Complications of poisoning

Serotonin syndrome Drugs causing serotonin syndrome

Ruben Thanacoody Increase in serotonin production
• L-tryptophan

Inhibition of serotonin metabolism

• Phenelzine
• Moclobemide
• Selegiline
• Linezolid

Increase in serotonin release

Abstract • Amphetamines
The serotonin syndrome is the clinical manifestation of serotonin toxi­ • Methylphenidate
city in patients taking one or more serotonergic agents. It is character­ • MDMA (‘ecstasy’)
ized by features of neuromuscular hyperactivity, autonomic instability
Inhibition of serotonin re-uptake
and alteration of mental status. Management consists of discontinuation
• SSRI
of the offending drug and supportive care. Cyproheptadine and chlor­
• Tricyclic antidepressants
promazine which have 5-HT2A antagonistic properties may be useful in
• Venlafaxine
­severe cases.
• Trazodone
• Dextromethorphan
Keywords adverse drug reaction; antidepressants; drug interaction;
• Tramadol
­iatrogenic; serotonin; toxidrome
• Pethidine
• Fentanyl
• Duloxetine
• Bupropion
The serotonin syndrome is a potentially life-threatening reaction
• Sibutramine
resulting from drug interactions or intentional overdose involv-
• St John’s wort
ing drugs acting on central and peripheral serotonergic recept­
ors. The syndrome is not an idiosyncratic drug reaction but a Serotonin receptor agonism
manifestation of excess serotonin and encompasses a spectrum • Buspirone
of clinical features ranging from minor symptoms to death. • Sumatriptan
Serotonin is produced in pre-synaptic neurones from • Lithium
L-tryptophan and remains within vesicles until released into the • LSD
synaptic space following axonal stimulation and acts at post-
­synaptic serotonin receptors. Reuptake mechanisms, degradation Table 1
by monoamine oxidase type A and feedback loops exist to keep
its effects tightly controlled under normal circumstances. syndrome due to drug interactions, the most severe cases are
A wide variety of drugs, including over-the-counter medicat­ seen when monoamine oxidase inhibitors, which inhibit the
ions, drugs of abuse and herbal products, either interfere with breakdown of serotonin, are taken in combination with SSRIs,
these homeostatic mechanisms or act as agonists at serotonin tricyclic antidepressants or venlafaxine.
receptors (Table 1). Reports of serotonin syndrome in the medi-
cal literature have increased as a result of better recognition by Clinical features
clinicians and increasing availability and use of serotonergic Onset of symptoms occurs within minutes to hours after starting
drugs. Prescribers need to remain vigilant about the development therapy with a second serotonergic drug, or following overdose,
of this syndrome since the serotonergic properties of some drugs, with up to 60% of patients presenting within 6 hours.
such as linezolid, may not be well recognized. Although the serotonin syndrome classically consists of a triad
In the setting of acute overdose, around 15% of patients taking of features including alteration of mental status, neuromuscular
an overdose of selective serotonin re-uptake inhibitors (SSRIs) hyperactivity and autonomic instability, all three features are not
develop features of serotonin syndrome.1 In cases of serotonin always present.
Around 40% of patients have mental status changes rang-
ing from agitation, confusion, delirium and hallucinations, to
Ruben Thanacoody MD FRCPE is Consultant Physician and Clinical drowsiness and coma. Around 50% of patients have evidence
Toxicologist at the Royal Infirmary, Edinburgh, UK. He qualified from of neuromuscular hyperactivity including profound shivering,
the University of Newcastle upon Tyne, and trained in general medicine tremor, teeth grinding, myoclonus, ocular clonus, inducible or
and clinical pharmacology in Newcastle upon Tyne. His research spontaneous clonus and hyper-reflexia. Autonomic instability
interests include drug-induced QT prolongation and N-acetylcysteine occurs in around 40% of patients and includes features such as
regimens for the treatment of paracetamol overdose. Competing dilated pupils, diarrhoea, profuse sweating, flushing, tachycar-
interests: none declared. dia, hypertension or hypotension.2

MEDICINE 35:10 556 © 2007 Elsevier Ltd. All rights reserved.

 Complications of poisoning

In severe cases, seizures, hyperthermia, rhabdomyolysis,
renal failure and disseminated intravascular coagulopathy may
develop. Laboratory abnormalities may include metabolic aci-
dosis, elevated creatine kinase and transaminases, and renal
impairment.
Several diagnostic criteria have been developed including
Sternbach’s criteria3 and the Hunter serotonin toxicity criteria4 to
aid diagnosis of this protean symptom complex (Table 2). How-
ever, in routine practice, the finding of clonus and hyper-reflexia
in patients taking serotonergic agents should raise suspicion of
the syndrome.2
Management
Any precipitating drug should be discontinued and supportive
care instituted. Vital signs (temperature, pulse, blood pressure)
and renal function should be monitored. Intravenous fluids
should be given to replace insensible fluid losses or correct hypo-
tension. Agitation or convulsions may be controlled with diaz-
epam or lorazepam. Physical restraint should be avoided. Mild
cases usually resolve spontaneously within 24 hours.
More severe cases should ideally be managed in a high-
dependency unit. As hyperthermia is the result of excessive
muscle acti­vity, antipyretics are not useful. Cooled intravenous
fluids, tepid sponging and use of fans, may help in reducing the
temperature. If these measures fail, sedation, neuromuscular
paralysis and ventilation should be undertaken.2 Although no
controlled trial evidence is available, drugs acting as antagonists
at 5-HT2A receptors have been used successfully.5 Administra-
tion of cyproheptadine (orally or via nasogastric tube) or chlor-
promazine (intramuscularly or intravenously) should therefore
be considered. ◆

Diagnostic criteria of serotonin syndrome

Sternbach’s criteria Hunter serotonin toxicity criteria

At least three of: • Clonus (inducible/ References

• Mental status changes spontaneous/ocular) 1 Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of
(confusion/hypomania) • Agitation/confusion/ selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol
• Agitation hypomania Clin Toxicol 2004; 42: 277–85.
• Myoclonus • Tremor/shivering/myoclonus 2 Boyer EW, Shannon M. Current concepts: the serotonin syndrome.
• Hyper-reflexia • Diaphoresis N Engl J Med 2005; 352: 1112–20.
• Diaphoresis • Fever 3 Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148:
• Tremor • Hyper-reflexia 705–13.
• Diarrhoea • Hypertonia/rigidity 4 Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The
• Incoordination/ataxia Hunter serotonin toxicity criteria: simple and accurate diagnostic
• Fever decision rules for serotonin toxicity. QJM 2003; 96: 635–42.
5 Gillman PK. The serotonin syndrome and its treatment.
Table 2 J Psychopharmacol (Oxford) 1999; 13: 100–9.

MEDICINE 35:10 557 © 2007 Elsevier Ltd. All rights reserved.