Serotonin syndrome is described in the literature as a potentially serious drug-related condition characterized by a number of mental, autonomic and neuromuscular changes.¹ Although serotonin syndrome can cause death, the condition is mild in most persons, and with supportive care alone they tend to recover completely. The syndrome, first described in animal models in the 1950s, was referred to as the "serotonin behavioral" or "hyperactivity syndrome."¹ Reports of serotonin syndrome in humans followed, and have become increasingly frequent since the 1960s. The earliest reports involved persons who were taking monoamine oxidase inhibitors (MAOIs). Some of the early reports included patients who were also taking tryptophan, a serotonin precursor.^1,2

Serotonin syndrome is most often reported in patients taking two or more medications that increase CNS serotonin levels by different mechanisms. The most common drug combinations associated with serotonin syndrome involve the MAOIs, selective serotonin reuptake inhibitors (SSRIs), and the tricyclic antidepressants.³ Because of the dramatic rise in the use of SSRIs, it is predicted that emergency room physicians are going to encounter the serotonin syndrome more frequently than in the past.¹ Symptoms associated with the condition appear in TABLE 1.

Several other medications can precipitate the serotonin syndrome (TABLE 2). Increased reporting of cases appears to be related to at least three things: recently published diagnostic criteria describing serotonin syndrome; greater use of antidepressant medications, such as the SSRIs; and an increased attempt by physicians to differentiate serotonin syndrome from neuroleptic malignant syndrome.⁴

Mild to moderately severe cases of serotonin syndrome usually resolve in 24 to 72 hours.¹ Though most cases can be treated and resolve within a week, some patients become acutely ill and require hospitalization. In some instances patients have been admitted to the ICU and required mechanical ventilation. Mortality associated with this condition is estimated to be 11%.⁴

Serotonin Receptors

Serotonin (5-HT; 5-hydroxytryptamine) occurs naturally in the body. In the periphery, serotonin acts both as a gastrointestinal regulating agent and a modulator of blood vessel tone.⁵ Although only 2% of the body’s serotonin is found in the brain as a neurotransmitter, the chemical can have a profound effect on body functions. As a neurotransmitter, serotonin is involved in the modulation of motor function, pain perception, appetite, and outflow from the sympathetic nervous system.⁴

Serotonin acts at receptors generally classified into one of four categories, depending upon function and location. The four recognized serotonin receptors identified are 5-HT₁, 5-HT₂, 5-HT₃ and 5-HT₄. Receptor subtypes also have been identified. For example, the 5-HT_1d subtype lies outside the CNS and is the receptor through which sumatriptan exerts its antimigraine effect. Researchers agree that the majority of signs and symptoms associated with serotonin syndrome involve excessive stimulation of the 5-HT_1A receptor.^1,6 Recent studies, however, show that the 5-HT₂ receptor may be at least partially responsible for the serotonin syndrome.^1,4 The 5-HT₂ receptors are located in the brain and peripheral blood vessels.

Most cerebral functions are the result of the convergence of many different neurotransmitters, including serotonin.⁷ This complex network of neurotransmitters makes it possible for serotonin to affect many functions and actions of the brain. For example, serotonin often serves as a cotransmitter along with gamma-aminobutyric acid (GABA) and norepinephrine. Serotonin antagonizes GABA_B receptors, causing upregulation of this subtype. The activity of benzodiazepines in the treatment of serotonin syndrome is thought to occur because these compounds act as strong agonists at GABA_B receptors. Certain dopaminergic neurons have serotonin receptors, resulting in serotonin-modulated release of dopamine in different areas of the brain.

Serotonin Syndrome Risk Factors

Risk factors for the development of serotonin syndrome are unclear, but some trends are becoming apparent as more cases appear in the literature. Some researchers have suggested that peripheral vascular disease and atherosclerosis may lead to severe vasospasm and hypertension in the presence of elevated serotonin levels. This seems paradoxical, since in peripheral areas of the body serotonin usually causes vasodilation. However, in patients with vascular disease serotonin can lead to profound vasoconstriction.⁶

Another risk factor relates to drug metabolism rate. Slow metabolizers of SSRIs (approximately 7% of the population) may produce higher than normal levels of these antidepressants in the blood. A slow metabolizer receiving an SSRI in combination with another agent that raises serotonin levels is therefore at increased risk of developing serotonin syndrome.⁶

Clinical Features and Differential Diagnosis

Mental status changes are the most frequently reported symptoms associated with serotonin syndrome.² Other commonly reported features include motor abnormalities, cardiovascular changes, gastrointestinal problems and miscellaneous changes such as diaphoresis and fever (TABLE 1).^2,4 Martin refers to three categories of symptoms that are present: altered mental status, autonomic dysfunction and neuromuscular abnormalities.¹ Sporer indicates that at least three of the following must be present for a diagnosis: mental status changes, agitation, myoclonus, hyperreflexia, fever (hyperpyrexia), shivering, diaphoresis, ataxia and diarrhea in the setting of a recent addition or increase in dose of an agent that raises serotonin levels. Sporer also points out that there should be no other obvious causes of the confusion and/or fever, and that no antipsychotic medications have been used or increased in dose prior to the onset of symptoms.³

Poisonings and other diseases, such as neuroleptic malignant syndrome (NMS), can cause symptoms that are very similar to serotonin syndrome (TABLE 3). Martin offers suggestions that may be useful in differentiating serotonin syndrome from these conditions. One is an observation that bromocriptine has been proposed as a treatment for NMS and a cause or precipitant of serotonin syndrome. Another is that NMS occurs from prolonged exposure to neuroleptic agents or withdrawal of dopamine agonists, and there is lead-pipe rigidity with NMS, in contrast to myoclonus or hyperreflexia seen in persons with serotonin syndrome.¹

Medications Linked with Serotonin Syndrome

Causative agents associated with serotonin syndrome include those that: increase serotonin synthesis (L-tryptophan); decrease serotonin metabolism (MAOIs); increase serotonin release; inhibit serotonin uptake (SSRIs); and stimulate certain serotonin receptors directly, and provide a nonspecific increase in serotonin activity (TABLE 2).

The largest number of cases reported in the literature and the most serious consequences of serotonin syndrome have resulted from use of the MAOIs.³ Most cases were reported when an MAOI was used in conjunction with meperidine, tryptophan, dextromethorphan (an ingredient in many over-the-counter products), a tricyclic antidepressant, or an SSRI antidepressant.^2,3 The long half-life (SSRIs) and duration of effect (irreversible MAOIs) seen with some of these medications increase the possibility of serotonin syndrome occurring several weeks after these drugs have been discontinued.¹ It is important to note that serotonin syndrome has been precipitated by medications that are not usually thought of as being serotonergic. One author asserts that both meperidine and dextromethorphan are "notorious for precipitating acute serotonin syndrome."⁴

Case Reports

Select cases of suspected or confirmed serotonin syndrome illustrate the broad range of circumstances in which this condition can occur. Although there are many reports of "possible" serotonin syndrome reactions in the literature, in many instances the syndrome is not fully developed as there may be question as to whether the symptoms reported are really the result of serotonin syndrome. In such instances the diagnostic criteria developed by Sternbach, Martin and Sporer should be followed.^1-3

Case No. 1: A case reported in 1994 involved a 48-year-old man brought to the emergency room due to agitation and confusion. He had a three-year history of depression which was being treated with tranylcypromine (Parnate), an MAOI. The tranylcypromine was discontinued prior to E.R. presentation. Fourteen days after the MAOI was discontinued, fluoxetine (40 mg daily) was begun. Over the next 72 hours the patient developed agitation, diaphoresis and confusion. During his hospital stay he developed tachycardia and profound muscle rigidity and had to be intubated. In addition to supportive measures, the patient received diazepam and propranolol to relieve muscle rigidity, hypertension and tachycardia. By the third hospital day his temperature returned to normal and he rapidly recovered. He was released on the fifth day.⁸

This case underlines the extreme importance of implementing a "wash out" period after the discontinuation of one serotonergic drug before the implementation of another. Even after two weeks, the effect of tranylcypromine was still active enough to cause a serotonergic crisis when therapy with fluoxetine was begun.

Case No. 2: A 72-year-old man was admitted to the hospital for presumed Parkinson’s disease and depression. He was placed on selegiline and fluoxetine. After nine weeks of treatment, he presented with acute delirium which progressed to lethargy, malaise, myoclonic jerking and grand mal seizures. The fluoxetine was discontinued, but seven days later he experienced acute delirium, convulsions, and became unresponsive. The selegiline was discontinued. Five days later symptoms resolved completely.⁹ This case demonstrates the ability of fluoxetine to exert its serotonergic effects for a few days up to weeks after discontinuation. The effect probably is due to the long half-life of both fluoxetine and its active metabolite, norfluoxetine.

Case No. 3: A recent report describes a 51-year-old man who developed serotonin syndrome when he combined Nyquil with paroxetine (Paxil). Pertinent medical history included depression, for which he was taking paroxetine, and peripheral vascular disease. Four days prior to admission, he developed nasal congestion which he self-medicated with Nyquil. Two days later, he experienced nausea, extreme shortness of breath, and confusion. Upon admission to the hospital he was experiencing tachycardia and his blood pressure was 202/110. During hospitalization the patient became rigid and more confused. Potential causes of symptoms, including strychnine poisoning, anxiolytic withdrawal and tetanus were ruled out (TABLE 3). Administration of lorazepam resolved all symptoms, and he was transferred to the ICU with normal mental status. The paroxetine was discontinued, and after a four-week follow-up, the patient remained asymptomatic.⁵

The most probable explanation for the development of serotonin syndrome in this patient was the combination of dextromethorphan (an ingredient in Nyquil) and paroxetine. The pseudoephedrine in Nyquil (10 mg/5 mL) may have produced the adrenergic effect (e.g., increased blood pressure). In addition, the vascular disease may have been a predisposing factor. Dextromethorphan inhibits reuptake of serotonin (TABLE 2) and has previously been implicated in serotonin syndrome when combined with an MAOI.^4,5 It has been shown that persons with a history of vascular endothelial damage are at risk of vasospasm in the presence of increased serotonin levels.¹ The authors of this case report suggest that patients with pre-existing vascular disease may be at increased risk of developing complications related to increased serotonin levels. As a result, caution should be exercised when administering serotonergic medications to patients with vascular disease. If possible, such patients should consult a physician or pharmacist before self-medicating with over-the-counter cough medicines.

Case No. 4: The newer antidepressants may pose a potential problem as well. For example, nefazodone (Serzone), blocks 5-HT₂ receptors and also inhibits reuptake of serotonin. Recently there was a report of a 51-year-old woman with a history of bipolar disorder who was brought to the emergency room unresponsive, diaphoretic, hyponatremic and with muscle rigidity. The patient had taken nefazodone (Serzone) for six months and had just discontinued the drug for two days. One day before admission she was started on paroxetine (Paxil). She improved dramatically after supportive treatment and dantrolene.¹⁰ Although nefazodone is a relatively weak 5-HT reuptake inhibitor, it is still capable of causing serotonin syndrome when combined with a stronger 5-HT reuptake inhibitor. While the researchers who reported this case believe it to be the first case of serotonin syndrome reported from the use of nefazodone and paroxetine, they point to other reports involving the use of trazodone and paroxetine.

Management and Prevention

No specific therapeutic approach to the treatment of serotonin syndrome has been fully evaluated in the literature. The most common treatment involves the use of the benzodiazepines. In severe cases, the antiserotonergic agents cyproheptadine, methysergide, and propranolol have been used.^3,6,11 In all cases the suspected agent should be discontinued. Over-the-counter drugs containing ingredients known to increase serotonin levels or exacerbate the patient’s condition, such as dextromethorphan, pseudoephedrine or phenylpropanolamine, also should be discontinued.

Initial treatment should consist of supportive measures aimed at reducing hypertension, tachycardia, hyperthermia and respiratory distress if these conditions are present. Lorazepam and diazepam have been shown to be effective in treating myoclonus associated with serotonin syndrome, and in mild cases, are usually the only treatment necessary. It is important to note that clonazepam has been found to be ineffective in treating serotonin syndrome. Unlike diazepam and lorazepam, clonazepam is not a potent agonist of the GABA_B receptor.⁶ The more severe cases that do not respond to benzodiazepines may respond to dantrolene, which may be effective in relieving muscle rigidity and hyperthermia.¹

Pharmacists should recognize potential problems associated with the concurrent use of certain medications, such as the MAOIs and the SSRIs and other agents that can cause serotonin syndrome. Due to the potentially serious nature of this condition, it seems prudent that pharmacists always monitor patients who are taking combinations of serotonergic drugs and be alert to the possibility of "serotonergic duplication" and notify physicians and other prescribers when the risk of drug adversity appears eminent. The use of therapeutic alternatives in certain instances could be life-saving.