Serotonin Syndrome

Serotonin Syndrome

Serotonin syndrome is a potentially fatal condition triggered by too much nerve cell activity.

Symptoms in moderate to severe cases may also include bilateral Babinski sign.

In severe cases body temperature can increase to greater than 41.1 °C (106.0 °F). Complications may include seizures and extensive muscle breakdown.

Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. However a single antidepressant can cause serotonin syndrome if a patient overdoses on the drug. Another cause is starting a new antidepressant before an old antidepressant has been completely washed out of the body.

Examples of agents that can precipitate serotonin syndrome

Mechanism	Agent involved
Increases serotonin formation	Tryptophan, oxitriptan*
Increases release of serotonin	Amphetamines (including dextroamphetamine, methamphetamine)
	MDMA (ecstasy)
	Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)
	Cocaine
	Mirtazapine
Impairs serotonin reuptake from the synaptic cleft into the presynaptic neuron	Cocaine
	MDMA (ecstasy)
	Meperidine
	Tramadol
	Pentazocine
	Dextromethorphan
	Selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
	Serotonin-norepinephrine reuptake inhibitors (SNRIs; desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine)
	Sibutramine
	Bupropion
	Serotonin modulators (nefazodone, trazodone, vilazodone, and vortioxetine)
	Cyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine)
	St. John's wort (Hypericum perforatum)
	5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)
	Cyclobenzaprine
	Methylphenidate, dexmethylphenidate
Inhibits serotonin metabolism by inhibition of monoamine oxidase (MAO)	MAO inhibitors, nonselective (isocarboxazid, linezolid, phenelzine, Syrian rue [Peganum harmala, harmine], and tranylcypromine)
	MAO-A inhibitors (methylene blue, moclobemide)
	MAO-B inhibitors (rasagiline, safinamide, and selegiline)
Direct serotonin receptor agonist	Buspirone
	Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)
	Ergot derivatives (including dihydroergotamine, ergotamine, methylergonovine)
	Fentanyl
	Lysergic acid diethylamide (LSD)
	Lasmiditan
	Lorcaserin
	Metaxalone
Increases sensitivity of postsynaptic serotonin receptor	Lithium

 DIAGNOSIS AND DIAGNOSTIC CRITERIA

Diagnosis is based on a person's symptoms and history of medication use. Other conditions that can produce similar symptoms such as neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, heat stroke, and meningitis should be ruled out. No laboratory tests can confirm the diagnosis of Serotonin Syndrome.

The diagnosis is likely only in the setting of starting or increasing the dose (or, indeed overdose) of a potent serotonergic drug, or shortly after a second serotonergic drug is added leading to a drug interaction.

Symptoms usually occur within six hours of taking the provoking drug.

We suggest diagnosing serotonin syndrome using the Hunter Toxicity Criteria Decision Rules. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:

●Spontaneous clonus

●Inducible clonus PLUS agitation or diaphoresis

●Ocular clonus PLUS agitation or diaphoresis

●Tremor PLUS hyperreflexia

●Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Several sets of diagnostic criteria have been developed to define serotonin syndrome, of which the Hunter Criteria are most accurate (84 percent sensitive and 97 percent specific when compared with the gold standard of diagnosis by a medical toxicologist). In a comparison with the original Sternbach Criteria, the Hunter Criteria performed with greater accuracy and were less likely to miss early, mild, or subacute forms of serotonin syndrome.

Differential diagnosis:

• Anticholinergic poisoning (normal reflexes, dry mouth, hot and dry skin, absent bowel sounds).
• Malignant hyperthermia (caused by inhalational anaesthetics; mottled and patchily cyanotic skin, severe rigidity and hyporeflexia).
• Neuroleptic malignant syndrome (slow-onset idiopathic reaction to dopamine antagonists, with bradykinesia and 'lead-pipe' muscular rigidity).
• Other poisoning.
• Catatonia.
• Dystonia.
• Recreational drug toxicity, especially amfetamines/cocaine (many features of their toxicity are due to serotonergic effects).
• Hyperthyroidism.
• Tetanus.
• Delirium tremens.
• Encephalitis.
• Rhabdomyolysis.
• Meningitis.
• Withdrawal syndromes.
• Wernicke's encephalopathy.

A single antidepressant can cause serotonin syndrome if a patient overdoses on the drug. Another cause is starting a new antidepressant before an old antidepressant has been completely washed out of the body.

Initial treatment consists of discontinuing medications which may be contributing. In those who are agitated, benzodiazepines may be used.

Questions remain regarding the exact point at which serotonergic signs associated with therapeutic drug administration become the toxic reaction known as serotonin syndrome. The transition point likely depends upon an assessment of the risks and benefits of therapy. As an example, an individual treated for major depression with a serotonergic agent may develop mild tremor and hyperreflexia. Although technically meeting the diagnostic criteria for serotonin syndrome, the patient may benefit more (ie, be significantly less depressed) with continued administration of the agent, even though it produces obvious but tolerable signs of serotonergic excess. However, clinicians should be extremely careful not to add other serotonergic drugs to the regimen of such a patient, and must remain vigilant for any worsening in condition.

Common poisoning syndromes (toxidromes):

Toxidrome Mental status Pupils Vital signs Other manifestations Examples of toxic agents Sympathomimetic Hyperalert, agitation, hallucinations, paranoia Mydriasis Hyperthermia, tachycardia, hypertension, widened pulse pressure, tachypnea, hyperpnea Diaphoresis, tremors, hyperreflexia, seizures Cocaine, amphetamines, cathinones, ephedrine, pseudoephedrine, phenylpropanolamine, theophylline, caffeine Anticholinergic Hypervigilance, agitation, hallucinations, delirium with mumbling speech, coma Mydriasis Hyperthermia, tachycardia, hypertension, tachypnea Dry flushed skin, dry mucous membranes, decreased bowel sounds, urinary retention, myoclonus, choreoathetosis, picking behavior, seizures (rare) Antihistamines, tricyclic antidepressants, cyclobenzaprine, orphenadrine, antiparkinson agents, antispasmodics, phenothiazines, atropine, scopolamine, belladonna alkaloids (eg, Jimson Weed) Hallucinogenic Hallucinations, perceptual distortions, depersonalization, synesthesia, agitation Mydriasis (usually) Hyperthermia, tachycardia, hypertension, tachypnea Nystagmus Phencyclidine, LSD, mescaline, psilocybin, designer amphetamines (eg, MDMA ["Ecstasy"], MDEA) Opioid CNS depression, coma Miosis Bradypnea, apnea characteristic; may develop: hypothermia, bradycardia, hypotension Hyporeflexia, pulmonary edema, needle marks Opioids (eg, heroin, morphine, methadone, oxycodone, hydromorphone), diphenoxylate Sedative-hypnotic CNS depression, confusion, stupor, coma Variable Often normal, but may develop: hypothermia, bradycardia, hypotension, apnea, bradypnea Hyporeflexia Benzodiazepines, barbiturates, carisoprodol, meprobamate, glutethimide, alcohols, zolpidem Cholinergic Confusion, coma Miosis Bradycardia, hypertension or hypotension, tachypnea or bradypnea Salivation, urinary and fecal incontinence, diarrhea, emesis, diaphoresis, lacrimation, GI cramps, bronchoconstriction, muscle fasciculations and weakness, seizures Organophosphate and carbamate insecticides, nerve agents, nicotine, pilocarpine, physostigmine, edrophonium, bethanechol, urecholine Serotonin syndrome Confusion, agitation, coma Mydriasis Hyperthermia, tachycardia, hypertension, tachypnea Tremor, myoclonus, hyperreflexia, clonus, diaphoresis, flushing, trismus, rigidity, diarrhea MAOIs alone or with: SSRIs, meperidine, dextromethorphan, TCAs, L-tryptophan

	If SS is suspected then the likely causative drug(s) should be stopped. Refer patients with severe symptoms or patients who have ingested an MAOI and an SSRI to the hospital, as their condition can worsen quickly. Once SS has resolved, try other drugs or restart low doses slowly, and rule out other contributing drugs such as OTC medications or illicit drugs. For most patients who experience serotonin-mediated side-effects, appropriate changes to their medications will manage symptoms and prevent toxicity. In all cases the most important step is to remove the offending agent or interacting drugs. In cases of recent ingestion/large overdose, activated charcoal may help to prevent absorption. Supportive measures such as IV fluids and control of agitation with benzodiazepines are also used. Mild cases usually resolve within 24 hours of discontinuation and may need supportive measures only. Beware of drugs with long half-lives or active metabolic breakdown products (for example, fluoxetine), where it may take longer. Moderately severe cases should have cardiovascular and thermal disturbances corrected and receive 5-HT2A antagonists such as cyproheptadine (as yet there is no definitive evidence for its efficacy). Severe cases need aggressive treatment and intensive care with early sedation, neuromuscular paralysis and ventilatory support. Antipyretic agents have no role, as hyperthermia is due to muscular activity rather than hypothalamic mechanisms. Chlorpromazine may be used to treat agitation and hyperthermia.