Serotonin Syndrome

GENERAL PRINCIPLES

• Serotonin syndrome is a clinical condition of neuromuscular abnormalities, mental status changes, and

hyperthermia in patients exposed to serotonergic xenobiotics.

• Serotonin syndrome is a spectrum of disease that ranges from mild to life-threatening. ¹⁵

î Some authors prefer the term “serotonin toxicity” or “serotonin excess” for all but the sickest patients.

î Mild serotonin excess may not require any treatment or medical evaluation.

• Serotonin syndrome classically develops when two or more serotonergic xenobiotics are coadministered, but it may also occur following an acute overdose of one or more serotonergic xenobiotics, dose titration of serotonergic xenobiotics, and initiation of therapy with a single serotonergic xenobiotic.

Pathophysiology

• Serotonin syndrome is thought to occur due to excessive stimulation of 5HT₁ and 5HT₂ receptors.

• Many classes of xenobiotics have been implicated in the development of the serotonin syndrome.

î Psychotropics: SSRIs, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, other atypical serotonergic antidepressants, bupropion, lithium, amphetamines, certain atypical antipsychotics

î Opioids: meperidine, tramadol, dextromethorphan, and possibly fentanyl

î Other pharmaceuticals: linezolid, triptans, valproate, lamotrigine, bromocriptine, methylene blue î Recreational drugs: methamphetamine and other amphetamines, cocaine, serotonergic hallucinogens (MDMA, psilocybin, tryptamine derivatives)

DIAGNOSIS

Clinical Presentation

HISTORY

• Consider serotonin syndrome in any patient who has been exposed to one or more serotonergic xenobiotics who presents with mental status changes, anxiety, tremulousness, GI upset, or abnormal extremity tone or movements.

• The onset of serotonin syndrome is typically very rapid (on the order of hours) following the culprit exposure.

PHYSICAL EXAMINATION

• Patients may present with mental status changes, neuromuscular abnormalities, and/or other serotonergic signs.

• Mental status changes may range from anxiety to coma.

• The neuromuscular abnormalities of serotonin syndrome typically consist of hyperreflexia, tremor, and clonus.

î These findings are predominantly in the lower extremities. Prominent upper extremity findings should prompt consideration of an alternative diagnosis.

î The “rigidity”’ of serotonin syndrome is due to profound hypertonia; the examiner will generally be able to passively range the patient's extremities with significant effort. Complete unmovable “lead- pipe” rigidity is not consistent with serotonin syndrome.

• Other serotonergic signs, such as mydriasis, diaphoresis, flushing, shivering, and vomiting or diarrhea, may also be present. ¹⁵

• The presence of hyperthermia is a late and ominous sign and indicates severe serotonin syndrome. The absence of hyperthermia should never be used to rule out serotonin syndrome.

Differential Diagnosis

• The toxicologic differential diagnosis of serotonin syndrome includes neuroleptic malignant syndrome (NMS), malignant hyperthermia, alcohol or sedative-hypnotic withdrawal, sympathomimetic intoxication, and the antimuscarinic toxidrome.

î The most important distinguishing factor is the exposure history.

î NMS typically presents with lead-pipe rigidity of all four extremities and bradykinesia with subacute onset, over the course of days.

• The nontoxicologic differential diagnosis of serotonin syndrome includes sepsis of any source (especially in older patients), meningitis and encephalitis, thyrotoxicosis, and carcinoid syndrome.

Diagnostic Testing

LABORATORIES

• Laboratory testing is not routinely indicated in mild cases.

• In moderate or severe cases, laboratory testing may be helpful:

î BMP and/or blood gas to evaluate for acidosis

î Creatinine kinase to evaluate for rhabdomyolysis.

• Laboratory testing may be helpful in questionable cases to evaluate for alternative causes of symptoms, for example, CSF (cerebrospinal fluid) studies to rule out meningitis.

TREATMENT

• The first principle of treatment is to discontinue the offending agent(s) and avoid all serotonergic xenobiotics.

• Benzodiazepines and other directly GABAergic sedatives should be used liberally to treat psychomotor agitation and neuromuscular hyperexcitation.

î Heat generation in serotonin syndrome is entirely peripheral; aggressive control of neuromuscular abnormalities and agitation prevents progress to life-threatening hyperthermia.

î The goal of treatment is for the patient to be resting comfortably with normal neuromuscular tone and improving vital signs.

î In severe cases, intubation and deep sedation may be necessary to achieve this goal. Paralysis with nondepolarizing neuromuscular blocking agents may be used as a last resort if muscular rigidity is refractory to deep sedation.

• Patients with any hyperthermia should be rapidly and aggressively cooled in addition to appropriate sedation as above.

° The most effective external cooling method is evaporative cooling—spray the patient with water and circulate air over them with large fans.

î If evaporative cooling is unavailable, consider immersion in an ice water bath.

î Antipyretic medications are not effective.

• Patients with mild to moderate symptoms may benefit from cyproheptadine. Cyproheptadine has no role in the treatment of patients with severe serotonin syndrome or patients who are critically ill.