Serotonin Syndrome

Serotonin syndrome is a rare and potentially lethal disorder that can be caused by any drug with serotonergic activity.

Incidence

• The incidence of serotonin syndrome, while believed to be rare, is unknown. Serotonin syndrome is difficult to study as it cannot be prospectively examined and retrospective studies are limited by underreporting due to unrecognized symptoms and confusion with other pathologies.
• Serotonin syndrome is often attributed to newer antidepressants as a result of their serotonergic activity. Prescription event-monitoring studies have indicated an incidence of 0.5-1 per 1000 patient months of treatment with the drugs: fluoxetine, sertraline, paroxetine, moclobemide, nefazodone, and venlafaxine.
• Individuals with serotonin syndrome commonly have underlying illnesses. Predictably, depression is common among those with serotonin syndrome, suicide as depressive disorders are often treated with one or more serotonergic drugs.
• The occurrence of death with serotonin syndrome is also unknown. Among 38 cases reported between 1982-1991 and 41 reported cases between 1995-2000, two patients died, both of whom had complicated presentations involving several drugs.

Clinical Features

Onset of Serotonin Syndrome

• The onset of serotonin syndrome may occur from minutes to days after ingestion of serotonergic drugs.
• Serotonin syndrome usually occurs in conjunction with the increase in dose of a serotonergic drug, or the combination of serotonergic drugs. Combining drugs with different mechanisms of increasing serotonergic activity may be particularly dangerous. Serotonin syndrome caused by a single agents is often associated with over ingestion.
  • Antidepressants including MAOIs, TCAs, and SSRIs have been associated with serotonin syndrome when used in monotherapy or with other serotonergic agents.
  • Elicit drugs including MDMA "ecstasy" and cocaine have been implicated in causing serotonin syndrome.

Table: Drug combinations commonly associated with serotonin syndrome

Primary Drug	Potentially Dangerous Combinations
SSRIs	L-Trp, MAOIs, tricycle antidepressants, buspirone, lithium, trazodone, selegiline, moclobemide, and dextromethorphan
MAOIs	L-Trp, 3,4 metachlorophenylpiperazine (mCPP), trazodone, lithium, meperidine, MDMA, selegiline, dextromethorphan, SSRIs, tricyclic antidepressants
TCAs	3,4 meta-chlorophenylpiperazine (mCPP), nefazodone, trazodone, venlafaxine
Reversible inhibitors of MAO-A (such as moclobemide)	Venlafaxine, lithium, tricyclic antidepressants, SSRIs

Diagnosis of Serotonin Syndrome

• The diagnosis of serotonin syndrome is made clinically based on strong suspicion or known exposure to serotonergic agents, demonstration of specific signs and symptoms of the disorder, and exclusion of other medical and psychiatric symptoms.
• Serotonin syndrome may not be an all-or-nothing phenomenon, rather there appears to be a continuum of serotonin-induced hyperactivity. Thus, patients may present with one or more symptoms, but not meet complete diagnostic criteria.
• The clinical presentation of serotonin syndrome is characterized by a triad of cognitive/ behavioral changes, autonomic instability, and neuromuscular changes.
  • Cognitive and behavioral symptoms may include confusion, disorientation, hypomania, agitation, and coma in severe cases.
  • Autonomic problems include fever, dilated pupils, shivering, diaphoresis, tachycardia, tachypnea, nausea, and diarrhea.
  • Neuromuscular dysfunction manifests as clonus, ocular clonus, restlessness, hyperreflexia, myoclonus, tremor, incoordination, rigidity, trismus, bilateral Babinski signs, rhabdomyolysis, nystagmus, seizures, and ataxia.
• Definitive diagnostic criteria for serotonin syndrome are lacking, though the diagnostic criteria proposed by Sternbach are commonly referenced (see Table 17.13).
• As Sternbach's diagnostic criteria do not consider the severity of symptoms a Serotonin Syndrome Scale (SSS) has been developed which measures 9 factors on a scale of 0 (absent) to 3 (severe). The symptoms assessed are agitation, disorientation, myoclonus, hyperreflexia, tremor, dizziness, hyperthermia, sweating, and diarrhea. A score >6 is said to be indicative of serotonin syndrome. While this scale has not been rigorously validated, it may have value as a guideline for assessing the possibility of serotonin syndrome.

Differential Diagnosis

• Disorders with similar presentations to serotonin syndrome include sepsis, stiff-man syndrome, heat stroke, delirium tremens, poisonings, and neuroleptic malignant syndrome (NMS).

  Table: Sternbach's diagnostic criteria for serotonin syndrome

  Diagnostic Criteria Recent increased dose or addition of serotonergic agent Other causes excluded Patient should not have had a recent increase of a neuroleptic agent Three of the following must be present: altered mental status, agitation, tremor, shivering, diarrhea, hyperreflexia, myoclonus, ataxia, or fever

• Serotonin syndrome is commonly confused with NMS. Relative to serotonin syndrome, NMS is more likely to be associated with high fevers, rhabdomyolysis, and mortality. The symptoms of NMS are more likely to include lead-pipe rigidity and EPS, whereas the symptoms of serotonin syndrome are more likely to include myoclonus, hyperreflexia, or dilated pupils. Serotonin syndrome is also sometimes associated with unusual ocular movement and preferential increased tonicity of lower limbs that is not seen in NMS.

Treatment

• If serotonin syndrome is suspected, serotonergic drugs should be immediately discontinued. In general, if the offending agent is withdrawn the syndrome tends to resolve on its own within 1-3 days, though recovery may take longer depending on the severity of symptoms.
• Supportive care measures should be initiated and may include: cooling blankets for hyperthermia, hydration, and maintenance of cardiac and renal function. In some cases. In some cases paralysis with neuromuscular blocking agents and mechanical ventilation may be required.
• Benzodiazepines may be effective in decreasing anxiety and agitation and treating seizures that may develop as a result of serotonin syndrome. However, benzodiazepines are not regarded as a first-line treatment for serotonin syndrome.
• High urine outputs should be maintained to prevent myoglobinuria from causing renal injury. Sodium bicarbonate has proven efficacious in preventing renal impairment.
• Throughout the course of the treatment, autonomic functioning should be closely monitored and precautions against seizures should be taken.
• For patients in whom supportive therapy alone is insufficient, treatment with an antiserotonergic drug may be given (see Table 17.14). It is unclear whether these drugs shorten the duration of serotonin syndrome, but they do appear to provide symptomatic relief.
  • Currently, cyproheptadine is regarded as the antiserotonergic drug of choice for serotonin syndrome. Cyproheptadine is generally effective at doses of 2-8 mg orally, 3-4 times/day.
  • Chlorpromazine may also be effective in the treatment of serotonin syndrome and has the advantage that it is available in parenteral form. It can be given in an initial parenteral dose of 12.5 mg. Due to its action as a dopamine (D2) antagonist, chlorpromazine should not be used if NMS is suspected. Chlorpromazine has also been associated with hypotension, dystonic reactions, NMS, and possibly reduction of seizure threshold.
  • Methysergide and propranolol may also be effective in treating serotonin syndrome.
• As a result of the antagonistic effect of certain atypical antipsychotics on certain serotonin receptors, these drugs may someday have a role in the treatment of serotonin syndrome. Though research in this area is virtually nonexistent, risperidone has displayed a prophylactic effect in preventing serotonin syndrome in an animal study.

  Table: Mechanisms of drugs commonly prescribed for serotonin syndrome

  Drug	Mechanism
  Cyproheptadine	5-HT1A and 5-HT2 antagonism as well as additional antimuscarinic properties
  Chlorpromazine	Antagonistic properties at 5-HT1A and 5-HT2 receptors, blocks D2 á-adrenergic receptors, and has antimuscarinic effects
  Methysergide	Non-selective 5-HT antagonist
  Propanolol	Beta-blocker with antagonistic properties at 5-HT1A receptors

• Supportive treatment is essential as untreated patients are at a risk of developing rhabdomyolysis, renal failure, hepatic dysfunction, disseminated intravascular coagulation, and in massive overingestion, cardiovascular collapse and death.