US Pharm. 2010;35(11):HS-16-HS-21.

A potentially lethal condition, serotonin syndrome (SS) is caused most often when certain antidepressant agents are taken concurrently with other drugs that modulate synaptic serotonin levels.1,2 When patients take two or more antidepressants from different pharmacologic classes, drug-drug interactions may occur; these interactions may lead to potentially severe serotonin toxicity, or SS. This syndrome was first described during the 1960s in studies of monotherapy and combination therapy with antidepressant medications.

In a review of suspected SS cases from physician office-based practices, inpatient hospital visits, and emergency room visits, the Toxic Exposure Surveillance System found that selective serotonin reuptake inhibitors (SSRIs) caused significant toxic effects in more than 8,000 people, leading to more than 100 deaths.2 One notable case that garnered national attention was that of Libby Zion, an 18-year-old college freshman with a history of depression who was being treated with phenelzine.3 She was admitted to Manhattan's New York Hospital on the evening of October 4, 1984, with agitation, disorientation, fever, and jerky body motions. Libby was prescribed an injection of meperidine to calm her and control her shaking, and, later, when her agitation increased, an injection of haloperidol. She eventually fell asleep, but when her temperature was taken at 6:30 am, it was 107°F. Emergency measures were undertaken to lower her temperature, but Libby experienced cardiac arrest and died.3

The incidence of adverse drug reports with SSRIs has continued to increase as more serotonergic drugs have become available.4,5 The true incidences of SS and associated morbidity are likely unknown. Also, SS may be underdiagnosed. Some reasons for this are that SSRIs are not the only contributing class of drugs; SS symptoms can range from mild to severe and may be nonspecific; diagnostic criteria vary; and some clinicians are unfamiliar with the condition. It has been suggested that more than 85% of physicians are unaware of the existence of SS or of which drugs or drug combinations are capable of causing it.5 In addition, mild SS symptoms may be ignored or not attributed to drug therapy. Polymedicine is pandemic in our society, and the incidence of SS may be on the rise. A wide variety of medications have the potential to elevate serotonin levels in the body. When these agents are combined, the risk of SS increases.

Causative Agents

SS may occur when central and peripheral serotonin receptors are overstimulated through the action of antidepressant medications or drugs of abuse.4 Both drug factors and patient factors can contribute to the toxicity of SSRIs in some individuals. Drug classes implicated include antimigraine agents; triptans (e.g., sumatriptan); antidepressants (e.g., SSRIs, serotonin norepinephrine reuptake inhibitors [SNRIs], buspirone, tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs]); antipsychotics; anticonvulsants; antiparkinsonian agents; analgesics (e.g., meperidine, tramadol); OTC products (e.g., cough and cold medication containing dextromethorphan); herbal products (e.g., St. John's wort [Hypericum perforatum]; and the antibiotic linezolid.6-13 Mild SS episodes have been reported when St. John's wort or triptans have been used concurrently with SSRIs, SNRIs, or tricyclic antidepressants (e.g., amitriptyline). More severe SS episodes have been reported with the use of an MAOI with other serotonergic drugs (e.g., SSRIs, SNRIs).14,15 See TABLE 1 for a more comprehensive list of drugs commonly associated with SS.6-13

SS typically occurs when a patient takes two or more drugs that elevate serotonin levels through different mechanisms, but the syndrome can occur with the use of individual agents.16 Mechanisms that cause SS include increased serotonin production, inhibition of serotonin reuptake, inhibition of serotonin metabolism, increased serotonin release, and stimulation of serotonin receptors.16 Certain drugs may affect serotonin levels through more than one mechanism. Mechanisms of action and their causative agent(s) include the following:

Increased Serotonin Production: One substance that increases serotonin production is the dietary supplement L-tryptophan. This serotonin precursor has been implicated in SS.4,17,18

Inhibition of Serotonin Reuptake: Drugs that inhibit serotonin reuptake include chlorpheniramine; cyclobenzaprine; dextromethorphan (e.g., Robitussin DM); meperidine; methadone; pentazocine; sibutramine; SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); St. John's wort; tramadol; trazodone; and tricyclic antidepressants (e.g., clomipramine, imipramine). Clomipramine and imipramine have relatively high serotonergic activity compared with amitriptyline, which inhibits serotonin reuptake to a lesser degree.4,5,16,18-21

Inhibition of Serotonin Metabolism by MAO: This category includes isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, and tranylcypromine.4,17-19,22,23

Increased Serotonin Release: Some drugs that increase serotonin release are dextromethorphan, meperidine, methadone, methylenedioxymethamphetamine (also known as MDMA or ecstasy), and mirtazapine.4,19,21,24

Stimulation of Serotonin Receptors: Drugs that stimulate serotonin receptors include buspirone; dihydroergotamine; lithium; lysergic acid diethylamide (LSD); meperidine; metoclopramide; and triptans (e.g, sumatriptan).4,19,24,25 SS also can occur when the metabolism and elimination of a serotonergic drug are altered; e.g., some SSRIs inhibit the metabolism of tramadol by CYP2D6 inhibition and may increase serotonergic activity.26

Clinical Signs and Symptoms

Clinical symptoms of SS typically develop within 2 hours of an increase in dose or the addition of a serotonergic drug.19,27 About 67% of affected patients present with symptoms within 6 hours of medication initiation, change in dose, or overdose. Approximately 75% of affected patients experience symptoms within 24 hours.4,28 The clinician must be proactive to identify early symptoms of SS--e.g., cognitive changes--when they occur. Confusion about symptoms may be responsible for the difficulty in assessing the actual incidence of SS.24 Agitation is a cardinal symptom of SS, and it occurs to some degree with most SSRIs.27 The Hunter Serotonin Toxicity Criteria are recommended for diagnosing SS (TABLE 2).11,28

A triad of clinical features characterize SS: 1) cognitive or mental-status changes (e.g., agitation, confusion, delirium, hallucinations, hyperactivity, hypervigilance, hypomania, pressured speech); 2) neuromuscular abnormalities (clonus [spontaneous, inducible, or ocular], hyperreflexia, increased muscle tone and spasms, restlessness, rhabdomyolysis, rigidity, shivering, tremor); and 3) autonomic hyperactivity symptoms (diaphoresis, diarrhea, fever, flushing, hypotension or hypertension, increased bowel sounds, mydriasis, increased respiratory rate, tachycardia, tearing).4,17,29,30

Mild SS may have a more subacute or even chronic presentation. In such cases, symptoms might be dismissed by clinicians or not attributed to the medication.4 A patient who presents with rapidly increasing temperature and muscle rigidity should probably be considered a medical emergency, as progression to multiorgan failure can occur within hours.27

Two serotonergic drugs do not need to be administered concurrently to cause SS; the syndrome can occur up to 6 weeks after discontinuation of just one such drug with a long-acting dosage form, like fluoxetine (Prozac, Sarafem) or an MAOI (e.g., isocarboxazid, phenelzine).17

Concurrent use of medications that interact with serotonergic drugs, thereby resulting in inhibition of the CYP450 metabolic pathway, can also contribute to SS.31 In this regard, caution should be observed when a patient is taking an SSRI in addition to a CYP2D6 inhibitor or a CYP3A4 inhibitor: SSRIs are extensively metabolized in the liver by these isozymes, and some patients lack the capacity to metabolize certain drugs.

One of the key enzymes involved in adverse drug reactions--the CYP2D6 system--has a high degree of genetic polymorphism.32 A study reported on four elderly patients who apparently developed SS as a result of an interaction between tramadol and mirtazapine.33 These patients presented with auditory and visual hallucinations, myoclonus, hypertension, and behavioral changes. Tramadol is reported to be subject to genetic polymorphism, and about 7% of white patients are poor metabolizers of drugs metabolized by CYP2D6.34,35 Consequently, these patients would have higher serum levels of tramadol and would be at increased risk for SS if a second serotonergic agent were added to the drug regimen.34


In general, treatment of SS first involves discontinuing the offending drug(s) and providing the patient with supportive care. Many mild-to-moderate SS cases are self-limiting and usually resolve within 24 to 72 hours.19 Resolution of more severe cases will likely take much longer. In such cases, supportive care, drug discontinuation, and administration of medication (e.g., diazepam 5 mg IV to reduce hypertonicity and neurologic excitability) may be sufficient to resolve mild symptoms.2,13,36 Patients with severe symptoms may need sedation, paralyzation, and intubation.

Administration of drugs with serotonin antagonist properties, such as cyproheptadine and chlorpromazine, has been utilized in a few patients.4,16,18 Cyproheptadine 4 mg orally is the most widely used antidote for SS.36 Although increased body temperature is common in patients with severe SS, antipyretic therapy usually is not recommended. This is because the fever that occurs with SS is caused by excessive muscular activity, not a change in the hypothalamic temperature set point.2

Role of the Pharmacist

Severe episodes of SS are generally considered rare with monotherapy; SS is more prevalent with polymedicine, even across medication classes. The pharmacist should be knowledgeable about individual drugs and drug combinations with the propensity to cause SS (TABLE 1), the mechanism of action associated with the syndrome, and common signs and symptoms of SS. With this information, the pharmacist is better prepared to advise a patient having this reaction or to advise physicians about necessary drug changes to assure patient safety.

When a pharmacy's computer sounds an alert of a potential drug-drug interaction, the clinician should thoroughly examine the patient's medication history: What medication has the patient taken previously? What adverse drug reactions have been previously experienced? When making drug therapy recommendations, it is essential for the pharmacist to apply knowledge of pharmacology and pharmacokinetics of causative drugs and to carry out a sound risk-benefit assessment. Awareness of SS and education about its effects are vital. All of these factors must be considered to avoid harm to the patient.37


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