Serotonin syndrome:
myth or reality
Dr Yolande Knight
GP ST2
BASH GpwSI meeting
15 March 2012
Serotonin syndrome
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Quick reminder about serotonin
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History
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What is it
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Clinical findings
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Diagnostic criteria
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Triptans
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Evidence
Serotonin
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Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine
neurotransmitter
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Biochemically derived from trytophan
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Found in the GI tract, platelets and CNS
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90% of the body's serotonin is in enterochromaffin cells
in the gut, where it regulates intestinal movements
Remainder is synthesised in CNS serotonergic neurons
Serotonin
Serotonin agonists
Origins of serotonin syndrome
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First described in 1959 in a patient with TB given
mepiridine (pethidine) who developed clonus, severe
muscular hyperactivity, rigidity. Death was described as
'fatal toxic encephalitis'.
Later observed that patients on MAOI who took tryptophan
developed an unsteady gait, clonus, tremor,
incoordination, paraesthesia, pupil dilation, hyperactive
reflexes
In 1982 the term Serotonin Syndrome was used to
describe the constellation of symptoms observed with
administration of two or more medications that elevated
serotonin concentrations.
Famous case of Libby Zion
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Libby Zion aged 18 y.o. died March 1984 in
New York Hospital emergency dept.
Had been taking phenelzine (MAOI) and cocaine. Junior
doctors in ED gave mepiridine for 'jerking motions'. She
developed agitation, T 42ºC then died of cardiac arrest.
Later identified as serotonin syndrome.
The treating doctors were sued for 38 counts of negligence
for giving pethidine when they knew she took phenelzine,
and for clinical negligence due to tiredness after working a
40hour shift (father was a lawyer writing for the New York
Times)
Resulted in the Libby Zion Law 1989 restricting doctors to
working 80 hours a week.
Serotonin syndrome
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Serotonin syndrome (SS) or serotonin toxicity or
serotonin-mediated morbidity, triad of
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altered mental status
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dysautonomia
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confusion, agitation, seizures
diarrhoea, diaphoresis, hypertension, fever/shivering,
mydriasis, tachycardia
neuromuscular changes
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myoclonus, tremor, ataxia, hyperreflexia, rigidity
Spectrum of clinical findings
NEJM, 352;11. 2005
Clinical findings in serotonin syndrome
NEJM, 352;11. 2005
Diagnostic criteria- the Hunter criteria
validated in >2000
SSRI overdoses
Pathophysiology
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Mediated via the final common pathway of
elevated intra-synaptic serotonin
Risk of serious morbidity arises from
hyperthermia, which is mediated in a doseresponsive manner via 5-HT2A receptors
Reversed by 5-HT2A antagonist
Degree of 5-HT elevation required for toxicity is
10-50 times above baseline level
Drugs associated with serotonin toxicity
Drugs associated with serotonin toxicity
Serotonin reuptake inhibitors
Selective SSRIs: Fluoxetine, Paroxetine, Citalopram, Sertraline, Escitalopram
Other antidepressants: Venlafaxine, Clomipramine, Imipramine, St John's Wort
Opioid analgesics: Pethidine, Tramadol, Fentanyl, Dextromethorphan
Monoamine oxidase inhibitors
Irreversible MAOAIs: Phenelzine, Tranylcypromine
Reversible MAOAIs: Moclobemide
Others: Linezolid, Methylene blue
Serotonin-releasing agents
Fenflouramine, Amphetamines, MDMA (ecstasy)
Miscellaneous
Lithium, Tryptophan
Treatment
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Cyproheptadine and chlorpromazine are the 5-HT2antagonists
that have been used most extensively.
Oral cyproheptadine (4–12 mg) is probably the most useful 5HT2 antagonist for moderate toxicity. Limited usefulness in
severe toxicity.
In severe serotonin toxicity use IV chlorpromazine
Neurone
NEJM,
352;11.
2005
Examples of known drug combinations
causing severe serotonin toxicity
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An irreversible MAOI (in normal dose) plus any serotonin
reuptake inhibitor in normal dose
–
Tranylcypromine (or phenelzine) + clomipramine or
venlafaxine or any SSRI
–
Tranylcypromine (or phenelzine) + tramadol or
pethidine
Any reverisble MAOAI in high dose (eg Moclobemide) + any
SSRI in normal dose or SRI analgesic (e.g. tramadol)
MDMA (ecstasy) + Moclobemide (but not SSRIs)
Epidemiology- serotonin toxicity
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In 2002 in US, 93 deaths and 7349 cases of significant toxicity
due to SSRI exposure (Watson et al, 2003)
Of SSRI overdoses serotonin syndrome occurs in 15% of cases
(Isbister et al, 2004)
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85% of GPs in a UK study were unaware of the diagnosis of
serotonin syndrome (Mackay et al, BJGP 1999)
Epidemiology- triptans and SSRI/SNRIs
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Migraine and depression are co-morbid, so many patients
may be prescribed both a triptan and an SSRI or SNRI
US study (Sclar et al, Headache 2012) with 2007-2008 data showed that of
73.8 million patients
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5.2 million were prescribed triptans
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68.6 million prescribed an SSRI or SNRI
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1.4 million prescribed a triptan with an SSRI or SNRI
(1.8% of study pop'n, vs 1.3% in 2003-04, an increase
of 38.5%)
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25.1% of those who were prescribed triptans
simultaneously were prescribed an SSRI or SNRI
With so much co-prescription, “where is the epidemic of SS?"
Safety alert- warranted?
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In 2006 the US FDA (and supported by UK MHRA) issued
a warning based on 27 'case reports' gathered over 5
years of triptan and SSRI/SNRI combination producing
serotonin syndrome
Triptans- relevant pharmacology
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Mostly 5-HT1B/1D agonists (Kis ~10nM = potent) (excluding
Sumatriptan which is purely 5-HT1D, and Eletriptan which is 5HT1B/1D/1F
Very poor affinity at 5-HT2A receptors (Kis ~10,000nM = very
very weak)
Safety data produced by drug companies on the triptans shows
no signs of serotonin toxicity when overdose on triptan
In rats given 100 times the usual dose of Naratriptan (30mg/kg)
no behavioural effects of SS were observed
Other drugs with greater affinity for 5-HT1A receptors also do not
cause SS in overdose e.g. buspirone
Co-prescribing: the evidencepharmacokinetics
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Most SSRIs don't inhibit cytochrome P-450 isozymes involved
in the metabolism of triptans
Fluoxetine and Paroxetine are potent inhibitors of CYP2D6, but
this isozyme is not important for triptan metabolism
Concern: Fluvoxamine, which is a potent inhibitor of CYP1A2
isozyme which metabolizes Zolmitriptan and Frovatriptan. Use
caution in combining these
Fluvoxamine is also a moderate inhibitor of CYP3A4, involved in
metabolism of Eletriptan.
Nonetheless, clinical trials have found little evidence of an
adverse interaction between CYP3A4 inhibitors (even potent
ones) and Eletriptan
Co-prescribing: the evidenceclinical data
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Dr. Randall Evans, using the Freedom of Information Act, (USA)
obtained and reviewed the FDA cases
Not one case met the Hunter criteria, and only 10 of the 29 met
the Sternbach criteria.
A number of the FDA case reports consisted of patient selfreports, and contained no symptoms suggestive of a diagnosis
of SS.
The evidence- clinical data
A second set of 11 patients was reported in the New England
Journal of Medicine as proof of triptan monotherapy-induced
serotonin syndrome ().
The authors of this report did not describe whether either the
Sternbach or Hunter criteria were met.
The authors also suggested the symptoms remitted with
supportive care or intravenous diphenhydramine, which is not
a treatment for SS.
Questionable diagnoses?
4 subsequent pro- and retrospective studies showed no clinically
observable interaction between triptans and antidepressants (Blier
et al J Clin Psychopharm 1995; Putnam et al Cephalalgia 1999, Gardner et al Ann Pharmacother
1998; Hettiarachi et al Cephalalgia 2001)
What explains the reports of serotonin syndrome
in co-prescribed triptan and SSRI/SNRI?
Some of the published case reports provided insufficient
detail to determine if
1. SS was the diagnosis
2. the symptoms were caused by a drug acting alone,
rather than drug interaction
3. the reaction was caused by some other drug given
around the same time (within 5 weeks)
Are some patients at greater risk?
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Can't rule out that a triptan-SSRI/SNRI interaction could
occur
Possible that only certain patients develop SS when
SSRI/SNRIs are used with triptans
This could explain the rarity of case reports
Genetic factors determine isozyme profile- differentially
metabolise triptans and SSRI/SNRIs
Position Paper
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The American Headache Society (AHS) Position Paper on
Serotonin Syndrome:
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"With only Class IV evidence available in the literature and
available through the FDA registration of adverse events,
inadequate data are available to determine the risk of
serotonin syndrome with the addition of a triptan to
SSRIs/SNRIs or with triptan monotherapy.
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“The currently available evidence does not support limiting
the use of triptans with SSRIs or SNRIs, or the use of
triptan monotherapy, due to concerns for serotonin
syndrome (Level U)”.
Myth or reality?
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Poor evidence base
None of the FDA case reports use the
diagnostic criteria, or report the unifying clinical
feature for diagnosis (clonus)
Proceed with caution?