AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. 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. SS is often caused by combinations of SSRIs with other proserotonergic agents, including monoamine oxidase inhibitors (MAOIs), TCAs, trazodone (Desyrel), lithium, opioids, and amphetamines, including 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 pre-synaptic 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. 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.

Excess serotonergic activity can be precipitated through any of the several mechanisms listed below. Large dosages or combinations of any of these drugs can produce serotonin toxicity or the SS.

• 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.

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.

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. 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).

Frequency

United States

Data from the 2003 Annual Report of the American Association of Poison Control Centers' Toxic Exposures Surveillance System (AAPCC-TESS) showed almost 2.4 million total toxic exposures. Antidepressants (both SSRIs and TCAs) accounted for 101,331 exposures and 112 deaths and were the third most common class of drug associated with fatalities. Amitriptyline was the most commonly implicated antidepressant; no fatalities were related to ingestion of SSRIs alone. Of 1,106 fatalities, SSRIs were involved in 56 deaths, all in combination with other medications or illicit substances.

Mortality/Morbidity

AAPCC-TESS 2003 data showed that, of 65,344 adult antidepressant exposures, no deaths were attributable to SSRIs alone. Most exposures were classified as causing mild-to-moderate effects.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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. 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. 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

SS 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. 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Malignant hyperthermia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnosis of serotonin toxicity begins with a detailed history of the patient's medications, changes to regimen, history of suicide attempts, and availability of serotonergic drugs as well as a careful physical examination.
• • Serum and urine toxicology screen - Opiates/opioids (meperidine), salicylates, acetaminophen, TCAs, amphetamines, phencyclidine (detection of dextromethorphan by cross-reactivity), and cocaine
  • Total CPK
  • Urine myoglobin
  • Basic electrolytes, including calcium, magnesium, and phosphorus levels, as well as lactate and ketone levels, to evaluate for metabolic acidosis
  • Blood urea nitrogen (BUN) and creatinine levels
  • Serum pH level
  • Liver function tests
  • Complete blood count and blood cultures if febrile
  • Prothrombin time/activated partial thromboplastin time in severe cases; DIC panels if necessary
  • Pregnancy testing if indicated
• Electrocardiogram, rhythm strips

Imaging Studies

• Chest radiograph after intubation or in any patient with hypoxia or aspiration
• Head CT scan in any patient with suspected trauma, new-onset seizures, or hypertension and localizing neurologic findings

Procedures

• Intubation should be considered in any unstable patient or any patient with altered mental status who cannot protect his or her airway.
• ECG to determine rhythm, morphology, and intervals, particularly in suspected co-ingestions.
• Lumbar puncture is indicated in any patient with fever and altered mental status.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital care includes airway management and arrhythmia treatment per ACLS protocols; consider naloxone 2 mg IV, 50 mL of D50W, and thiamine 100 mg IV as well as a fingerstick glucose level for altered mental status. Of prime importance is getting history from any bystanders or family members and collecting ancillary materials, such as pills, empty pill bottles or medication packets, and suicide notes. If given, naloxone should be gradually titrated starting with 0.05 or 0.1 mg, and repeated if needed, to avoid rapid precipitation of opioid withdrawal.

Emergency Department Care

As for all care in the emergency department, the patient needs immediate evaluation and stabilization of the airway, breathing, and circulation, even without knowledge of the ultimate diagnosis. Treatment of serotonin syndrome is primarily supportive. The severity of presentation helps to guide appropriate emergency department care.

• Mild cases: Check laboratory results as indicated, intravenous fluids, benzodiazepines for agitation/restlessness, avoidance of all serotonergic medications.
• Moderate cases: Treat hyperthermia with cooling blankets, fans, ice packs, and intravenous fluids. The role for antipyretics is limited, as the mechanism of temperature alteration is centrally mediated. Administer activated charcoal if a potentially lethal amount has been ingested and if presentation is within 1-2 hours. Treat neuromuscular abnormalities with benzodiazepines.
• Severe cases: Patients with hyperthermia, depressed mental status, and vital sign abnormalities should be treated aggressively. All patients should be treated as above, with the addition of airway protection and ventilation if needed. Paralysis and mechanical ventilation are necessary to avoid worsening muscle rigidity and increasing hyperthermia in any patient with a temperature higher than 41ºC. Patients with severe hyperthermia that is unresponsive to aforementioned measures should be immersed into an ice bath to achieve rapid cooling and to prevent development of DIC and multiorgan failure (MOF). Avoid succinylcholine as a paralytic in any patient with possible rhabdomyolysis to prevent development of hyperkalemia.
• Severely ill patients could be treated pharmacologically with 5HT antagonists, such as cyproheptadine (see dosing information below). Efficacy has not been established in randomized clinical trials; however, it has shown benefit in animal models and case reports. It is available only in oral form, which can be crushed and infused via nasogastric tube. Caution should be exercised in hyperthermic patients, because cyproheptadine has anticholinergic properties and theoretically can worsen hyperthermia.
• Autonomic instability requires treatment with short-acting agents that are amenable to titration, such as nitroprusside and esmolol.
• Treat rhabdomyolysis with aggressive hydration, and alkalinize urine with sodium bicarbonate for renal protection.

Consultations

• Medical toxicologist
• Poison Control Center at (800) 222-1222 (US and territories only)
• Psychiatrist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Pharmacologic treatment of the serotonin syndrome is largely based on anecdotal case reports and on animal models. Supportive care remains the basis of treatment; however, severe cases may benefit from the following interventions.

Drug Category: Adsorbent antidotes

These agents inhibit GI absorption of certain toxic agents or irritants.

Drug Category: Serotonin antagonists

Cyproheptadine, chlorpromazine, and methylsergide have all been reported to be useful in SS to block postsynaptic serotonin receptors. No formalized dosing regimens have been established; the following recommendations are based on case reports and reviews of serotonin toxicity treatment.

Drug Category: Sedatives and anticonvulsants

Benzodiazepines are considered mainstay treatment in treating SS, particularly neuromuscular symptoms and seizures. They are also excellent for controlling agitated behavior.

Drug Category: Antihypertensives

Used for the treatment of autonomic instability and malignant hypertension as evidenced by end-organ damage of the brain, heart, and/or kidneys.

Drug Category: Neuromuscular Blockade, Paralytic

To control hyperreflexia, clonus, and hyperthermia, total neuromuscular paralysis may be required. Succinylcholine should be avoided in SS given the risk of hyperkalemia secondary to rhabdomyolysis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• All patients with significant ingestions requiring intubation or vasopressors or those with a temperature higher than 40ºC or ECG changes/dysrhythmias should be admitted to an intensive care unit. Moderate toxicity can be safely observed in the hospital for 24 hours, and mild cases can be safely discharged (if asymptomatic) from the emergency department once cleared by psychiatry and after 6-8 hours of observation.
• Inpatient care should include ongoing fluid resuscitation, appropriate treatment of rhabdomyolysis, DIC, and renal or hepatic dysfunction, as well as psychiatric evaluation.

Transfer

• Transfer any patient who requires a level of care that is not available (eg, an intensive care unit).

Deterrence/Prevention

• Patients taking SSRI's and MAOI's should be cautioned about taking over-the-counter medications or supplements with serotonergic activity. They should be closely monitored if dosages are adjusted or medications are added to their regimen.

Complications

• Seizures
• Aspiration pneumonia
• Rhabdomyolysis
• DIC
• Acute renal failure
• Respiratory failure

Prognosis

• Most cases will fully resolve without residual deficits if supportive care has been provided. The prognosis is generally favorable.
• Most fatalities occur within the first 24 hours.
• Patients who remain asymptomatic for 6-8 hours after ingestion are unlikely to require further treatment.

Patient Education

• Patients should be counseled about potential interactions among any medications they take and over-the-counter drugs and so-called herbal supplements that may precipitate SS. They should be restarted on, or introduced to, serotonergic medications very gradually in the future (after "wash-out" period). They should report this reaction to all healthcare providers in future.
• All patients started on SSRIs by psychiatrists or primary care physicians should be educated about symptoms of serotonin toxicity and SS.
• A minimum of 2 weeks should elapse between termination of an SSRI or MAOI and initiation of a new one. Drugs with a longer half-life (i.e. fluoxetine) require up to five weeks of "wash-out". Elderly patients and those taking
  liver MFO's may require an extended wash-out period as well.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose SS and institute proper treatment
• Failure to obtain a complete history of a patient's medications, resulting in prescribing serotonergic medications to patients already taking SSRIs or MAOIs
• Failure to counsel patients with regard to over-the-counter medications (particularly dextromethorphan-containing cold remedies), illicit drugs (especially amphetamines, MDMA, cocaine, and mescaline), and herbal dietary supplements/nutraceuticals (such as St. John's wort, ginseng, and S-adenosyl-methionine) that might affect the patient's tissue concentrations of serotonin
• Symptomatic patients with citalopram/escitalopram overdose may require admission to the monitored bed for 24 hours because of the risk of delayed toxicity that can cause prolonged QTc interval and consequent cardiac dysrhythmias (eg, torsades de pointes).

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Badawy M, Maffei FA. Toxicity, Selective Serotonin Reuptake Inhibitor. eMedicine Journal [serial online]. 2005. [Full Text].
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• Marx J, Hockberger R, Walls R. Rosen's Emergency Medicine. 5th ed. CV Mosby;2002: 2087-2103.
• Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). Jul 2000;79(4):201-9. [Medline].
• Mills KC. Serotonin syndrome. Am Fam Physician. Oct 1995;52(5):1475-82. [Medline].
• Olfson M, Marcus SC, Druss B. National trends in the outpatient treatment of depression. JAMA. Jan 9 2002;287(2):203-9. [Medline].
• Pirraglia PA, Stafford RS, Singer DE. Trends in Prescribing of Selective Serotonin Reuptake Inhibitors and Other Newer Antidepressant Agents in Adult Primary Care. Prim Care Companion J Clin Psychiatry. Aug 2003;5(4):153-157. [Medline].
• Sternbach H. The serotonin syndrome. Am J Psychiatry. Jun 1991;148(6):705-13. [Medline].
• Watson WA, Litovitz TL, Klein-Schwartz W. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2004;22(5):335-404. [Medline].

Article Last Updated: Aug 9, 2006