Serotonin Syndrome

Primer

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.

Epidemiology

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.

Onset and Prognosis

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.

Risk Factors

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.

Medications

Drugs associated with SS

  • SSRIs: sertraline, fluoxetine, fluvoxamine, paroxetine, and citalopram
  • Antidepressant: trazodone, nefazodone, buspirone, clomipramine, and venlafaxine
  • Monoamine oxidase inhibitors: phenelzine, moclobemide, clorgiline, and isocarboxazid
  • Anticonvulsants: valproate
  • Analgesics: meperidine, fentanyl, tramadol, and pentazocine Antiemetic agents: ondansetron, granisetron, and metoclopramide
  • Antimigraine drugs: sumatriptan (5-HT1B/1D agonist)
  • Bariatric medications: sibutramine
  • Antibiotics: linezolid (a monoamine oxidase inhibitor) and ritonavir (through inhibition of cytochrome P-450 enzyme isoform 3A4) Over-the-counter cough and cold remedies: dextromethorphan
  • Drugs of abuse: methylenedioxymethamphetamine (MDMA, or “ecstasy”), lysergic acid diethylamide (LSD), 5-methoxydiisopropyltryptamine (“foxy methoxy”), Syrian rue (contains harmine and harmaline, both monoamine oxidase inhibitors)
  • Dietary supplements and herbal products: tryptophan, Hypericum perforatum (St. John’s wort), Panax ginseng (ginseng)
  • Mood stabilizers: lithium

Drug-drug Interactions associated with severe serotonin syndrome

Medication History is Critical!

On history, ask about the use of prescription and over-the-counter drugs, illicit substances, and dietary supplements, since all of these agents can potentially cause SS!

Diagnosis

Signs and Symptoms

  • SS encompasses a range of clinical findings. Clinicians and patients may dismiss symptoms of SS such as tremor with diarrhea, tachycardia, or hypertension as being unrelated to drug therapy. Anxiety and akathisia may also be misattributed to the patient's underlying psychiatric diagnosis. Patients with mild cases are also afebrile. Manifestations of SS include:
    • A core temperature > 40°C is common in moderate intoxication
    • Autonomic changes such as shivering, diaphoresis or mydriasis (pupil dilation)
    • Hyperactive bowel sounds, diarrhea
    • Neurologic examination may reveal horizontal ocular clonus, intermittent tremors, myoclonus, and/or hyperreflexia
    • Changes in mental status include mild agitation or hypervigilance, as well as slightly pressured speech, patients may easily startle or adopt a peculiar head-turning behaviour characterized by repetitive rotation of the head with the neck held in moderate extension
  • In severe SS, there can be a hypertensive crisis and tachycardia that can quickly evolve into shock, and hyperactive delirium.

Hunter Criteria

The Hunter criteria propose the following symptoms for diagnosing SS:

  1. Tremor and hyperreflexia
  2. Spontaneous clonus
  3. Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus
  4. Ocular clonus and either agitation or diaphoresis
  5. Inducible clonus and either agitation or diaphoresis

Mnemonic

The mnemonic MOIST can be used to remember the Hunter Criteria:

  • M - Muscle rigidity, temperature >38°C, and either ocular clonus or inducible clonus
  • O - Ocular clonus and either agitation or diaphoresis
  • I - Inducible clonus and either agitation or diaphoresis
  • S - Spontaneous clonus
  • T - Tremor and hyperreflexia

Hunter's Decision Rules

Hunter’s Decision Rules

Adapted from: Dunkley, E. J. C. et al. (2003). The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Qjm, 96(9), 635-642.
Sign/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

Pathophysiology

  • Remember that serotonin is a neurotransmitter produced by the decarboxylation and hydroxylation of l-tryptophan. The amount and actions of serotonin are regulated closely by a combination of reuptake mechanisms, feedback loops, and metabolizing enzymes. While no single receptor appears to be responsible for the development of SS, agonism of 5-HT2A serotonin receptors is believed to contribute substantially to the syndrome.[5]
  • Other neurotransmitters, including N-methyl-d-aspartate (NMDA) receptor antagonists and g-aminobutyric acid (GABA), and dopamine are also thought to be involved in the development of SS, but their roles are less clear.

Differential Diagnosis

  • Anticholinergic poisoning
    • Patients with the anticholinergic toxicity have normal reflexes and show the classic anticholinergic toxidrome of mydriasis, hyperactive delirium, dry oral mucosa, dry erythematous skin, urinary retention, and an absence of bowel sounds. Hyperactive bowel sounds with clonus, hyperreflexia, or tremor, diaphoresis, and normal skin color would thus favour a diagnosis of SS from an anticholinergic toxidrome
  • Malignant hyperthermia (MH)
    • MH occurs within minutes after exposure to inhalational anesthetic agents. On physical examination, the skin is often mottled, with cyanotic areas contrasting with patches of bright red flushing. The rigor mortis–like rigidity of skeletal muscles and hyporeflexia that are seen in malignant hyperthermia further distinguish this condition from SS.
  • Neuroleptic malignant syndrome
    • Signs and symptoms of NMS typically evolve during several days, in contrast to the rapid onset and hyperkinesia of SS

Comparison with Related Conditions

Manifestations of Severe Serotonin Syndrome and Related Clinical Conditions

Adapted from: Boyer, E. W. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.
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

Comparing Serotonin Syndrome and Neuroleptic Malignant Syndrome Treatments

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

Investigations

  • SS is a clinical diagnosis. There is no single laboratory investigation to confirm the diagnosis of SS.
  • Laboratory abnormalities that occur in severe cases include metabolic acidosis, rhabdomyolysis, elevated aminotransferase and creatinine, renal failure, and disseminated intravascular coagulopathy.
  • Many of these lab abnormalities arise from poorly treated hyperthermia. Close monitoring of these laboratory values is important.

Physical Exam

  • The presence of tremor, clonus, hyperreflexia, or akathisia without additional extrapyramidal signs should lead clinicians to consider the diagnosis. The common physical findings of SS include:
    • Diaphoresis
    • Dryness of oral mucosa
    • Size and reactivity of the pupils
    • Hypertension, autonomic instability
    • Tachycardia
    • Bowel sounds are increased
    • Hyperkinetic neuromuscular findings
    • Clonus (greatest in lower extremities) whether inducible, spontaneous, and ocular is the single most important clinical finding
    • Deep-tendon reflexes hyperreflexia (greater in lower extremities) is the single most important sign to check for in SS!
    • Rigidity
    • Tremor (greater in lower extremities)

Clonus Can Be Masked!

In severe cases, hyperthermia and hypertonicity (rigidity) can occur. This means the muscle rigidity seen may actually mask the highly distinguishing findings of clonus and hyperreflexia. In these cases, serotonin syndrome might be misdiagnosed as Neuroleptic Malignant Syndrome (NMS)!

Treatment

Don't Use Physical Restraints (Unless Imminent Emergency or Risk of Injury)!

Physical restraints should be avoided. They may contribute to increased mortality by reinforcing isometric muscle contractions that may cause severe lactic acidosis and hyperthermia. If physical restraints are used, they must be rapidly replaced with chemical sedation.
  • Treatment of SS involves immediately discontinuing the triggering serotonergic agents, followed by supportive care, comprising of intravenous fluids and correction of vital signs. Control of autonomic instability, hyperthermia, and agitation is also important.
    • In mild cases: supportive therapy as per above
    • In moderate cases: all cardiorespiratory and thermal abnormalities should be aggressively corrected and may benefit from the administration of 5-HT2A antagonists.
    • In severe cases: individuals with a temperature > 41.1°C are severely ill and should receive the above therapies as well as immediate sedation, neuromuscular paralysis, and intubation
    • In all cases: Control of agitation with benzodiazepines is essential in the management of SS, and help blunt the hyperadrenergic component of the syndrome
  • The use of 5-HT2A antagonists include:
    • Cyproheptadine, a first-generation antihistamine with anticholinergic, antiserotonergic, and local anesthetic properties.
      • An initial dose of 12 mg is recommended, followed by 2 mg q2 hours if symptoms continue.
      • Maintenance dosing of 8 mg q6h is recommended
      • Typically, 12 to 32 mg is given over a 24-hour period, will bind 85 to 95% of serotonin receptors.
    • Atypical antipsychotics with 5-HT2a–antagonist activity
  • There is no role for antipyretic agents (e.g. - acetaminophen) in the management of SS, since the increase in body temperature is due to muscular activity, and not an alteration in the hypothalamic temperature set point.
  • Therapies such as propranolol, bromocriptine, and dantrolene are not recommended.

Resources

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References

1) Simon, L. V., & Keenaghan, M. (2019). Serotonin Syndrome. In StatPearls [Internet]. StatPearls Publishing.
2) Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.
3) Mason, P. J., Morris, V. A., & Balcezak, T. J. (2000). Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine, 79(4), 201-209.
4) Gill, M., LoVecchio, F., & Selden, B. (1999). Serotonin syndrome in a child after a single dose of fluvoxamine. Annals of emergency medicine, 33(4), 457-459.
5) Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. The New England journal of medicine, 352(11), 1112–1120.