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.
A study by Hawton et al of antidepressant toxicities found evidence that the SSRI citalopram has a higher toxicity than the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[1] Nelson et al compared the relative morbidity and mortality associated with drugs used to treat depression and reported that citalopram had a morbidity index fourfold greater than sertraline. Citalopram was associated with higher rates of conduction disturbance, seizures (single and multiple), acidosis, and electrolyte disturbances than did other SSRIs.[2] However, in both studies the toxicity of all SSRIs was below that of the TCAs[1, 2]
In addition, although case fatality rates for SSRIs are low, citalopram has a higher mortality rate in overdose than other SSRIs.[3] Nelson et al found citalopram exposures were about four times as likely to be fatal than sertraline or escitalopram.[2]
The US Food and Drug Administration (FDA) has issued a public health advisory that directed manufacturers of all antidepressant drugs, including SSRIs, to revise the labeling for their products to include a boxed warning and expanded warning statements alerting health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents.[4]
The risk of suicidality associated with these drugs was identified based on a combined analysis of short-term (up to 4mo), placebo-controlled trials of 9 antidepressant drugs, including SSRIs, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events drug therapy was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.[4]
Based on these data, FDA has determined that the following points are appropriate for inclusion in the boxed warning[4] :
Only fluoxetine is FDA approved for use in treating major depressive disorder (MDD) in pediatric patients. Fluoxetine, and sertraline are approved for OCD in pediatric patients. None of those drugs is approved for other psychiatric indications in children.[4]
Serotonin syndrome, the most serious drug-related adverse effect of SSRIs, is characterized by mental status changes, neuromuscular dysfunction, and autonomic instability. It 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. (See Presentation.)
Although SSRIs are commonly linked to serotonin syndrome, many other drugs (eg, amphetamines, monoamine 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, therapeutic doses. SSRI overdosage does not necessarily lead to the development of serotonin syndrome. Patients with SSRI overdose who remain asymptomatic for several hours are unlikely to need any further medical evaluation and treatment. (See Treatment.)
Accidental ingestion by toddlers and illicit drug use in adolescents (eg, 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. (See Etiology, DDx, and Treatment.)
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. After discontinuation of serotonergic drug therapy, a new serotonergic drug should not be initiated until ensuring an adequate washout period (4-6 wk) for the recently discontinued serotonergic agent.
Serotonin is a neurotransmitter that is synthesized from the amino acid L-tryptophan. Synthesis is necessary in 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 monoamine 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 serotonin syndrome, especially when combined with selective serotonin reuptake inhibitors (SSRIs).
Serotonin binds 1 of 7 postsynaptic 5-hydroxytryptophan (5-HT) receptors. The cause of serotonin syndrome is hyperstimulation of the 5-HT receptors in the brain and/or spinal cord.[5] Various mechanisms can potentially increase the quantity or activity of serotonin; these mechanisms and corresponding agents include the following:
Symptoms of serotonin syndrome 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 another 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.
As with most pediatric ingestions, selective serotonin reuptake inhibitor (SSRI) toxicity occurs in a bimodal distribution. Most accidental ingestions of SSRIs occur in toddlers, whereas adolescent ingestions are usually intentional.
The 2017 annual report of the American Association of Poison Control Centers National Poison Data System (AAPCC-NPDS) revealed that 24,819 SSRI exposures (from a total of 53,934 antidepressant single exposures) occurred; 8785 exposures to SSRIs occurred in adolescents aged 13-19 years, and 5187 exposures occurred in children younger than 6 years. The lowest number of pediatric exposures (1357) were seen in children aged 6-12.[8]
Most cases resolve without sequelae within 24-36 hours with adequate supportive measures. The patient who remains asymptomatic for several hours following a selective serotonin reuptake inhibitor (SSRI) overdose is unlikely to need further medical evaluation and treatment.
AAPCC-NPDS 2017 data revealed that 3056 exposures resulted in moderate or major morbidity, with 4 deaths.[8] SSRIs have a high toxic-to-therapeutic ratio, and fatalities are uncommon with pure SSRI overdoses.
Patients should be advised that all medications should be stored appropriately in safe containers away from the reach of children. In addition, patients on SSRIs should be warned about the symptoms and signs of serotonin syndrome.
For patient education information, see Drug Overdose Basics, Depression in Children, and Serotonin Syndrome: Causes, Symptoms, and Treatments
Because the enteric nervous system is richly innervated by serotonin, acute toxicity frequently manifests as altered gastrointestinal (GI) motility and nausea. The most serious drug-related adverse effect of selective serotonin reuptake inhibitors (SSRIs) 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.[9]
Symptoms attributed to serotonin excess may include the following:
Following an extensive review of the literature, Sternbach defined the following criteria for the diagnosis of serotonin syndrome[10] :
Signs of serotonin excess vary and can be subdivided into the following 3 categories:
The following laboratory studies are indicated in patients with selective serotonin reuptake inhibitor (SSRI) toxicity[12] :
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.
Emergency department care in patients with selective serotonin reuptake inhibitor (SSRI) toxicity is mainly supportive,[13] with most cases resolving within 24-36 hours with such care. However, serotonin receptor antagonists may be considered in selected cases (eg, cyproheptadine, chlorpromazine, methysergide, propranolol).
Most patients with serotonin syndrome return to baseline in 24 hours with supportive care, removal of the precipitating drug, and treatment with benzodiazepines.[14]
The following consultations are indicated in patients with SSRI toxicity:
Frequent assessment of the airway, circulatory, and neurologic parameters is essential in patients with SSRI toxicity. Adequate fluid therapy is critical.
Patients on SSRIs should consult their physician prior to taking new medications and should be cautioned about the concomitant use of SSRIs and over-the-counter medications without consulting their physician. Examples of common nonprescription serotinergic drugs include cold preparations containing dextromethorphan and St. John's Wort, an herbal product. Allow an appropriate washout period of 4-6 weeks between SSRI and monoamine oxidase inhibitor (MAOI) administration.
Pay careful attention to the airway, breathing, circulatory, and neurologic 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.[13]
Gastric lavage is generally not indicated but may be performed within 60 minutes of suspected ingestion, provided that 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.
Arterial catheter placement is necessary in the patient with progressive cardiovascular dysfunction. An arterial catheter provides continuous arterial pressure monitoring and waveform analysis.
Hemodialysis and hemoperfusion are generally ineffective in enhancing elimination because of the large volume of distribution of SSRIs and should not be routinely used.
Seizures and muscular rigidity are managed best by the use of a benzodiazepine, such as clonazepam or lorazepam.
Antihypertensives often are unnecessary unless the hypertension is persistent and clinically significant. If needed, the agent should have a short half-life.
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 of 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.
No drug of choice (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.
As previously mentioned, antihypertensives often are unnecessary unless the hypertension is persistent and clinically significant. If needed, the agent should have a short half-life. Seizures and muscular rigidity are managed best by the use of a benzodiazepine such as clonazepam or lorazepam.
Clinical Context: Activated charcoal is used in the emergency treatment of poisoning caused by drugs and chemicals. A network of pores present in activated charcoal adsorbs 100-1000mg of drug per gram of charcoal. Activated charcoal does not dissolve in water. For maximum effect, administer it within 30 minutes of poison ingestion.
GI decontamination with activated charcoal should be performed with careful attention to the possibility of impending airway compromise. If progressive deterioration is present, secure the airway via endotracheal intubation before any decontamination attempts.
These agents decrease the extent to which selective serotonin reuptake inhibitors (SSRIs) and other serotonergic substances are absorbed from the GI tract, thereby reducing systemic toxicity.
Clinical Context: Sodium nitroprusside produces arterial and venous vasodilation. It decreases afterload and preload and may produce a reflex tachycardia.
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.
Clinical Context: Cyproheptadine has been shown in animal studies and case reports to reduce the symptoms of serotonin syndrome. It may be helpful in mild-to-moderate cases of serotonin syndrome. Cyproheptadine is available in the form of tablets or oral suspension.
Clinical Context: Following charcoal administration, chlorpromazine is a better choice in treating toxicity because it can be administered IV while cyproheptadine is not available IV. However, it is best to avoid chlorpromazine if the drugs inducing serotonin toxicity have significant cardiogenic or epileptogenic properties.
Serotonin antagonists (eg, cyproheptadine, chlorpromazine) 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.
Clinical Context: Clonazepam is an anticonvulsant that may be useful in the setting of myoclonus.
Clinical Context: Lorazepam is a benzodiazepine used for the control of seizures and agitation.
Benzodiazepines are useful, particularly for the control of seizures and agitation. Clonazepam may be useful, especially in the setting of myoclonus.