Pediatric Selective Serotonin Reuptake Inhibitor Toxicity 

As selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed, pediatricians, child psychiatrists, and emergency physicians should be familiar with the manifestations of serotonin syndrome resulting from pediatric SSRI toxicity. (See Presentation and Workup.)

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. (See Etiology.)

However, on Oct 15, 2004, the US Food and Drug Administration (FDA) 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.

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 that involved 4400 patients were included. The average risk of suicidality in those using the drug was 4%, twice the placebo risk of 2%.

A 9-year cohort study using population-wide data from British Columbia supported the FDA's inclusion of all antidepressants in the black box warning regarding potentially increased suicidality risk among children and adolescents starting antidepressants.^[1]

Serotonin syndrome

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). (See Etiology, Presentation, and Workup.)

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. (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 such an ingestion 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 (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.)

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) for the recently discontinued serotonergic agent.

Relative toxicity

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. However, the toxicity of the SSRIs was below that of the TCAs used in the study.^[2]

Patient education

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 the First Aid and Injuries Center, the Mental Health Center, and the Depression Center, as well as Poisoning, Drug Overdose, Activated Charcoal, Poison Proofing Your Home, and SSRIs and Depression.

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.^[3] 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 - Monoamine oxidase inhibitors (MAOIs)
• Increased release of stored serotonin - Amphetamine, cocaine, fenfluramine, methylenedioxymethamphetamine (MDMA, or ecstasy), or meperidine
• Prevention of reuptake of serotonin released into the synapse - SSRIs, tricyclic antidepressants (TCAs), MDMA, dextromethorphan, meperidine, or St. John's Wort^{[4, 5]}
• Direct stimulation of serotonin receptors - Buspirone, lysergic acid diethylamide (LSD)
• Unknown mechanism - Lithium

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.

Occurrence in the United States

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.^[6]

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-TESS 2004 data revealed that 8187 exposures resulted in moderate or major morbidity, with 103 deaths.^[6] SSRIs have a high toxic-to-therapeutic ratio, and fatalities are uncommon with pure SSRI overdoses.