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11.3 Psychotic disorders
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11.9 Serotonin syndrome
11.10 Somatic symptom disorder
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11.9 Serotonin syndrome
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11. Behavioral science

Serotonin syndrome

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Serotonin syndrome is a mild to potentially fatal condition caused by excess serotonin that overactivates serotonin (5-HT) receptors, especially 5-HT2A.

Drugs can raise serotonin activity through several mechanisms, including:

  • Inhibiting serotonin reuptake
  • Decreasing serotonin metabolism
  • Increasing serotonin synthesis
  • Increasing serotonin release
  • Directly activating serotonergic receptors

Another mechanism involves inhibition of certain cytochrome P450 enzymes (including CYP2D6 and CYP3A4) by SSRIs. This can cause accumulation of serotonergic drugs, including SSRIs themselves.

Symptoms usually appear within 24 hours of the inciting event. Common triggers include starting a serotonergic drug, increasing its dose, or introducing a new drug combination.

It presents with hyperthermia, hypertension, muscle rigidity, mydriasis, diaphoresis, tremors, myoclonus, hyperreflexia, agitation, pressured speech, diarrhea, flushed skin, dry mucosa, arrhythmias, dramatic swings in pulse rate and blood pressure, seizures etc.

Complications include rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, ARDS, DIC, coma and death. Babinski sign may be positive bilaterally.

Laboratory findings include leukocytosis, elevated transaminases and creatinine levels.

Drugs and drug combinations that can precipitate serotonin syndrome

  • MAOIs alone or in combination with SSRIs/SNRIs/TCAs or opiates

  • SSRIs alone or in combination with MAOIs/SNRIs/TCAs/Triptans/opiates

  • Fluoxetine* with carbamazepine

  • Venlafaxine alone or with lithium/tramadol/MAOIs/SSRIs/TCAs/opiates

  • Atypical antipsychotics

  • Buspirone

  • Mirtazapine

  • Dextromethorphan with SSRIs/amitriptyline/chlorpheniramine

  • Ciprofloxacin with venlafaxine/methadone

  • Fluconazole with citalopram

  • Linezolid with SSRIs

  • Cocaine, MDMA (Ecstasy), LSD

  • St John’s wort

  • L tryptophan

  • Lithium

  • Metoclopramide

*Fluoxetine can cause serotonin syndrome even after being discontinued, due to its long half life.

Management includes stopping the offending drug, supportive measures, critical care, cooling measures, diazepam, cyproheptadine (5HT antagonist), esmolol/nitroprusside for hypertension and paralysis with a nondepolarizing agent with intubation and mechanical ventilation.

Pathophysiology and Mechanisms

  • Excess serotonin overactivates 5-HT receptors, especially 5-HT2A
  • Mechanisms: inhibit reuptake, decrease metabolism, increase synthesis/release, direct receptor activation
  • CYP2D6/CYP3A4 inhibition by SSRIs can cause drug accumulation

Onset and Triggers

  • Symptoms appear within 24 hours
  • Common triggers: starting/increasing serotonergic drugs, new drug combinations

Clinical Presentation

  • Autonomic: hyperthermia, hypertension, diaphoresis, mydriasis, flushed skin, dry mucosa
  • Neuromuscular: muscle rigidity, tremors, myoclonus, hyperreflexia, positive Babinski sign
  • CNS: agitation, pressured speech, seizures
  • GI: diarrhea
  • Cardiovascular: arrhythmias, swings in pulse/BP

Complications

  • Rhabdomyolysis, myoglobinuria, metabolic acidosis
  • Renal failure, ARDS, DIC, coma, death

Laboratory Findings

  • Leukocytosis
  • Elevated transaminases
  • Increased creatinine

Causative Drugs and Combinations

  • MAOIs, SSRIs, SNRIs, TCAs, opiates (alone or in combinations)
  • Fluoxetine (even after discontinuation), venlafaxine, lithium, tramadol
  • Atypical antipsychotics, buspirone, mirtazapine
  • Dextromethorphan, chlorpheniramine, amitriptyline
  • Ciprofloxacin, fluconazole, linezolid (with serotonergic agents)
  • Cocaine, MDMA, LSD, St John’s wort, L-tryptophan, metoclopramide

Management

  • Discontinue offending drug(s)
  • Supportive and critical care, cooling measures
  • Diazepam for agitation/seizures
  • Cyproheptadine (5-HT antagonist)
  • Esmolol/nitroprusside for hypertension
  • Paralysis with nondepolarizing agent, intubation, mechanical ventilation if needed

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Serotonin syndrome

Serotonin syndrome is a mild to potentially fatal condition caused by excess serotonin that overactivates serotonin (5-HT) receptors, especially 5-HT2A.

Drugs can raise serotonin activity through several mechanisms, including:

  • Inhibiting serotonin reuptake
  • Decreasing serotonin metabolism
  • Increasing serotonin synthesis
  • Increasing serotonin release
  • Directly activating serotonergic receptors

Another mechanism involves inhibition of certain cytochrome P450 enzymes (including CYP2D6 and CYP3A4) by SSRIs. This can cause accumulation of serotonergic drugs, including SSRIs themselves.

Symptoms usually appear within 24 hours of the inciting event. Common triggers include starting a serotonergic drug, increasing its dose, or introducing a new drug combination.

It presents with hyperthermia, hypertension, muscle rigidity, mydriasis, diaphoresis, tremors, myoclonus, hyperreflexia, agitation, pressured speech, diarrhea, flushed skin, dry mucosa, arrhythmias, dramatic swings in pulse rate and blood pressure, seizures etc.

Complications include rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, ARDS, DIC, coma and death. Babinski sign may be positive bilaterally.

Laboratory findings include leukocytosis, elevated transaminases and creatinine levels.

Drugs and drug combinations that can precipitate serotonin syndrome

  • MAOIs alone or in combination with SSRIs/SNRIs/TCAs or opiates

  • SSRIs alone or in combination with MAOIs/SNRIs/TCAs/Triptans/opiates

  • Fluoxetine* with carbamazepine

  • Venlafaxine alone or with lithium/tramadol/MAOIs/SSRIs/TCAs/opiates

  • Atypical antipsychotics

  • Buspirone

  • Mirtazapine

  • Dextromethorphan with SSRIs/amitriptyline/chlorpheniramine

  • Ciprofloxacin with venlafaxine/methadone

  • Fluconazole with citalopram

  • Linezolid with SSRIs

  • Cocaine, MDMA (Ecstasy), LSD

  • St John’s wort

  • L tryptophan

  • Lithium

  • Metoclopramide

*Fluoxetine can cause serotonin syndrome even after being discontinued, due to its long half life.

Management includes stopping the offending drug, supportive measures, critical care, cooling measures, diazepam, cyproheptadine (5HT antagonist), esmolol/nitroprusside for hypertension and paralysis with a nondepolarizing agent with intubation and mechanical ventilation.

Key points

Pathophysiology and Mechanisms

  • Excess serotonin overactivates 5-HT receptors, especially 5-HT2A
  • Mechanisms: inhibit reuptake, decrease metabolism, increase synthesis/release, direct receptor activation
  • CYP2D6/CYP3A4 inhibition by SSRIs can cause drug accumulation

Onset and Triggers

  • Symptoms appear within 24 hours
  • Common triggers: starting/increasing serotonergic drugs, new drug combinations

Clinical Presentation

  • Autonomic: hyperthermia, hypertension, diaphoresis, mydriasis, flushed skin, dry mucosa
  • Neuromuscular: muscle rigidity, tremors, myoclonus, hyperreflexia, positive Babinski sign
  • CNS: agitation, pressured speech, seizures
  • GI: diarrhea
  • Cardiovascular: arrhythmias, swings in pulse/BP

Complications

  • Rhabdomyolysis, myoglobinuria, metabolic acidosis
  • Renal failure, ARDS, DIC, coma, death

Laboratory Findings

  • Leukocytosis
  • Elevated transaminases
  • Increased creatinine

Causative Drugs and Combinations

  • MAOIs, SSRIs, SNRIs, TCAs, opiates (alone or in combinations)
  • Fluoxetine (even after discontinuation), venlafaxine, lithium, tramadol
  • Atypical antipsychotics, buspirone, mirtazapine
  • Dextromethorphan, chlorpheniramine, amitriptyline
  • Ciprofloxacin, fluconazole, linezolid (with serotonergic agents)
  • Cocaine, MDMA, LSD, St John’s wort, L-tryptophan, metoclopramide

Management

  • Discontinue offending drug(s)
  • Supportive and critical care, cooling measures
  • Diazepam for agitation/seizures
  • Cyproheptadine (5-HT antagonist)
  • Esmolol/nitroprusside for hypertension
  • Paralysis with nondepolarizing agent, intubation, mechanical ventilation if needed