
For personal use only.

malignant syndrome.
• The clinical features seen in ST represent a concentration-
dependent range of toxicity resulting from an increase in Declaration of interest
the intrasynaptic concentration of serotonin in the central
nervous system [5]. This dose–effect relationship is referred C Sun-Edelstein has no interests to declare.
to as the spectrum concept. The critical serotonin receptor SJ Tepper has received grants/research support (at The
required for activation of ST is the 5-HT2A receptor. New England Center for Headache) from Allergan, Alexza,
• Overdoses of SSRIs alone rarely or never cause fatal ST. ANS/Advanced Bionics, AstraZeneca, Eisai, Endo, Forrest,
Life-threatening ST generally occurs only when MAOIs are GlaxoSmithKline, King, Merck, Medtronix, Minster,
combined with either SRIs (selective or nonselective) or Neurochem, NMT, Novartis, Ortho-McNeil, Pfizer, Pozen,
serotonin releasers such as amfetamine or the recreational Proethic, Takeda, Winston, Vernalis. He has been a
drug ecstasy. Death can also occur from a large overdose of consultant (since 2007) for Allergan, AstraZeneca, Coherex,
an older irreversible MAOI (i.e., tranylcypromine) alone. Elan, Endo, Forrest, GlaxoSmithKline, Merck, NMT,
The newer reversible MAOIs (i.e., moclobemide) do not Ortho-McNeil, Vernalis. Since 2007, he has been on
cause ST alone in overdose. the speakers bureau of Allergan, AstraZeneca, Endo,
• The triad of ST signs and symptoms comprise GlaxoSmithKline, Merck, NMT, Ortho-McNeil, Pfizer,
neuromuscular hyperactivitiy, altered mental status and Valeant. Since 2007, he has been on the advisory board
autonomic hyperactivity. of GlaxoSmithKline, Merck and Nupathe.
• Some clinical features are more predictive of ST than RE Shapiro has received grants/research support (since 2007)
others. For example, mydriasis may be typical of ST but from Merck. Since 2007, he has been on the advisory board
also present in other toxic syndromes. The Hunter of MAP Pharma, Merck, NuPathe.

Expert Opin. Drug Saf. (2008) 7(5) 593

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