Serotonin syndrome is a mild to potentially fatal condition caused by high levels of serotonin that overactivate the serotonin (5HT) receptors, most importantly 5HT2A. Drugs may increase serotonin levels by the inhibition of serotonin uptake, decreased serotonin metabolism, increased serotonin synthesis, increased serotonin release, and activation of serotonergic receptors. Another mechanism involves the inhibition of certain cytochrome P450 enzymes including CYP2D6 and CYP3A4 by SSRIs. This inhibition results in the accumulation of certain serotonergic drugs, including SSRIs themselves.
Symptoms are seen within 24 hours of the inciting event which may be starting or increasing the dose of a serotonergic drug or introducing a new drug combination. It presents with hyperthermia, hypertension, muscle rigidity, mydriasis, diaphoresis, tremors, myoclonus, hyperreflexia, agitation, pressured speech, diarrhea, flushed skin, dry mucosa, arrhythmias, dramatic swings in pulse rate and blood pressure, seizures etc. Complications include rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, ARDS, DIC, coma and death. Babinski sign may be positive bilaterally. Laboratory findings include leukocytosis, elevated transaminases and creatinine levels.
Drugs and drug combinations that can precipitate serotonin syndrome
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MAOIs alone or in combination with SSRIs/SNRIs/TCAs or opiates
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SSRIs alone or in combination with MAOIs/SNRIs/TCAs/Triptans/opiates
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Fluoxetine* with carbamazepine
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Venlafaxine alone or with lithium/tramadol/MAOIs/SSRIs/TCAs/opiates
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Atypical antipsychotics
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Buspirone
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Mirtazapine
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Dextromethorphan with SSRIs/amitriptyline/chlorpheniramine
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Ciprofloxacin with venlafaxine/methadone
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Fluconazole with citalopram
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Linezolid with SSRIs
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Cocaine, MDMA (Ecstasy), LSD
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St John’s wort
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L tryptophan
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Lithium
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Metoclopramide
*Fluoxetine can cause serotonin syndrome even after being discontinued, due to its long half life.
Management includes stopping the offending drug, supportive measures, critical care, cooling measures, diazepam, cyproheptadine (5HT antagonist), esmolol/nitroprusside for hypertension and paralysis with a nondepolarizing agent with intubation and mechanical ventilation.
