The Serotonin Syndrome

Serotonin
5hydroxytryptamine or 5HT
Discovered in 1948
Major role in multiple states
aggression, pain, sleep, appetite
anxiety, depression
migraine, emesis

Serotonin metabolism
Dietary tryptophan
converted to 5hydroxy tryptophan by tryptophan
hydroxylase
then to 5-HT by a nonspecific decarboxylase

Specific transport system into cells

Degradation
mainly monoamine oxidase (MAOA > MAOB)
5hydroxyindoleacetic acid (5-HIAA) in urine

Serotonin roles
Peripheral

peristalsis
vomiting
platelet aggregation and haemostasis
inflammatory mediator
sensitisation of nociceptors
microvascular control

Serotonin roles
Central

control of appetite
sleep
mood
hallucinations
stereotyped behaviour
pain perception
vomiting

Serotonin excess
Oates (1960) suggested excess serotonin as the
cause of symptoms after MAOIs with tryptophan
Animal work (1980s) attributed MAOI/pethidine
interaction to excess serotonin
Insel (1982) often quoted as describing the serotonin
syndrome
Sternbach (1991) developed diagnostic criteria for
serotonin syndrome

The serotonin syndrome

A clinical triad of
Mental-status changes
Autonomic hyperactivity
Neuromuscular abnormalities

Hunter Area Toxicology Service

Sternbach criteria
Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Fever
Diarrhoea

Now typically used as an assessment tool in helping diagnose serotonin syndrome

Hunter Serotonin Toxicity Criteria (HSTC)

which includes the use of at least 1serotonergic agent with
1 of the following stiuations:
Tremor with hyperreflexia, spontaneous clonus , ocular
clonus with diaphoresis
Agitation, inducible clonus with diaphoresis
Agitation, presence of muscle rigidity with a temperature
>38C (> 100.4F) with inducible or ocular clonus
The best diagnostic criteria, with good sensitivity (84%) and specificity (97%)

Boyer and Shannon algorithm

Serotinergic drugs
Serotonin reuptake inhibitors
citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline, venlafaxine
clomipramine, imipramine
nefazodone, trazodone
chlorpheniramine
cocaine, dextromethorphan, pentazocine, pethidine

Serotinergic drugs
Serotonin agonists

fenfluramine, pchloramphetamine
bromocriptine, dihydroergotamine, gepirone
sumatriptan
buspirone, ipsapirone
eltoprazin, quipazine

Serotinergic drugs
Monoamine oxidase inhibitors (MAOIs)
clorgyline, isocarboxazid, nialamide, pargyline,
phenelzine, tranylcypromine
selegiline
furazolidone
procarbazine

Serotinergic drugs
Reversible inhibitors of MAO (RIMAs)
brofaramine
befloxatone, toloxatone
moclobemide

Serotinergic drugs
Miscellaneous/mixed
lithium
lysergic acid diethylamide (LSD)
3,4methylenedioxymethamphetamine (MDMA,
ecstasy), methylenedioxyethamphetamine (eve)
propranolol, pindolol

 Anticonvulsants: valproate
Analgesics: meperidine, fentanyl, tramadol, and
pentazocine
Antiemetic agents: ondansetron, granisetron, and
metoclopramide
Antimigraine drugs: sumatriptan
Antibiotics: linezolide (a monoamine oxidase inhibitor)
and ritonavir
Over-the-counter cough and cold remedies:
dextromethorphan

Drug interactions associated with

severe serotonin syndrome
Paroxetine and buspirone
Linezolide and citalopram
Moclobemide and selective serotonin-reuptake
inhibitors
Tramadol, venlafaxine, and mirtazapine

Incidence
Over last 10 years
4130 admissions for deliberate self poisoning
267 admissions for serotinergic drug overdose
41 admissions with serotonin syndrome

Major features

Minor features
Ataxia/incoordination
Nystagmus
Tachycardia
Coma
Rhabdomyolysis

4.7 (1.514.3)
3.8 (1.212.2)
3.3 (1.76.6)
2.6 (1.16.5)
(1.6)

Nonfeatures
Akathisia
Seizures
Diarrhoea
Mydriasis
Lacrimation
Oculogyric crisis
Opisthotonus

5.6 (0.391.8)
1.9 (0.218.3)
1.5 (0.64.2)
1.6 (0.83.1)

Suggested criteria
Agitation/confusion/hypomania
Clonus (inducible/spontaneous/ocular)
Tremor/shivering/myoclonus
Diaphoresis
Fever
Hyperreflexia
Hypertonia/rigidity

Signs suggestive of serotinergic

drug overdose
Hyperreflexia
Hypertonia/rigidity
Myoclonus
Fever
Mydriasis

6.2 (4.78.2)
3.8 (2.26.6)
3.8 (1.59.5)
2.9 (1.84.7)
2.7 (2.13.6)

Linezolid
A broad spectrum antimicrobial agent, is a monoamine
oxidase inhibitor (MAOI) that increases the risk of
developing serotonin syndrome when concomitantly
administered with other serotonergic agents

Since the introduction of linezolid

at least 17 published case reports describe the occurrence of serotonin
syndrome in patients coadministered linezolid and other serotonergic
agents.
A retrospective study at the Mayo Clinic evaluated patients who were
prescribed concomitant linezolid and serotonergic agents or had received
concomitant treatment within the past 14 days. Of the 72 patients in the
study who met inclusion criteria, 4 patients met clinical criteria for
serotonin syndrome according to the Sternbach criteria and the Boyer and
Shannon algorithm. In these patients, symptoms generally subsided within 5
days after discontinuation of at least 1 of the serotonergic agents.

Cyproheptadine
is widely used as an antidote for
serotonin syndrome

Cyproheptadine may have a therapeutic role in the

treatment of cognitive and negative symptoms of
schizophrenia, especially when used with typical
antipsychotics as adjunctive therapy to achieve a 5HT
/dopamine 2 (D ) binding affinity ratio similar to atypical
antipsychotics.

Evidence suggests
Improves efficacy against positive symptoms of
schizophrenia.
Resulting in a lower incidence of extrapyramidal side
effects and hyper prolactinemia

In major depressive disorder,

5HT receptor antagonists facilitate activity at 5HT
auto receptors leading to receptor desensitization and
subsequent antidepressant effects

CASE REPORT
Mr A , a 39years old white male , developed osteomyelitis
secondary to cervical spinal cord surgery. His pastmedical history
was remarkable for depression ,hypercholesterolemia, seizure
disorder, and deep vein thrombosis. The medication regimen
included carbamazepine 600 mg twice daily, fluoxetine 20 mg
daily,gabapentin 400 mg 2 times daily, topiramate 50 mg twice
daily, vancomycin 15 mg/kg daily, and warfarin 5 mg daily.

The decision was made to remove the central line, discontinue

vancomycin therapy, and initiate oral treatment with linezolid
600 mg twice daily. However, this decision was made cautiously,
keeping in mind the increased
risk of developing serotonin syndrome. The decision to continue
carbamazepine 600 mg twice daily for treatment of seizures,
while discontinuing long term treatment of fluoxetine 20 mg
daily for depression, compounded this risk further due to
fluoxetines long half life and an insufficient washout period

Cyproheptadine 2 mg twice daily was initiated along with

linezolid 600 mg twice daily. In addition, appropriate and
diligent monitoring was initiated the physicians, nurses, and
pharmacists assessed for serotonin syndrome daily per HSTC.
Mr A continued carbamazepine 600 mg twice daily despite the
contraindication of concomitant use with a MAOI, such as
linezolid. The infection resolved after approximately 1 month
of this medication regimen, while no report of serotonin
syndrome or worsening of Mr As psychiatric illness occurred.

A 30 year old man with a social history significant for drug abuse who
developed a temperature of 40C and was empirically treated with
linezolid.
Following initiation of dual antimicrobial therapy, the patients highgrade
Fever did not subside, and additional symptoms of altered mental status
and tremors manifested. Linezolid was discontinued in the patient, while
cyproheptadine 4 mg 3 times daily was initiated. Symptom improvement
was seen within 48 hours.

Treatment of serotonin syndrome

Depends on severity
Many (if not most) do not require treatment
Many would benefit if a safe effective therapy
was available

Severity of serotonin syndrome

Mild
three symptoms are present but they are not progressive and
not significantly affecting the patient
no action is required

Moderate
four or more definite symptoms that between them cause
significant impairment of functioning or distress to the
patient
specific therapy may be indicated

Severity of serotonin syndrome

Severe
most symptoms are present and significant impairment
of consciousness or functioning is also present
often progression of symptoms, particularly fever
rapidly rising temperature (>39oC) is an indication for
urgent intervention
specific therapy may be very beneficial

Drugs used to treat serotonin

syndrome
Nonspecific blocking agents
methysergide
cyproheptadine

blockers
propranolol
pindolol

Drugs used to treat serotonin

syndrome
Benzodiazepines
lorazepam
diazepam
clonazepam

Neuroleptics
chlorprothixene
chlorpromazine
haloperidol

5HT receptors in serotonin

syndrome
Originally thought to be 5HT1 mediated (5HT1A)
methysergide
cyproheptadine

More recent evidence implicates 5HT2

failure of propranolol (5HT1A blocker) in several cases
Cyproheptadine more potent at 5HT2 than 5HT1

Therapy
Moderate
when oral therapy suitable
Cyproheptadine

8 mg stat then 4 mg q46h

when oral therapy unsuitable or cyproheptadine fails

Chlorpromazine

50 mg IMI/IVI stat then up to 50

mg orally or IMI/IVI q6h

Therapy
Severe
when symptoms are not progressive and fever < 39 oC
Chlorpromazine 50100 mg IMI/IVI stat then 50100 mg
orally or IMI/IVI q6h
when symptoms are progressive and fever < 39oC
Chlorpromazine 100400 mg IMI/IVI over first two hours
when symptoms are progressive and fever > 39oC
Barbiturate anaesthesia, muscle relaxation active cooling
Chlorpromazine 100400 mg IMI/IVI over first two hours