eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Selective Serotonin Reuptake Inhibitor

Author: Tracy A Cushing, MD, MPH, Instructor in Medicine, Department of Emergency Medicine, Harvard Medical School; Attending Physician, Department of Emergency Medicine, Mount Auburn Hospital
Coauthor(s): Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for the treatment of depression, obsessive-compulsive disorder, bulimia, anorexia nervosa, panic disorder, and social phobia. The majority of all antidepressants prescribed in the United States are from the SSRI family.^1,2 Commonly prescribed SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox). SSRI toxicity and other adverse drug reactions can occur with overdose, in combination with other medications, or infrequently at therapeutic doses.

SSRIs have a high therapeutic to toxicity ratio and are associated with less toxicity than tricyclic antidepressants (TCAs). However, they are often involved in co-ingestions that can precipitate the potentially lethal "serotonin syndrome" (SS). SS is characterized by mental status changes, neuromuscular hyperactivity, and autonomic instability.^3,4 SS is often caused by combinations of SSRIs with other proserotonergic agents, including monoamine oxidase inhibitors (MAOIs), TCAs, trazodone (Desyrel), lithium, opioids, and amphetamine/stimulants, including methylphenidate (Ritalin), 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy), cocaine, and herbal dietary supplements or nutraceuticals (St. John's wort, ginseng, and S-adenosyl-methionine). All of these affect the production, release, or breakdown of serotonin at the presynaptic cleft, thereby increasing its levels and toxicity. Less frequently, SS can be precipitated by overdose of a single SSRI.

Venlafaxine (Effexor) and duloxetine (Cymbalta) are serotonin-norepinephrine reuptake inhibitors (SNRIs) that are also associated with serotonin toxicity, as is the tetracyclic drug mirtazapine (Remeron), an alpha-2 adrenergic heteroreceptor blocking agent that causes increased norepinephrine and serotonin release in addition to blocking serotonin receptors. Trazodone (Desyrel) is a tetracyclic drug that blocks serotonin reuptake and also has an antagonistic effect at the serotonin 5-HT2 receptor site.

Several opioids are serotonergic and have been associated with SS. These include meperidine (Demerol), tramadol (Ultram), dextromethorphan, and pentazocine. The historically significant Libby Zion medicolegal case involved meperidine, cocaine, and an MAOI and was instrumental in changing the working conditions of postgraduate training programs.

Pathophysiology

Serotonin, or 5-hydroxytryptamine (5HT), is a neurotransmitter found in both the central and peripheral nervous system. Serotonin is produced in the brainstem raphe nucleus from L-tryptophan and is then stored in presynaptic vesicles. Neuronal activation causes release of 5HT into the synapse. Excess serotonin is taken back up into presynaptic vesicles by an active transport mechanism or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Systemic metabolism is through liver mixed function oxidases (MFOs). Inhibition of particular MFOs, by other medications or plant materials (eg, grapefruit), may cause increased drug effect from decreased metabolism.⁵ Seven distinct 5HT receptors with further specific subtypes exist and produce a wide variety of physiologic effects. This diverse activity gives rise to the multiple signs and symptoms of toxicity.^6,7

Excess serotonergic activity can be precipitated through any of the several mechanisms listed below.⁸ Large dosages or combinations of any of these drugs can produce serotonin toxicity or the SS. The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT_1a and 5HT₂ receptors.⁹

• Direct 5HT receptor stimulation - Buspirone (BuSpar), triptans (Imitrex, Amerge, Zomig, others), lithium, carbamazepine (Tegretol), lysergic acid diethylamide (LSD), and mescaline-containing cacti (peyote and others)
• Direct 5HT release from stored vesicles - Amphetamines, MDMA, cocaine, reserpine, levodopa, MAOIs, codeine, dextromethorphan, pentazocine
• Increased availability of 5HT precursors - L-tryptophan
• Decreased 5HT reuptake - SSRIs, trazodone (Desyrel), nefazodone, venlafaxine (Effexor), TCAs, dextromethorphan, tramadol, meperidine (Demerol), cocaine, Hypericum species (St. John's wort), amphetamines, carbamazepine (Tegretol), methadone
• Decreased 5HT degradation - MAOIs, St. John's wort

Serotonergic projections to the thalamus and cortex result in effects on sleep-wake cycles, mood, thermoregulation, appetite, pain perception, and sexual function. Excess 5-HT in these pathways causes the mental status changes, confusion, agitation, ataxia, and fever associated with SSRI toxicity and SS. Toxicity of descending pathways to the brainstem and medulla results in hyperreflexia, myoclonus, and tremor.

Autonomic nervous system effects include diaphoresis, mydriasis, hypertension, tachycardia, hyperthermia, piloerection, and muscular rigidity.

Cardiovascular effects most commonly include sinus tachycardia, flushing, hypertension, and in rare cases, hypotension. Citalopram (Celexa) was associated with prolonged QTc in one series.¹⁰

Due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells, the most common minor adverse effects of SSRI therapy are gastrointestinal, eg, abdominal cramping, nausea, and diarrhea. SSRIs have also been shown to moderately increase the risk of upper gastrointestinal bleeding.¹¹

Pharmacokinetics

SSRIs are metabolized in the liver by cytochrome P-450 MFO microsomal enzymes. They are highly bound to plasma proteins and have a large volume of distribution. Peak plasma levels are reached in 2-10 hours. Half-lives are variable, but most SSRIs have half-lives of 20-24 hours.⁵ A notable exception is fluoxetine (Prozac), and its active metabolite, norfluoxetine, which have half-lives of 2-4 days and 8-9 days, respectively. Hence, addition of serotonergic medications to a patient's regimen must not occur until 2-3 weeks after discontinuation of an SSRI (some recommend a 5-week "wash-out" period for fluoxetine prior to initiation of an MAOI).^12,9

Frequency

United States

Data from the 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (AAPCC-NPDS) showed 2.4 million total toxic exposures in 2007.¹³ Antidepressants (SSRIs, TCAs, and atypicals) accounted for 98,898 exposures and 220 deaths and were the third most common class of drug associated with fatalities. Ten fatalities were related to ingestion of SSRIs alone. Of 220 total antidepressant-related fatalities, SSRIs were involved in 61 deaths, mostly in combination with other medications or illicit substances. Atypical antidepressants such as venlafaxine (Effexor) and bupropion (Wellbutrin) were involved in a significant number of fatalities.¹³

Mortality/Morbidity

AAPCC-NPDS 2007 data showed that, of 98,898 adult antidepressant exposures, 10 deaths were attributable to SSRIs alone. Most exposures were classified as causing mild-to-moderate effects. A significant number of deaths involved ingestions of bupropion (Wellbutrin) or venlafaxine (Effexor), often in combination with alcohol or other prescription medications.¹³

Sex

Incidence of reported SSRI ingestions is higher in women than in men. Incidence of death from antidepressant ingestions is higher in men than in women.

Age

Incidence of SSRI toxicity is highest in persons aged 19-39 years, the age group with the greatest overall number of intentional ingestions. Side effects from SSRIs are not age-specific, but they may occur more in elderly persons who are more likely to be taking several serotonergic agents or other medications that alter MFO CYP metabolism.

Clinical

History

Serotonin toxicity is most likely to develop following the initiation of a new serotonergic medication or the increase in dosage of a previously prescribed SSRI.⁷

Symptom onset from SSRI toxicity presents within 2-8 hours after acute ingestion, or it may occur over several days if SS develops from initiation of new therapy or addition of a second serotonergic agent.

History of mental illness, particularly affective disorders, and prior suicide attempts, should be elicited.

Serotonin syndrome (SS) represents a constellation of signs and symptoms that manifest in the neuromuscular, autonomic nervous, and GI systems in which concentrations of 5HT receptors are the highest. SS represents the most severe end of a spectrum of serotonin excess. Diagnostic criteria were developed in 1991 by Sternbach et al to assist in diagnosis.³ The Sternbach criteria include the following:

• Symptoms coincide temporally with the addition of a serotonergic agent to a patient's regimen or with increasing the dose of a previously prescribed serotonergic agent.
• At least 3 of the following physical findings are present: agitation, ataxia, diaphoresis, diarrhea, hyperreflexia, mental status changes, myoclonus, shivering, tremor, or hyperthermia.
• A neuroleptic agent has not been recently added to the patient's regimen or increased in dose, if previously prescribed.
• Other etiologies such as infection, intoxication, metabolic derangements, substance abuse, or withdrawal have been ruled out.

These criteria have been modified over time to account for symptoms associated with more mild cases, but they provide a framework for important clues in the history and physical examination to aid in diagnosis.

Remember that mild cases of SS due to vague symptomatology may often go unrecognized.

Physical

Signs of excess serotonin can range from subtle tremor to frank coma.¹⁴ Mental status changes, autonomic instability, and neuromuscular agitation are the primary findings used to delineate Sternbach's criteria. However, more specific signs and physical findings have become recognized as reliable predictors of serotonin toxicity; several decision rules have been established to help clinicians identify patients with possible SS.

• Neuromuscular findings, such as clonus, hyperreflexia, muscular rigidity, and ataxia, may be present, as well as myoclonic jerks, teeth chattering, and resting tremor. The clonus is spontaneous, inducible, or ocular. Hyperreflexia is often more pronounced in the lower extremities. Muscular rigidity may mask clonus. Among these findings, clonus is the most important in diagnosing SS.
• Mental status findings may be subtle, such as pressured speech, restlessness, and confusion. More severe cases may manifest with agitation, hypomania, coma, or seizures.
• Autonomic instability includes diaphoresis, hyperthermia, which is exacerbated by prolonged muscular rigidity or seizure activity, tachycardia, mydriasis, and blood pressure variations; both hypertension and hypotension have been observed. Electrocardiographic changes such as QTc prolongation have been reported in citalopram (Celexa) ingestions in particular.
• Peripheral findings may include increased GI motility, eg, diarrhea or hyperactive bowel sounds, coagulopathy (disseminated intravascular coagulation [DIC] in severe cases), and increased vascular tone.

Physical examination findings are helpful when distinguishing serotonin toxicity from other toxic ingestions in the differential diagnosis. Neuroleptic malignant syndrome, associated with dopamine antagonists, has a slower onset of symptoms than SS and is associated with bradykinesia and "lead-pipe" muscular rigidity, rather than hyperkinesias and tremors. Anticholinergic toxicity involves dry erythematous skin, enlarged pupils (mydriasis), decreased bowel sounds, and normal reflexes in contrast to serotonin toxicity, which includes diaphoresis, increased bowel sounds, diarrhea, and hyperreflexia. Ingestion of multiple agents in suicide attempts can make physical findings less reliable.

Causes

Serotonin syndrome is most often caused by simultaneous ingestion of 2 or more proserotonergic medications, which may be associated with therapeutic error, idiopathic response, or intentional overdose. No particular SSRI has been associated with an increased incidence of toxicity.^15,16 A recent increased dose of a chronic medication or a new addition to an extensive medication regimen is an important component of the history that may provide the diagnosis. Use of over-the-counter medications or dietary supplements in addition to prescribed serotonergic medications is also an important etiology.

The physiologic manifestations of serotonin toxicity are due to the locations of 5HT receptors throughout the body. Most CNS 5HT receptors are located in the brainstem raphe nuclei. The neurons of the proximal raphe are involved in regulation of sleep and waking, hunger and satiety, affective and sexual behavior, as well as thermoregulation and emesis. Peripheral effects of serotonin are due to receptors in the gastrointestinal tract that stimulate motility, as well as endovascular effects on blood pressure and coagulation.

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