Serotonin syndrome

Serotonin syndrome is caused by excessive central nervous system and peripheral serotonergic activity. It most commonly occurs with a combination of serotonergic agents, but may also occur with a single agent. A combination of agents increasing serotonin by different mechanisms, such as by inhibition of serotonin uptake and serotonin metabolism, is associated with a high risk of the syndrome.¹ Table 1 lists agents which have been associated with serotonin syndrome.

Serotonin syndrome is a clinical triad of cognitive-behavioural changes, autonomic dysfunction and neuromuscular dysfunction. At least three of the features listed in Table 2 must be present.^1,2 There is no laboratory test to aid diagnosis. The syndrome often occurs within a day of a change in treatment (increase in dose or addition of another serotonergic agent) and the evolution of symptoms is rapid. It should not be confused with neuroleptic malignant syndrome which is clinically similar, but is an idiosyncratic response to neuroleptic agents, usually occurs after longer periods of treatment and develops over a period of days or weeks.¹

Table 1: Agents causing serotonin syndrome

Antidepressants	SSRIs, monoamine oxidase inhibitors (including moclobemide), tricyclics, mirtazapine, venlafaxine
Antiparkinsonians	Amantadine, bromocriptine, levodopa, selegiline, carbergoline, pergolide
Illicit drugs	Cocaine, hallucinogenic amphetamines such as MDMA (ecstasy), LSD, etc.
Migraine therapy	Dihydroergotamine, naratriptan, sumatriptan, zolmitriptan
Other agents	Tramadol, carbamazepine, lithium, reserpine, sibutramine, St. John's wort, bupropion, pethidine, morphine

ADRAC has received 161 reports of serotonin syndrome. The majority describe the syndrome in association with the concomitant use of 2 or more serotonergic agents, in particular SSRIs (68), tramadol (29), moclobemide (23), venlafaxine (18), tricyclic antidepressants (18) and St John's wort (8). In 61 reports, the serotonin syndrome developed in association with a single agent: SSRIs (40), moclobemide (5), venlafaxine (5) and tramadol (5). Serotonin syndrome with tramadol was the subject of an earlier Bulletin article.³

Table 2: Clinical features of serotonin syndrome

Cognitive-behavioural changes	agitation mental status changes (confusion, hypomania)
Autonomic dysfunction	sweating diarrhoea fever shivering hypertension
Neuromuscular dysfunction	hyperreflexia incoordination myoclonus tremor

Serotonin syndrome is potentially serious. Reports to ADRAC have described confusion (31), convulsions (23), hypertension (22), hallucinations (12) and delirium (7). In the majority of reports, the signs and symptoms developed within 24 hours of the addition of another serotonergic agent or an increase in dose of an agent. Patients responded to withdrawal of the serotonergic agent(s) and appropriate treatment. Recovery was documented in 85% of the cases where the outcome was known and the remainder of patients had not recovered at the time of reporting.

Health professionals should note the drugs that may cause serotonin syndrome, alone or in combination with other serotonergic agents, and be alert to the features of serotonin syndrome. Patients should be informed of the risk and symptoms of serotonin syndrome when serotonergic agents are prescribed.

Reference

1. Langford N.J. Serotonin Syndrome. Adverse Drug Reaction Bulletin December 2002, No. 217
2. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13.
3. Tramadol and serotonin syndrome. Aust Adv Drug Reactions Bull 1991;21:14