Serotonin syndrome (SS) is a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular changes (hyperreflexia and clonus) due to excess serotonin. Patient's symptoms can vary significantly, from mild symptoms such as tremor and diarrhea to delirium, neuromuscular rigidity, and hyperthermia in life-threatening cases.
The true incidence of SS is unknown, since mild cases are not diagnosed or dismissed.[1] More serious presentations may also be confounded by other toxidromes. SS can occurs in approximately 14 to 16% of individuals who overdose on SSRIs.[2] SS is not rare and has been identified in the elderly, children, and newborn infants. Certain drugs, such as MAOIs are strongly associated with severe cases of SS, especially when these agents are used in combination with meperidine, dextromethorphan, SSRIs, or MDMA.
The onset of symptoms is rapid, with clinical symptoms occurring within minutes after a change in medication or overdose. Approximately 60 percent of patients with SS present within six hours after initial use of medication, an overdose, or a change in dosing.[3] Many cases of the serotonin syndrome resolve within 24 hours after the initiation of treatment and the discontinuation of the serotonergic drugs, but symptoms may persist in patients taking drugs with long elimination half-lives.
Both the initiation and withdrawal of serotonergic agents have been associated with SS. There have been case reports of a single therapeutic dose of an SSRI has causing SS.[4] Adding drugs that inhibit cytochrome CYP2D6 and CYP3A4 to patients already on SSRIs has also been associated SS.
Drugs associated with SS
Drug-drug Interactions associated with severe serotonin syndrome
The Hunter criteria propose the following symptoms for diagnosing SS:
MOIST
can be used to remember the Hunter Criteria:
M
- Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonusO
- Ocular clonus and either agitation or diaphoresisI
- Inducible clonus and either agitation or diaphoresisS
- Spontaneous clonusT
- Tremor and hyperreflexiaSign/Symptom | Serotonin Toxicity? | |
---|---|---|
IF | • Spontaneous clonus = yes | YES |
ELSE IF | • Inducible clonus = yes, AND • [ (Agitation = yes) OR (Diaphoresis = yes) ] | YES |
ELSE IF | • Ocular clonus = yes, AND • [ (Agitation = yes) OR (Diaphoresis = yes) ] | YES |
ELSE IF | • Tremor = yes, AND • Hyperreflexia = yes | YES |
ELSE IF | • Hypertonia = yes, AND • Temperature > 38ºC, AND • [ (Ocular clonus = yes) OR (inducible clonus = yes) ] | YES |
ELSE | • None of the above | NO |
Condition | Time Onset | Vital Signs | Pupils | Mucosa | Skin | Bowel Sounds | Muscle Tone | Reflexes | Mental Status |
---|---|---|---|---|---|---|---|---|---|
Serotonin syndrome (Proserotonergic drug) | <12 hrs | Hypertension, tachycardia, tachypnea, hyperthermia (>41.1°C) | Mydriasis (dilation) | Sialorrhea | Diaphoresis | Hyperactive | Increased, predominantly in lower extremities | Hyperreflexia, clonus (unless masked by increased muscle tone) | Agitation, coma |
Anticholinergic toxidrome (Anticholinergic drug) | <12 hrs | Hypertension (mild), tachycardia, tachypnea, hyperthermia (typically 38.8°C or less) | Mydriasis (dilation) | Dry | Erythema, hot and dry to touch | Decreased or absent | Normal | Normal | Agitated delirium |
Neuroleptic malignant syndrome (Dopamine antagonist) | 1-3 days, definitely by 7-30 days | Hypertension, tachycardia, tachypnea, hyperthermia (>41.1°C) | Normal | Sialorrhea | Pallor, diaphoresis | Normal or decreased | “Lead-pipe” rigidity in all muscle groups | Bradyreflexia | Stupor, alert mutism, coma |
Malignant hyperthermia (Inhalational anesthesia) | 30 min to 24 hr | Hypertension, tachycardia, tachypnea, hyperthermia (can be as high as 46.0°C) | Normal | Normal | Mottled appearance, diaphoresis | Decreased | Rigor mortis–like rigidity | Hyporeflexia | Agitation |
Serotonin Syndrome | Neuroleptic Malignant Syndrome | |
---|---|---|
Benzodiazepines | Yes, safe to use | Yes, safe to use |
Antipsychotics (olanzapine) | Yes, indicated in SS | No, risk of worsening symptoms (last resort option) |
Bromocriptine | No, worsens SS due to its dopamine and serotonin agonist properties | Yes, dopamine agonism indicated in NMS |
Dantrolene | No, not indicated (may worsen outcomes or cause death) | Yes, indicated in NMS |