eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Selective Serotonin Reuptake Inhibitor

Author: Mohamed K Badawy, MB, BCh, MD, Assistant Professor, Departments of Emergency Medicine and Pediatrics, University of Rochester and Golisano Children's Hospital at Strong Memorial Hospital
Coauthor(s): Frank A Maffei, MD, FAAP, Associate Professor of Pediatrics, Temple University School of Medicine; Director of Medical Student Affairs, Geisinger Health System; Pediatric Critical Care Attending Physician, Janet Weis Children's Hospital at Geisinger Medical Center
Contributor Information and Disclosures

Updated: Nov 17, 2009

Introduction

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

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. A retrospective review reported that 5 of 7 patients with serotonin syndrome were initially diagnosed with exacerbation of their psychiatric disorder, 2 patients were diagnosed with gastroenteritis, and a severe drug overdose was diagnosed in 1 patient.⁴ The study concluded that although the characteristics of serotonin syndrome are well defined, some physicians may not be aware of the phenomenon.

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:⁵
  • 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.

• Search for CME/CE on This Topic »

• Toxicity, Selective Serotonin Reuptake Inhibitor (Emergency Medicine)
• Toxicity, Lidocaine (Emergency Medicine)
• Toxicity, Lead (Emergency Medicine)
• Chloroquine/Hydroxychloroquine Toxicity (Ophthalmology)

• Activated Charcoal
• Drug Overdose Center
• Poisoning Overview
• Drug Overdose Overview
• Poisoning - First Aid and Emergency Center
• Mental Health and Behavior Center
• Poison Proofing Your Home Introduction
• Antidepressants Center
• SSRIs and Depression

• FDA Safety Changes: Ultram, Ultracet, Sustiva, Kayexalate
• Dietary Supplement May Protect Against Acetaminophen-Induced Liver Toxicity
• "Substantial" Toxicity With Peginterferon Use: FDA Staff

• Escitalopram for the Treatment of Depression in Adolescents
• Use of Serotonin Receptor Agonists in Adolescents with Migraines: Focus on Almotriptan
• What Drug Interactions Are Common in Treatment-Resistant Depression?