Pediatric Selective Serotonin Reuptake Inhibitor Toxicity

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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]

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.)

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.

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. [2] However, the toxicity of the SSRIs was below that of the TCAs used in the study. [3]

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. [4] 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 [5, 6]

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.

The 2014 annual report of the American Association of Poison Control Centers Toxic Exposures Surveillance System (AAPCC-TESS) revealed that 20,579 SSRI exposures (from a total of 46,516 antidepressant single exposures) occurred; 7410 exposures to SSRIs occurred in children aged 6-19 years, and 10,280 exposures occurred in children younger than 6 years. [7]

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. [7] SSRIs have a high toxic-to-therapeutic ratio, and fatalities are uncommon with pure SSRI overdoses.

Schneeweiss S, Patrick AR, Solomon DH, et al. Comparative Safety of Antidepressant Agents for Children and Adolescents Regarding Suicidal Acts. Pediatrics. 2010 Apr 12. [Medline].

Klein-Schwartz W, Benson BE, Lee SC, Litovitz T. Comparison of citalopram and other selective serotonin reuptake inhibitor ingestions in children. Clin Toxicol (Phila). 2012 Jun. 50(5):418-23. [Medline].

Hawton K, Bergen H, Simkin S, Cooper J, Waters K, Gunnell D, et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry. 2010 May. 196(5):354-8. [Medline]. [Full Text].

Parks V, Philipp AW, Raje S, Plotka A, Schechter LE, Connell J, et al. Concomitant blockade of 5-HT(1A) receptor and 5-HT transporter: Use of the Hunter Serotonin Toxicity Criteria in a clinical pharmacology study. Eur Neuropsychopharmacol. 2011 Jul 4. [Medline].

Gordon JB. SSRIs and St.John’s Wort: possible toxicity?. Am Fam Physician. 1998 Mar 1. 57(5):950,953. [Medline].

Josey ES, Tackett RL. St. John’s wort: a new alternative for depression?. Int J Clin Pharmacol Ther. 1999 Mar. 37(3):111-9. [Medline].

Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015 Dec. 53 (10):962-1147. [Medline].

Prakash S, Patel V, Kakked S, Patel I, Yadav R. Mild serotonin syndrome: A report of 12 cases. Ann Indian Acad Neurol. 2015 Apr-Jun. 18 (2):226-30. [Medline].

Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991 Jun. 148(6):705-13. [Medline].

Attar-Herzberg D, Apel A, Gang N, Dvir D, Mayan H. The serotonin syndrome: initial misdiagnosis. Isr Med Assoc J. 2009 Jun. 11(6):367-70. [Medline].

Kant S, Liebelt E. Recognizing serotonin toxicity in the pediatric emergency department. Pediatr Emerg Care. 2012 Aug. 28(8):817-21; quiz 822-4. [Medline].

[Guideline] Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007 May. 45(4):315-32. [Medline].

Mohamed K Badawy, MD, FAAP Assistant Professor of Emergency Medicine and Pediatrics, University of Texas Southwestern Medical School; Associate Medical Director, Division of Emergency Medicine, Children’s Medical Center Dallas

Mohamed K Badawy, MD, FAAP is a member of the following medical societies: Academic Pediatric Association, Society for Academic Emergency Medicine, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Frank A Maffei, MD, FAAP Professor of Pediatrics, Geisinger Commonwealth School of Medicine; Chair of Pediatrics, Division Chief, Pediatric Critical Care, Geisinger Janet Weis Children’s Hospital

Frank A Maffei, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children’s Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians

Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children’s Medical Center

Disclosure: Merck Salary Employment

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Pediatric Selective Serotonin Reuptake Inhibitor Toxicity

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