Serotonin Syndrome

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Introduction

Serotonin syndrome, or serotonin toxicity, is a potentially life-threatening condition related to prescribed and over-the-counter medications, as well as illegal drugs, that increase the levels of serotonin in the body.

 

While it's recognition is increasing, many clinicians are not aware of offending medications nor signs and symptoms of serotonin syndrome. It is critical to increase awareness of providers to reduce the incidence and significant effects of this condition.

 

 

 

The Case of John R.

John is a 56 year-old man who comes to his family doctor, feeling depressed. He is started on citalopram 20 mg daily. He returns to the clinic 3 days later feeling very agitated and restless. His doctor is concerned that this could be a manifestation of serotonin syndrome.

• what questions should his doctor ask John?
• what should she look for on physical exam?

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Causes and Risk Factors

Many medications can cause serotonin syndrome, particularly in combination. Some have long half-lives, and symptoms can emerge after the drug has been discontinued.

 

Mechanism	Drugs	Combinations with major toxicity
increased 5-HT production	L-tryptophan	L-tryptophan and MAOI
increased 5-HT release	amphetamines MDMA	amphetamines and MAOI MDMA and MAOI MDMA and SSRI
5-HT1A antagonism	buspirone LSD	paroxetine and buspirone
decreased 5-HT reptake	SSRIs venlafaxine, duloxetine tri-cyclic antidepressants clomipramine, imipramine tramadol fentanyl meperidine methadone dextromethorphan St John's Wort	analgesics with MAOI clomipramine with MAOI SSRIs, venlafaxine with MAOI SSRI, venlafaxine wiith bupoprion (?)
MAO inhbition	MAOIs selgiline linazolid	moclobemide and SSRIs/venlafaxine linazolid and SSRIs
unknown	lithium

 

Other drugs include:

• carbamazepine
• mirtazepine
• trazodone
• triptans

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Pathophysiology

Serotonin is a neurotransmitter with activity in various organ sites. The predominant areas of serotonergic activity in the brain is the raphe nuclei, located in the brainstem (midbrain and medulla).

Serotonin is produced from the amino acid tryptophan and released into the intrasynaptic space upon axonal stimulation. There are various receptor families.

 

Serotonin is taken back into the presynaptic cell, where it is metabolized by monoamine oxidase.

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Signs and Symptoms

Findings of serotonin syndrome predominantly relate to vital signs (autonomic function), mental status, the gastrointestinal system, and the neurological system.

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Investigations

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Differential Diagnosis

It can sometimes be difficult to distinguish serotonin syndrome from neuroleptic malignant syndrome. NMS presents with fever, mental status changes, and autonomic instability, and muscle rigidity. As well, laboratory testing reveals elevations of white blood cell count, creatine kinase, and liver enzymes, with low serum iron; these are usually normal in serotonin syndrome.

 

Other conditions to rule out include:

• intoxication, especially with anticholinergic drugs
• infection
• tumour
• seizure disorder
• malignant hyperthermia

 

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Treatments

Case reports have suggested cyproheptadine, a serotonin and histamine antagonist, could be helpful.

Care should be supportive, including management of the ABCs. Hospitalization is often warranted, given clinical condition.

Other agents to be considered include:

• benzodiazepines for rigidity
• anticonvulsants for seizures
• antihypertensives for blood presure control
• dantrolene for hyperthermia

Dialysis may be required for kidney failure.

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Consequences and Course

Mild serotonin syndrome can resolve without consequence, with symptoms resolving after 1 week.

However, serious morbidity and even mortality can result from the following complications:

• renal failure, secondary to rhabdomyolysis
• seizures
• disseminated intravascular coagulation

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Resources and References

Birmes et al. 2003. Serotonin syndrome: a brief review. CMAJ. 168(11):1439-1442.

Boyer EW, Shannon M. 2005. The serotonin syndrome. NEJM. 352: 1112-20.

Frank C. 2008. Recognition and treatment of serotonin syndrome. CFP. 54(7): 988-992.

Perry PJ, Wilborn CA. 2012. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Annals of Clinical Psychiatry. 24(2):155-162.

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Topic Development

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