Serotonin syndrome

Author: Kirk C. Mills
Date: Oct, 1995

Serotonin syndrome is an important drug-related complication of psychopharmacologic therapy for depression, bipolar affective disorder, obsessive-compulsive disorder and Parkinson's disease. It is characterized by variable alterations in cognition and behavior, autonomic nervous system function and neuromuscular activity[1,2] (Table 1). Serotonin syndrome is an iatrogenic disorder: it only occurs in the setting of drug therapy that has a net effect of augmenting brain serotonin neurotransmission. Serotonin syndrome most commonly occurs when two or more serotonergic drugs are given concurrently. However, the syndrome has also been reported with single drug exposure in both therapeutic settings[3] and overdose settings.[4]

TABLE 1Signs and Symptoms of SerotoninSyndrome (Review of 100 Cases)(*) FrequencySign/symptom (%)

Serotonin Receptors

In general serotonin receptors are categorized into four separate classes designated as 5-[HT.sub.1], 5-[HT.sub.2], 5-[HT.sub.3] and 5-[HT.sub.4] (Figure 1). The 5-[HT.sub.1] class is the largest and most studied class of serotonin receptors. Some of these receptor classes also have different subclasses of receptors. In animal models, serotonin syndrome results from excessive stimulation of specific postsynaptic serotonin receptors located in the lower brainstem (pons, medulla) and spinal cord regions.[1,6] The 5-[HT.sub.1A] receptor subtype predominates in this region of the brainstem. In the past, the 5-[HT.sub.1A] postsynaptic receptor was believed to mediate the entire syndrome, but recent studies have demonstrated that the 5-[HT.sub.2] postsynaptic receptor is at least partially involved in the expression of this syndrome. In addition, other neurotransmitter receptors (dopamine, beta-adrenergic, etc.) may modulate the expression of the serotonin syndrome.[6]

Clinical Presentation

The diagnosis of serotonin syndrome is based entirely on a strong clinical suspicion and the exclusion of other medical and psychiatric conditions. The "typical" patient with serotonin syndrome demonstrates altered behavior-cognition ability, autonomic nervous system dysfunction and neuromuscular abnormalities. The frequency with which specific signs and symptoms were reported in 100 cases of serotonin syndrome reported in the literature is listed in Table 1.

Some patients report recurrent mild symptoms days to weeks before symptoms become more severe. In a few cases, patients rapidly progress to multiple organ failure and death. Serotonin syndrome has been reported in pediatric patients.[2,4]

Abnormalities of the neuromuscular system are the most commonly reported findings in patients with serotonin syndrome. Many of these symptoms are quite unusual and may cause the evaluating physician to mistakenly attribute the symptoms to malingering or a primary neurologic disorder (Table 3). Neuromuscular complaints include restlessness, involuntary myoclonic jerks (even when sleeping), resting extremity tremor, teeth chattering and difficulty walking. Generalized muscular rigidity develops in all severe cases. Sustained muscle contraction predisposes patients to hyperthermia, metabolic acidosis, rhabdomyolysis and impaired respiratory function. Isolated bilateral lower extremity rigidity is fairly specific for serotonin syndrome.

The initial cognitive-behavioral changes of serotonin syndrome are often overlooked. These alterations include anxiety, confusion, agitation, hypomania, headache and insomnia. A search of the literature volume 52, number 5 revealed that coma occurred in over 25 percent of all patients. Seizures are usually generalized, but focal seizures have been reported. Visual and auditory hallucinations are unusual but have also been reported.

Dysfunction of the autonomic nervous system commonly occurs in serotonin syndrome. Diaphoresis, hyperthermia, sinus tachycardia, hypertension and tachypnea are commonly reported. In addition, pupillary dilatation was noted in 28 percent of cases found in the literature. Twenty percent of patients had pupils unreactive to light. Other symptoms related to autonomic nervous system dysfunction include nausea, vomiting, diarrhea, skin flushing and abdominal cramps. Hypotension usually occurs as a preterminal event. Ventricular tachycardia has been reported but is unusual.

Laboratory Studies

No specific tests are available for the diagnosis of serotonin syndrome. Laboratory tests are best used to identify complications (e.g., rhabdomyolysis) and assist in overall patient care. Elevated serotonergic drug levels (e.g., lithium, fluoxetine, clomipramine) are not required to produce serotonin syndrome, and in over 90 percent of the cases in which drug levels (and metabolites) were measured, drug levels of serotonergic agents were within accepted therapeutic limits.

Serotonin syndrome is not associated with abnormalities in cerebrospinal fluid analysis, radiographic studies (including computed tomographic scanning), electroencephalography (excluding seizures) or routine serum electrolyte determinations. When laboratory abnormalities occur, they are almost always secondary to complications. These complications include hypoxia from respiratory muscle rigidity or coma, rhabdomyolysis from diffuse muscle rigidity, disseminated intravascular coagulation from multiple organ failure, metabolic acidosis secondary to seizures or ventricular tachycardia, and aspiration pneumonia from decreased consciousness.

Drug Interactions

Because serotonin syndrome most commonly occurs when two or more serotonergic drugs are used in combination, it becomes imperative to recognize and avoid potential serotonergic drug interactions, as well as to understand safe drug therapy alternatives.

Meperidine (Demerol) and dextromethorphan are potent inhibitors of serotonin uptake and are notorious for precipitating acute serotonin syndrome, especially in patients taking MAOIs, including selegiline (Eldepryl).[7,8] In general, it is best avoid prescribing either meperidine or dextromethorphan for any patient taking a serotonergic agent. Morphine, fentanyl, salicylates, acetaminophen and nonsteroidal anti-inflammatory drugs are considered safe analgesic alternatives to meperidine.[27] The safety of codeine as an alternative antitussive to dextromethorphan remains unproved.

All three SSRIs can produce serotonin syndrome, most commonly when taken concomitantly with other serotonergic drugs. The unique pharmacokinetics of fluoxetine make it especially prone to cause serotonin syndrome. The half-life of fluoxetine ranges from one to four days, and its active metabolite has a half-life of seven to 14 days.[9] A five-week abstinence period is commonly recommended once fluoxetine therapy has been stopped before initiating any other serotonergic agent. Paroxetine and sertraline (Zoloft) have half-lives of approximately 24 hours. Patients receiving these drugs require only a two-week abstinence period before starting new medications. Three new, recently released drugs also inhibit serotonin uptake: venlafaxine (Effexor), nefazodone (Serzone) and fluvoxamine (Luvox). Until proven otherwise, these three drugs should be viewed as having the potential to produce serotonin syndrome.

All currently available MAOIs produce irreversible inhibition of MAO enzyme activity. Return of MAO enzyme activity to an acceptable level occurs approximately two weeks after discontinuation of any of the irreversible MAOIs. This delay is due to the gradual production of uninhibited MAO enzyme. An abstinence period of at least two weeks is required before drugs with serotonergic activity can be administered after discontinuation of any of the MAOIs. Most MAOIs are used to treat depression, but selegiline is used as adjunctive therapy in Parkinson's disease because of its ability to inhibit MAO-B isoenzymes and thus secondarily increase dopamine availability. This selectivity in MAO-B inhibition is easily lost with dosages that are slightly higher than therapeutic. Therefore, selegiline should be viewed as having the same potential to precipitate serotonin syndrome as the other MAOIs.

Drugs that increase central nervous system dopamine concentrations, such as levodopa (Sinemet), bromocriptine (Parlodel) and selegiline, have the potential to precipitate serotonin syndrome by means of their ability to cause indirect serotonin release.2 l0 These medications should be used cautiously, if at all, with other serotonin agonists.

Address correspondence to Kirk C. Mills, M.D., Detroit Receiving Hospital, Department of Emergency Medicine, 4201 Saint Antoine Street, Detroit, Ml 48201.

COPYRIGHT 1995 American Academy of Family PhysiciansCOPYRIGHT 2004 Gale Group

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