Serotonin Syndrome

US Pharm. 2007;32(11):20-23.

One of the many ways that pharmacists make a difference in the care of their patients is through educating themselves about, monitoring for, and raising awareness of preventable medication-related conditions. Serotonin syndrome, also referred to as serotonin toxicity, is one such condition that, in some cases, may be fatal. Medications with serotonergic activity, some even available OTC ( TABLE 1), are the culprits of this potentially preventable complex of symptoms. The incidence of serotonin syndrome is increasing with the expanded use of serotonergic agents and, specifically, with polypharmacy.¹ The FDA recently asked the manufacturers of these medications to include warning labels on their products informing patients about the potential risk of serotonin syndrome.²

The most common drug combinations associated with serotonin syndrome involve the monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and the tricyclic antidepressants (TCAs).³ While there are several mechanisms that result in excess serotonin, severe, life-threatening serotonin toxicity occurs only with combinations of medications acting at different sites, most frequently including an MAOI and an SSRI.^4-6 The less-severe cases occur with other combinations and overdoses and may even present as a result of single-drug therapy in a susceptible individual.⁵ This condition is more likely to occur when a medication is initially introduced into the regimen or when the dosage is increased.²

Due to the current widespread use of SSRIs for a variety of conditions (e.g., depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa) and across the spectrum of patient populations (e.g., pediatric, teens, adults, and the elderly), it is potentially likely that serotonin syndrome will be more frequently encountered than in previous years. A revealing 2002 Toxic Exposure Surveillance System report indicated that of 26,733 individuals receiving SSRIs, 27% developed significant morbidity and 93 expired.⁷ While age and gender are not related to the incidence of or predisposition to serotonin syndrome, many of the medications with the potential to cause this condition are commonly used in the geriatric population.^8,9 For instance, SSRIs are the drugs of choice for depression in the elderly since they have relatively few cardiovascular and anticholinergic effects compared with other classes of antidepressants (e.g., tricyclic antidepressants). Pharmacists should become familiar with the underlying principles and characteristics of this syndrome to assist with its recognition, treatment, and prevention.

Recognition and Diagnosis of Serotonin Toxicity
Serotonin syndrome is a potentially preventable, drug-related complication that occurs from increased serotonin activity in the central nervous system through a variety of mechanisms including an increase in serotonin synthesis, a decrease in serotonin metabolism, an increase in serotonin release, inhibition of serotonin uptake, direct serotonin receptor stimulation, and a nonspecific increase in serotonin activity.^3,10 The toxicity is characterized by an altered mental status (e.g., anxiety, agitation, confusion), neuromuscular excitation, and autonomic stimulation. The patient's medication history is positive for serotonergic drugs. Presentation is described as a sudden onset of altered consciousness, muscle rigidity (usually in the lower extremities), hyperreflexia, clonus, myoclonus, diaphoresis, flushing, and tremor. Vital signs reflect hypertension, tachycardia, tachypnea, and hyperthermia.^4,9

Serotonin toxicity can be classified as mild (serotonergic features that may or may not concern the patient), moderate (toxicity that causes significant distress and deserves treatment, but is not life threatening), or severe (a medical emergency characterized by rapid onset of severe hyperthermia, muscle rigidity, and multiple organ failure).⁵ Serotonin syndrome is diagnosed only after all other potential causes of symptoms have been ruled out. The differential diagnosis includes, but is not limited to, neuroleptic malignant syndrome (NMS), infection, intoxication (e.g., anticholinergic agents), metabolic problems, delirium tremors, malignant hyperthermia, and drug withdrawal, all based on the patient's history and presentation.⁹ Some symptoms may even mimic those secondary to an overdose of cocaine, lithium, or an MAOI. In NMS, the medication history is positive for dopamine antagonists, the onset is gradual (within seven days), the muscle rigidity is "lead pipe" in all extremities, and there is bradyreflexia; NMS usually resolves in about nine days.⁹ Making the distinction between NMS and serotonin syndrome is important since dopamine agonists, such as bromocriptine, are commonly used to treat NMS but may exacerbate the symptoms of serotonin syndrome.⁹ Clonus has been found to be more specific to serotonin toxicity.⁵ Tests to assist with ruling out other causes of symptomatology may include complete blood count, thyroid function tests, drug screen, and electrocardiogram.²

Case Reports in Seniors
In an elderly patient, a change in mental status may indicate a variety of conditions and needs to be addressed and evaluated carefully. Potential causes or conditions need to be ruled out so the appropriate treatment, if necessary, may be implemented. Published case reports warn that clinicians treating patients with a combination of serotonergic antidepressants and atypical antipsychotics for psychotic depression should be aware of the potential for serotonin syndrome.¹¹ For example, one 69-year-old male treated for depression with psychosis with trazodone, risperidone, and sertraline developed myoclonus, tremor, cogwheel rigidity, and diaphoresis; another patient, a 72-year-old female who was receiving phenelzine and quetiapine, presented with increased confusion, lethargy, slurred speech, and a fever of 101.5.¹¹ In both cases, all symptoms resolved within 24 hours of discontinuation of the psychotropics. The conditions reported in these individuals were attributed to serotonin syndrome as a result of a combination of an antidepressant and an atypical antipsychotic.¹¹ Similar combinations of antidepressant and atypical antipsychotic agents have been associated with case reports of serotonin syndrome.

Linezolid and Some Lesser-Known MAOIs
As mentioned above, it is the combination of serotonergic drugs, acting by different mechanisms, that is capable of raising intrasynaptic serotonin to a level that is life threatening.⁴ Complications can occur, such as uncontrolled muscle spasms causing severe muscle breakdown and resulting in renal damage, if not recognized and treated appropriately.² The combination that most commonly does this is an MAOI drug combined with any serotonin reuptake inhibitor (SRI). A number of lesser-known agents are MAOIs, such as the antibiotic linezolid. After linezolid was released to the U.S. market, several case reports of serotonin syndrome emerged.¹² This antimicrobial agent, used to treat resistant gram-positive bacteria, is a weak MAOI and has been reported to interact with SSRIs.¹³ Controversy exists regarding whether linezolid and SSRIs can be given concomitantly.¹⁴ Caution should be used when linezolid is used in patients receiving an SSRI.¹³ Researchers from the Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, based on a recently published retrospective study, report that if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with the SSRI, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome.¹⁴ Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected. Clark et al. recommend that other antibiotic options be considered first, and linezolid be reserved as the last resort if possible.¹³

The analgesics meperidine, methadone, propoxyphene, and tramadol and the OTC cough-suppressant dextromethorphan appear to be weak SSRIs that have all been associated with serotonin toxicity reactions with MAOIs, including some fatalities.⁴ The alternative analgesics morphine, codeine, oxycodone, and buprenorphine are not known SRIs and do not precipitate serotonin toxicity with MAOIs.⁴ Understanding the mechanisms involved in these interactions and raising awareness of their properties will therefore help to ensure that problems can be avoided in most clinical situations and that appropriate treatment will be provided if problems do occur.⁴

Treatment
Treatment involves removal of the causative agents and may also include the use of serotonin antagonists (i.e., cyproheptadine). Immediate supportive care should be directed toward symptom management (e.g., therapy for hypertension, tachycardia, hyperthermia, and respiratory distress).^3,6,9 Symptoms typically resolve within 24 hours after withdrawal of the serotonergic medication. Benzodiazepines, such as diazepam or lorazepam, are often utilized to decrease agitation, myoclonus, and muscle rigidity; the addition of nondepolarizing paralyzing agents may be necessary as second-line therapy. ⁹ It has been recommended that patients with serotonin syndrome stay in the hospital for at least 24 hours for close observation.² In life-threatening cases, artificial ventilation is necessary.² Case reports of serotonin syndrome indicate that cyproheptadine reduced the severity of signs and symptoms but did not alter the time required for resolution.¹⁵ Additionally, cyproheptadine lacks dopamine antagonist activity and therefore can safely be administered in situations in which NMS cannot be differentiated from serotonin syndrome.¹⁶

Prevention of Serotonin Toxicity
Clinicians should obtain complete medication histories to identify patients at risk, strictly monitor medication therapy including concomitant agents, and receive education about serotonin syndrome.¹² Prescribers should reconsider the use of two or more serotonergic medications and/or consider switching to less-serotonergic alternatives, if appropriate.³

Pharmacists should monitor medication regimens for interactions between serotonergic agents and counsel patients and caregivers about the avoidance of OTC products that may elevate serotonin levels (e.g., dextromethorphan and St. John's wort). Educating patients at risk for potential adverse effects from serotonergic agents (e.g., confusion, muscle spasms, shaking, shivering, sweating) should be an integral part of counseling.

Summary
Serotonin syndrome is a potentially preventable, medication-related complication that occurs from increased serotonin activity in the central nervous system, usually secondary to the use of one or more serotonergic agents. Early diagnosis and prompt treatment are important in the resolution of this condition. Treatment involves removal of the causative agents and may also include the use of serotonin antagonists (i.e., cyproheptadine) and other interventions. Symptoms typically resolve within 24 hours after withdrawal of the offending medication. Pharmacists can make a difference in the lives of their patients by identifying individuals at risk for serotonin syndrome, recommending changes or alternatives to therapy, counseling patients to avoid prescription and OTC interactions, raising awareness among health care professionals regarding the potential for negative outcomes, and potentially preventing unnecessary human suffering, elevated health care costs, and possibly preventable deaths.

References

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2. Perez M. Medical Encyclopedia: Serotonin syndrome. Updated August 1, 2006. Available at: www.nlm.nihgov/medlineplus/ency/article/007272.htm. Accessed October 11, 2007.

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9. Prator BC. Serotonin syndrome. J Neurosci Nurs. 2006;38:102-105.

10. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:139-146.

11. Kohen I, Gordon ML, Manu P. Serotonin syndrome in elderly patients treated for psychotic depression with atypical antipsychotics and antidepressants: two case reports. CNS Spectr . 2007;12:596-598.

12. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26:1784-1793.

13. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy. 2006;26:269-276.

14. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006;43:180-187.

15. McDaniel WW. Serotonin syndrome: early management with cyproheptadine. Ann Pharmacother. 2001;35:870-873.

16. Chan BS, Graudins A, Whyte IM, et al. Serotonin syndrome resulting from drug interactions. Med J Aust. 1998;169:523-525.

17. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 12th ed. Hudson, OH: Lexi-Comp, Inc; 2007.

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