serotonin syndrome (serotonism)

Etiology

• excess serotonin or increased sensitivity to serotonin
• increased serotonin production
  • L tyrptophan, cocaine, amphetamines, phentermine
• inhibition of serotonin reuptake
  • SSRI, SNRI, tricyclic antidepressants (TCA), bupropion, nefazodone, trazodone, dextromethorphan, meperidine, pentazocine, St John's wort, tramadol, phentermine, granisetron, ondansetron, chlopheniramine
• inhibition of serotonin metabolism
  • monoamine oxidase inhibitors, linezolid, isocarboxazid, phenelzine, selegine, tranylcypromine, buspirone, rasagiline, safinamide
• increased serotonin release
  • dextromethorphan, meperidine, oxycodone, L-dopa, amphetamines, phentermine, methyleledioxymethamphetamine (MDMA, Ecstasy), mirtazapine
• serotonin receptor agonists
  • buspirone, lysergic acid diethylamide (LSD), meperidine, fentanyl, lithium, metoclopramide, dihydroergotamine, triptans, mirtazapine, trazodone, ondansetron, granisetron, dolasetron, palonosetron
• inhibition of elimination of serotonin via inhibition of cyt P450 isozymes
  • CYP2D6
    • inhibitors: fluoxetine, sertraline
    • substrates: dextromethorphan, oxycodone, phentermine, risperidone, tramadol
  • CYP3A4
    • inhibitors: ciprofloxacin, ritonavir
    • substrates: methadone, oxycodone, venlafaxine
  • CYP2C19
    • inhibitors: fluconazole
    • substrates: citalopram
• generally occurs when 2 or more drugs that affect the serotonin system through different mechanisms are prescribed
  • monoamine oxidase inhibitors (MAOi) with SSRI, SNRI, TCA, opiates
  • SSRI with MAOi, SNRI, TCA, opiates, or triptans
    • fluoxetine with carbamazepine, phentermine, fentanyl
  • SNRI with MAOi, TCA, opiates, or triptans
    • venlafaxine with lithium carbonate, calcineurin inhibitors, mirtazqpine, or tranylcypromine
    • venlafaxine with mirtazapine & tramadol, amitriptyline & meperidine, methadone & fluoxetine or sertraline, tramadole & trazodone & quetiapine
  • opiates with MAOi, SSRI, SNRI or triptans
    • tramadol with mirtazapine & olanzapine
  • dextromethorphan with SSRI, amitriptyline, or chlorpheniramine
    • dextromethorphan with risperidone & amitriptyline
  • olanzapine with lithium carbonate & citalopram
  • risperidone with fluoxetine or paroxetine
  • ciprofloxacin with venlafaxine & methadone
  • fluconazole with citalopram
  • linezolid with SSRI or tapentodol

Pathology

• autonomic hyperactivity
• hemodynamic changes
• neuromuscular disorder
• mental status changes
• potentially life-threatening

Clinical manifestations

• mild:
  • nausea/vomiting
  • flushing
  • sweating, diaphoresis
• headache
• dizziness
• agitation, restlessness, anxiety
• confusion, inattention
• ataxia
• neuromuscular hyperexcitability
  • myoclonus (spontaneous clonus), muscle twitching, muscle rigidity
    • especially lower extremities
  • hyperreflexia
  • tremor
  • shivering
  • hyperthermia, due to excessive muscular activity
    • temperature may be > 105.8 F (41C)
• ocular clonus
  • slow continuous horizontal eye movements
• hypertension or hypotension
• tachycardia, tachypnea
• diarrhea (late manifestation)
• mydriasis
• onset within 24 hours of initiating or increasing dose of offending agent - average onset < 12 hours
• gastrointestinal prodrome, hyperactive bowel sounds
• sleep disturbance

Diagnostic criteria

• see Hunter criteria

Complications

• disseminated intravascular coagulation
• rhabdomyolysis
• multiple organ failure
• shock
• coma

Management

• discontinuation of offending agent
• most cases resolve in 24-72 hours
• supportive care
  • oxygen therapy
  • intravenous fluids
  • cardiac monitoring, including QTc & QRS duration
  • external cooling if temperature > 40 C
  • esmolol for hypertension
• activated charcoal to assist with gastrointestinal decontamination may be considered
• severe cases
  • sedation, paralyzing agents, mechanical ventilation may be required in cases of recent exposure
  • benzodiazepine
  • serotonin antagonists have been used (no strong supporting evidence for their use)
    • cyproheptadine, chlorpromazine
• antipyretic therapy NOT recommended

More general terms

• syndrome