Serotonin syndrome and its differential diagnosis and treatment

Boyer EW, Shannon M. Current Concepts. The Serotonin Syndrome. NEJM 2005; 352:1111-20.

General notes
1. The serotonin syndrome (SS) is not an idiopathic drug reaction but a predictable consequence of excess serotonergic drug stimulation of the CNS and peipheral receptors.

2. It has a spectrum of findings ranging from barely perceptible to lethal.

The classical triad is mental status changes, autonomic hyperactivity and neuromuscular abnormalities. Symptoms can include tremor, diarrhea, delirium, rigidity, shivering, mydriasis, tachycardia, hypertension, and hyperthermia. Inadvertent increase in the dose of a causative drug can provoke a dramatic deterioration.

Drugs and drug combinations include MAOI's, TCA's, SSRI's, opiates, OTC cough suppressants, antibiotics, weight reduction drugs, antiemetics, antimigraine drugs, drugs of abuse, herbal products, drugs that inhibit CYP2D6 and CYP3A4 systems, PAST use of fluoxetine (within 6 weeks), or illegal drug ecstasy. Most cases occur within minutes to hours after initiating a new medicine or increasing a dose. It does not resolve if offending drugs are still given.

Clinical notes: lower extremity hyprereflexia and clonus is much worse than the upper extremity. Horizontal ocular clonus  and opsolclonus may occur. Mutism is not infrequent.  Startle is increased, and repetitive head rotaton may occur. Patients may degenerate into frank shock. Diagnosis: Clonus (inducible, spontaneous or ocular) is the most important finding. The differential includes anticholinergic poisoning, malignant hyperthermia, and NMS which all are differentiated on clinical/historical grounds.

Anticholinergic patients have normal reflexes and "toxidrome" of mydriasis, agitated delirium, dry oral mucosa, hot dry skin, urine retention, absent bowel sounds (always present in SS). Malignant hyperthermia has increasing end tidal CO2 levels, ypertonicity, hyperthermia, and metabolic acidosis, within minutes of exposure to inhalational anesthesia. Skin exam shows mottling, cyanosis juxtaposed to bright red flushing. The skeletal muscles are rigid, and there is areflexia. NMS is an idiopathic reaction to DA agonists with slow onset, bradykinesia, lead pipe rigiditym hyperthermia, fluctuating consciousness and autonomic instability that evolves over hours to days (whereas SS has rapid onset and hyperkinesia).

Management involves removing offending drug, supportive care, control of ANS instability, and occassionally benzodiazepines. Moderately ill patients should aggressively correct CV and respiratory problems and receive 5H2a antagonists. Severely hyperthermic patients (41) should also be sedated, paralyzed and intubated. Benzodiazepines may be life saving. Physical restraints are not advised. The antidote is usually cyproheptadine, giving 12-32 mg over a 24 hour period (initial dose of 12 mg then 2 mg q 2 hours prn, given po, crushed in a Dobhoff). I-m thorazine can be used. Hypertension and tachycardia can be treated with short acting drugs such as esmolol and nitroprusside. Hyperthermia should be treated with nondepolarizing drugs such as vecuronium, NOT succinylcholine. Antipyretics are not indicated since fever is due to muscle activity and the hypothalamic set point is working OK. Propanolol is not indicated as it can cause hypotension and shock, and abolish reflex tachycardia. BCT and dantrolene are not useful (unlike NMS and malignant hyperthermia).

Cyproheptadine can be sedating but that is OK. Chlorpromazine can cause hypotension which is irrelevant.