AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed psychotherapeutic agents. Safety and a favorable side-effect profile, as well as the lack of multiple receptor affinity associated with the tricyclic antidepressants (TCAs) have distinguished SSRIs from TCAs. SSRIs have a high toxic-to-therapeutic ratio, and fatalities are uncommon with pure SSRI overdoses.

However, on October 15, 2004, the FDA issued a public health advisory that directed manufacturers of all antidepressant drugs, including the SSRIs, to revise the labeling for their products to include a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents. The risk of suicidality associated with these drugs was identified based on a combined analysis of short-term (up to 4 mo) placebo-controlled trials of 9 antidepressant drugs, including the SSRIs and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials that involved 4400 patients were included. The average risk of suicidality in those using the drug was 4%, twice the placebo risk of 2%.

The most serious drug-related adverse effect of SSRIs is the potential to produce serotonin syndrome. Commonly prescribed SSRIs include sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and fluvoxamine (Luvox).

Serotonin syndrome, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Initial reports of such a syndrome date back to the 1950s; however, the full spectrum of the syndrome has only recently been appreciated. Increased use of SSRIs for various neurobehavioral disorders has led to a greater clinical awareness of the syndrome.

Although SSRIs are commonly linked to serotonin syndrome, many other drugs (eg, amphetamines, monamine oxidase inhibitors [MAOIs], TCAs, lithium) have the potential of causing hyperserotonergic symptoms. Toxicity of serotonergic drugs can be caused by overdosage, interaction with other drugs, and, rarely, with therapeutic doses. SSRI overdosage does not necessarily lead to the development of serotonin syndrome. Patients with such an ingestion who remain asymptomatic for several hours are unlikely to need any further medical evaluation and treatment.

Accidental ingestion by toddlers and illicit drug use in adolescents (methylenedioxymethamphetamine [MDMA] or ecstasy) are important pediatric considerations. In adults, serotonin syndrome typically develops after the addition of a serotonergic agent to a regimen that already includes a serotonin-enhancing drug.

Pathophysiology

Serotonin is a neurotransmitter synthesized from the amino acid L-tryptophan. Synthesis is necessary in both the central and peripheral nervous systems because serotonin cannot cross the blood-brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monamine oxidase (MAO) to 5-hydroxyindoleacetic acid. MAO may have preferential affinity to serotonin (MAO-A) or dopamine (MAO-B). Therefore, drugs inhibiting MAO-A have a higher risk of producing SS, especially when combined with SSRIs. Serotonin binds one of seven postsynaptic 5-hydroxytryptophan (5-HT) receptors. Various mechanisms can potentially increase the quantity or activity of serotonin. These mechanisms and corresponding agents include the following:

• Increasing production of serotonin by providing increased amount of precursors - L-tryptophan–containing substances
• Prevention of metabolism of stored serotonin - MAOIs
• Increased release of stored serotonin - Amphetamine, cocaine, fenfluramine, MDMA (ecstasy), meperidine
• Prevention of reuptake of serotonin released into the synapse - SSRIs, TCAs, MDMA, dextromethorphan, meperidine, St. John's Wort^{1, 2}
• Direct stimulation of serotonin receptors - Buspirone, lysergic acid diethylamide (LSD)
• Unknown mechanism - Lithium

Pharmacokinetics

All SSRIs are metabolized by cytochrome P450 microsomal enzymes. SSRIs undergo extensive metabolism. They possess a large volume of distribution and circulate highly bound to plasma proteins. Peak plasma levels are reached in about 5 hours. Half-lives vary depending on the specific drug but tend to be prolonged. For example, fluoxetine and its active metabolite, norfluoxetine, have half-lives that average 19 days. A new serotonergic drug should not be initiated until ensuring an adequate washout period (4-6 wk) of the recently discontinued serotonergic agent.

Frequency

United States

Data from the 2004 annual report of the American Association of Poison Control Centers Toxic Exposures Surveillance System (AAPCC-TESS) revealed that 48,204 SSRI exposures (from a total of 103,155 antidepressant exposures) occurred; 11,680 exposures to SSRIs occurred in children aged 6-19 years, and 8187 exposures occurred in children younger than 6 years.³

Mortality/Morbidity

AAPCC-TESS 2004 data revealed that 8187 exposures resulted in moderate or major morbidity, with 103 deaths.³

Age

As with most pediatric ingestions, SSRI toxicity occurs in a bimodal distribution. Most accidental ingestions occur in toddlers, whereas adolescent ingestions are usually intentional.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Selective serotonin reuptake inhibitors (SSRIs) have a high toxic-to-therapeutic ratio, and fatalities are uncommon with pure SSRI overdoses. Because the enteric nervous system is richly innervated by serotonin, acute toxicity is frequently manifested by altered GI motility and nausea. The most serious drug-related adverse effect of SSRI is the potential to produce serotonin syndrome.

Serotonin syndrome typically develops within hours or days of the addition of a new serotonergic agent to a medication regimen that already includes serotonin-enhancing drugs. Serotonin syndrome may also develop when a new serotonergic agent is started following the recent discontinuation of another serotonergic drug without allowing an adequate washout period. Isolated overdoses of SSRIs can also cause the syndrome.

Symptoms attributed to serotonin excess may include the following:

• Restlessness
• Hallucinations
• Shivering
• Diaphoresis
• Nausea
• Diarrhea
• Headache

Physical

• Signs of serotonin excess vary and can be subdivided into the following 3 categories:
• • Mental status changes - Confusion, agitation, coma
  • Neuromuscular findings - Myoclonus, rigidity, tremors, hyperreflexia (tends to be more prominent in the lower than the upper extremities), clonus, ataxia
  • Autonomic instability - Hyperthermia (excessive heat generation may develop secondary to prolonged seizure activity, rigidity, or muscular hyperactivity), mydriasis, tachycardia, blood pressure alterations (hypertension, hypotension)
• In 1991, following an extensive review of the literature, Sternbach defined the following criteria for the diagnosis of serotonin syndrome:⁴
• • Symptoms must coincide with the initiation or increase in dose of a known serotonergic agent.
  • At least 3 of the following symptoms and signs should be present: altered mental status, agitation, tremor, shivering, diarrhea, hyperreflexia, myoclonus, ataxia, or hyperthermia.
  • Other etiologies (infections, metabolic disturbances, substance abuse, withdrawal) must be excluded.
  • A neuroleptic agent should not have been initiated or increased in dose prior to the onset of the symptoms and signs.
• Serotonin syndrome produces a clinical picture that is very similar to neuroleptic malignant syndrome (NMS). Both syndromes are associated with autonomic dysfunction, alteration of mental status, rigidity, and hyperthermia. Clinical differentiation between these syndromes is very important because management may differ. For example, chlorpromazine may be of some benefit in serotonin syndrome, whereas it may cause further deterioration in NMS. Distinctions between the syndromes include the following:
• • NMS develops in association with neuroleptics, whereas serotonin syndrome develops in association with serotonergic agents.
  • NMS has a slow onset (days to weeks) and a slow progression of 24-72 hours, whereas serotonin syndrome has a more rapid onset and progression.
  • NMS is associated with bradykinesia and lead pipe rigidity, whereas serotonin syndrome is associated with hyperkinesia and less rigidity.
  • NMS is an idiosyncratic reaction to therapeutic doses, whereas serotonin syndrome is a manifestation of toxicity, frequently generated from the combination of two drugs with serotonergic activity.

Causes

The cause of serotonin syndrome is hyperstimulation of the 5-HT receptors in the brain and/or spinal cord by one of the mechanisms previously discussed.

• Symptoms may also be attributed to toxicity from drug interactions. Serotonin syndrome can ensue after the addition of a second serotonergic drug to an existing drug regimen or with administration of a serotonergic drug before allowing an inadequate washout period after discontinuation of a serotonergic drug.
• Overdosage of SSRIs can lead to inhibition of the cytochrome P450 enzyme system. If an SSRI overdose occurs in a patient on medication that relies on that system for its metabolism, toxicity from the concomitant medicine may occur. Examples include warfarin, digitalis, and carbamazepine.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Neuroleptic malignant syndrome (NMS)
Hyperthermia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

The following studies are indicated in patients with selective serotonin reuptake inhibitor (SSRI) toxicity:

• Rapid bedside glucose determination
• Serum pH
• Electrolytes, including calcium, magnesium, and phosphorus: Check for anion gap acidosis that may be present in co-ingestions.
• Serum salicylate and acetaminophen levels
• Creatine kinase (CK)
• Urinalysis and urine toxicological screen
• Urine pregnancy test (when indicated)
• Serotonin and 5-hydoxyindolacetic acid measurement: Although serotonin and its metabolite (5-hydroxyindolacetic acid) can be measured, these data are not readily available and, therefore, have limited clinical use.

Imaging Studies

• Chest radiography is indicated if any signs of respiratory distress are present or to confirm endotracheal tube placement. Although radiographic findings of suspected aspirations might initially be absent, an initial radiograph is often helpful.
• Electrocardiography is helpful to screen for any arrhythmia or conduction disturbances (ie, prolongation of the QRS or QTc interval) that may be due to co-ingestions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Emergency department care in patients with selective serotonin reuptake inhibitor (SSRI) toxicity is mainly supportive and can be summarized as follows:

• Pay careful attention to the airway, breathing, circulatory, and neurological parameters. Anticipate airway compromise due to deterioration of mental status, autonomic instability, and neuromuscular dysfunction. Secure the airway if gastric lavage and/or charcoal administration are to be performed in the setting of a decreasing level of consciousness.
• Gastric lavage is generally not indicated but may be performed within 60 minutes of suspected ingestion provided the airway is secure.
• Whole-bowel irrigation may substantially decrease the bioavailability of some ingested drugs; however, data to support or exclude its use in overdoses causing serotonin syndrome are insufficient.
• GI decontamination with activated charcoal should be performed with careful attention to the possibility of impending airway compromise. If progressive deterioration is present, the airway should be secured via endotracheal intubation prior to any decontamination attempts. Nasogastric tube placement may facilitate charcoal administration.
• Two large-bore intravenous catheters should be placed in anticipation of volume and medication administration. Central venous access is necessary in the patient with progressive cardiovascular dysfunction. Hydration is of utmost importance because of the risks of rhabdomyolysis and possible dehydration from increased insensible water losses due to hyperthermia.
• • Rhabdomyolysis should be dealt with quickly, with emphasis on maintaining a high urine output combined with alkalinization using sodium bicarbonate with a target urine pH of 6.
  • Aggressive cooling may be achieved by removal of clothing, fanning, cooling blankets, spraying with cool water, and intravenous fluids.
  • Mechanical ventilation with proper sedation and paralysis with a nondepolarizing muscle relaxant may be necessary in the setting of life-threatening hyperthermia or rhabdomyolysis.
  • Continuous monitoring of urine output is indicated if the patient requires vigorous fluid resuscitation, especially in the presence of rhabdomyolysis.
• Seizures and muscular rigidity are managed best by the use of a benzodiazepine, such as clonazepam or lorazepam.
• Most cases resolve within 24-36 hours with supportive care; however, serotonin receptor antagonists may be considered in selected cases (eg, cyproheptadine, chlorpromazine, methysergide, propranolol).
• Antihypertensives often are unnecessary unless the hypertension is persistent and clinically significant. If needed, the agent should have a short half-life.
• Arterial catheter placement is necessary in the patient with progressive cardiovascular dysfunction. An arterial catheter provides continuous arterial pressure monitoring and waveform analysis.
• Both hemodialysis and hemoperfusion are generally ineffective in enhancing elimination because of the large volume of distribution of SSRIs and should not be routinely used.

Consultations

• Pediatric intensivist
• Toxicologist
• Psychiatrist
• Social services specialist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No DOC for the treatment of serotonin syndrome has been identified; management is mainly supportive. Adequate hydration should be addressed before the initiation of any medication.

Drug Category: Decontaminants

These agents decrease the extent of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic substances absorption from the GI tract, thereby reducing systemic toxicity.

Drug Category: Antihypertensive agents

Antihypertensives, if needed, should have a short half-life because of the rapid changes in cardiovascular status in these patients. Sodium nitroprusside is the preferred agent because of its rapid onset and short half-life. It should be used only in a closely monitored setting. An arterial catheter should be inserted before its use.

Nitroglycerin has been used successfully to treat adults with serotonin syndrome. Limited data suggest that its use cannot be recommended in the pediatric population.

Drug Category: Serotonin antagonists

Serotonin antagonists (eg, cyproheptadine, chlorpromazine, methysergide) have been used successfully in isolated cases of serotonin syndrome. Most of the available information is derived from case reports. Further studies are needed before their general use can be recommended.

Cyproheptadine, an antihistamine with antiserotonergic properties, has been shown in animal studies and case reports to reduce the symptoms of serotonin syndrome. Chlorpromazine has been used effectively in some case reports, but neuroleptic malignant syndrome (NMS) must be ruled out before its use. Chlorpromazine may potentiate seizures by lowering the seizure threshold. Propranolol has mild serotonin antagonist properties.

Drug Category: Sedatives and anticonvulsants

Benzodiazepines are useful, particularly for the control of seizures and agitation. Clonazepam may be useful, especially in the setting of myoclonus.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Frequent assessment of the airway, circulatory, and neurological parameters is essential in patients with selective serotonin reuptake inhibitor (SSRI) toxicity. Adequate fluid therapy is critical.

Deterrence/Prevention

• As SSRIs are increasingly prescribed, pediatricians, child psychiatrists, and emergency physicians should be familiar with the manifestations of serotonin syndrome.
• Patients should be cautioned about the concomitant use of SSRIs and over-the-counter medications without consulting their physician. Examples of common drugs include cold preparations containing dextromethorphan and St. John's Wort, an herbal product.

Prognosis

• Most cases resolve without sequelae within 24-36 hours with adequate supportive measures.
• The patient who remains asymptomatic for several hours following an SSRI overdose is unlikely to need further medical evaluation and treatment.

Patient Education

• All medications should be stored appropriately in safe containers away from the reach of children.
• Patients on SSRIs should be warned about the symptoms and signs of SS.
• Allow an appropriate washout period of 4-6 weeks between SSRI and MAOI administration.
• Patients on SSRIs should consult their physicians prior to taking new medications.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center, Poisoning - First Aid and Emergency Center, Mental Health and Behavior Center, and Antidepressants Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, Poison Proofing Your Home, and SSRIs and Depression.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to manage the airway properly during decontamination in patients with selective serotonin reuptake inhibitor (SSRI) toxicity
• Overly aggressive treatment of clinically insignificant hypertension
• Prescribing a SSRI after the discontinuation of another without allowing an adequate washout period
• Failure to caution patients taking monamine oxidase inhibitors (MAOIs) or SSRIs about the use of herbal products and over-the-counter cold preparations

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Nov 12, 2008