AACN Advanced Critical Care Volume 24, Number 1, pp.15–20 © 2013, AACN Complex Rhythms Earnest Alexander, PharmD, and Gregory M. Susla, PharmD Department Editors Serotonin Syndrome: Recognition and Treatment Brad E. Cooper, PharmD Celeste A. Sejnowski, PharmD S erotonin syndrome (SS) is a complication resulting from excessive effects of serotonin on the central nervous system, and it usually results from taking medications, such as the antidepressant agents known as selective serotonin reuptake inhibitors (SSRIs), that elevate levels of serotonin either therapeutically or with intentional overdoses. Many reported cases are the result of unintended drug interactions that elevate the effects of the serotonergic medication.1,2 Because prompt recognition and appropriate treatment are necessary for patient recovery, all critical care practitioners should be aware of this syndrome. However, a study reported that more than 85% of physicians are unaware of SS as a clinical diagnosis.3 The purpose of this column is to review the pathophysiology, epidemiology, signs and symptoms, and appropriate treatment of SS. Pathophysiology Serotonin is produced by decarboxylation and hydroxylation of l-tryptophan. Several serotonin receptors are divided into seven 5-hydroxytryptophan (5-HT) families, and several of these receptors have subtypes.1 Agonism of 5-HT2A receptors contributes most substantially to SS. Serotonin is involved in regulating wakefulness, affective behavior, thermoregulation, emesis, and sexual behavior as well as regulation of vascular tone and gastrointestinal motility. Epidemiology The first cases of SS were reported in the 1950s with monoamine oxidase inhibitors (MAOIs). Reports have increased as the use of SSRIs has increased. A 2002 report from the Toxic Exposure Surveillance System identified 26 733 exposures to SSRIs, resulting in 7349 major or moderate adverse effects and 93 deaths.4 A 2004 report from the Toxic Exposure Surveillance System identified 48 204 exposures to SSRIs that resulted in moderate or major adverse outcomes in 8187 patients and death in 103 patients, with most fatalities associated with coingestions of other substances.5 Diagnosis of SS The signs and symptoms of SS can run the spectrum from mild to life-threatening and are summarized in Table 1. As reviewed by McAllen and Rhoney,6 3 sets of criteria have been developed to diagnose SS: the Sternbach criteria, the Hunter Brad E. Cooper is Clinical Pharmacist, Critical Care, UPMC Hamot, 201 State St, Erie, PA 16550 (cooperbe@upmc.edu). Celeste A. Sejnowski is PGY1 Pharmacy Resident, UPMC Hamot, Erie, Pennsylvania. The authors declare no conflicts of interest. DOI: 10.1097/NCI.0b013e31827eecc6 15 Copyright © 2013 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited. NCI200251.indd 15 16/01/13 7:31 AM Drug Update W W W .AACN AD V AN CE D CRITICALCARE .COM antiemetics, antimigraine agents, illicit drugs, and over-the-counter drugs (eg, St. John’s wort, dextromethorphan). Table 3 lists serotonergic agents that can cause SS either alone or in combination with other agents. Serotonin syndrome can be precipitated when MAOIs are given in combination with serotonin agonists, especially SSRIs. Taking multiple causative agents, self-poisoning with serotonergic agents, and drug interactions among SSRIs can lead to SS. People who are on a chronic regimen of SSRIs have a higher risk of SS, but it also has been documented in patients taking therapeutic doses of SSRIs.16 Table 1: Signs and Symptoms of Serotonin Syndrome Mild Moderate Severe Tachycardia Tachycardia Tachycardia Shivering Hypertension Hypertension (but can deteriorate to shock) Diaphoresis Hyperthermia (as high as 40°C) Delirium Mydriasis Mydriasis Muscle rigidity Tremor or myoclonus Hyperactive bowel sounds Hypertonicity Hyperreflexia Diaphoresis Severe hyperthermia (⬎41°C) Hyperreflexia and clonus greater in the lower extremities (may be inducible) Metabolic acidosis Ocular clonus Rhabdomyolysis Drug Interactions Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors are used to treat depression and anxiety, but they are used rarely because of the risk of toxicity and food and drug interactions. Examples of MAOIs include phenelzine and isocarboxazid. Selective serotonin reuptake inhibitors and MAOIs can interact, overstimulating the serotonin receptors in the brain. The serotonin transporter on presynaptic terminals of neurons mediates the reuptake of serotonin into the presynaptic terminal. Treatment with an SSRI blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission. Normally, serotonin in a neuron is removed from the synapse by active transport back into the presynaptic neuron. In the presynaptic neuron, serotonin is either “repackaged” for release into the synapse or broken down by monoamine oxidase.10 Monoamine oxidase is an intracellular enzyme that is bound to the mitochondrial membrane, and its function is to inactivate norepinephrine, dopamine, and serotonin via oxidation. When monoamine oxidase is inhibited, neurotransmitters accumulate in the presynaptic nerve.17 When an MAOI is taken concomitantly with an SSRI, the serotonin reuptake mechanism as well as serotonin breakdown is blocked by the MAOI. As a result, no serotonin is released into the synapse. To avoid potential interaction between medications causing SS, clinicians should wait an adequate length of time between discontinuation of one medication and initiation of another; this waiting time is known as a “washout period.” For example, the SSRI fluoxetine has a long half-life as a result of its metabolite, so a 5-week washout period between discontinuing fluoxetine and adding an Elevation of serum aminotransaminases and creatinine Seizure Disseminated intravascular coagulopathy Serotonin Toxicity criteria, and the Radomski criteria.7–9 Table 2 summarizes the criteria for each of these sets. The Sternbach criteria rely heavily on mental status changes, and patients with delirium due to anticholinergics may be diagnosed as positive for SS by the Sternbach criteria.9 The Radomski criteria differentiate mild and severe SS. The Hunter criteria may be the most accurate criteria, with 84% sensitivity and 97% specificity when compared to diagnosis by a medical toxicologist.8 Causative Drugs Serotonin syndrome is most commonly caused by SSRIs. Other drugs that can lead to the development of SS include tricyclic antidepressants (TCAs), opiate analgesic agents, antibiotics, 16 Copyright © 2013 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited. NCI200251.indd 16 16/01/13 7:31 AM V O LU ME 24 • N U M BER 1 • JANUARY–M ARCH 2013 Drug Update Table 2: Diagnostic Criteria for Serotonin Syndromea Sternbach Radomski Hunter Must have recent addition of known serotonergic agent, absence of other causes, and no recent addition of a neuroleptic agent and must exhibit at least 3 of the following: Mild state: Must have taken a serotonergic agent and meet one of the following criteria: • Restlessness • Insomnia • Spontaneous clonus • Incoordination • Inducible clonus plus agitation or diaphoresis • Mental status changes • Dilated pupils • Agitation • Akathisia • Hyperreflexia • Tachycardia • Myoclonus • Tachypnea/dyspnea • Diaphoresis • Diarrhea • Shivering • Tremor • Diarrhea • Autonomic instability • Ocular clonus plus agitation or diaphoresis • Tremor plus hyperreflexia • Hypertonia plus temperature higher than 38°C plus ocular clonus or inducible clonus Severe state: • Incoordination • Impaired level of consciousness • Elevated temperature • Elevated mood • Coma • Myoclonus • Tremor • Shivering • Rigidity • Hyperreflexia • Hyperthermia • Sweating a Adapted from McAllen and Rhoney.6 Reproduced with permission of the publisher. Copyright 2012 Society of Critical Care Medicine. MAOI is required to decrease the risk of SS.18 Other SSRIs should have a washout period of 2 weeks.10 Other Antidepressants Trazodone and nefazodone are weak inhibitors of serotonin uptake. Serotonin syndrome can occur if MAOIs are administered with these drugs. Of note, trazodone has serotonin reuptake inhibition at antidepressant doses of 150 mg or higher.20 Tricyclic antidepressants (TCAs) have actions similar to those of the SNRIs but have more adverse effects than SNRIs. Each TCA has different selectivity toward serotonin and norepinephrine. For example, clomipramine is a potent serotonin reuptake inhibitor. The other TCAs can be used with caution for patients who are severely resistant to treatment.20 Tricyclic antidepressants should not be used concurrently with MAOIs or within 14 days Serotonin-Norepinephrine Reuptake Inhibitors Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that binds both serotonin and norepinephrine inhibitors. A 14-day washout period is required after ending MAOI therapy and before starting venlafaxine treatment.19 Only a 7-day washout is required after discontinuing venlafaxine and beginning an MAOI. Duloxetine, another SNRI, requires only a 5-day washout period after discontinuing duloxetine and before beginning MAOI treatment.19 17 Copyright © 2013 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited. NCI200251.indd 17 16/01/13 7:31 AM Drug Update W W W .AACN AD V AN CE D CRITICALCARE .COM of discontinuing MAOI therapy. Cyclobenzaprine, carbamazepine, and oxcarbazepine are structurally related to the TCAs; however, these drugs do not block serotonin or norepinephrine uptake, so they can be used with caution.20 Table 3: Serotonergic Agentsa Inhibitors of serotonin reuptake Amphetamines Analgesic agents: tramadol, meperidine, methadone Other Prescription Medications Cocaine Opiates such as dextromethorphan, fentanyl, meperidine, methadone, and tramadol have serotonin reuptake inhibition. The level of risk with serotonergic opiates is most likely low based on the level of evidence that exists, but opiates not known to be serotonergic reuptake inhibitors should be used with caution.18 Morphine, hydromorphone, aspirin, and acetaminophen are presumed safe analgesic alternatives.2 Buspirone is a 5-HT1A partial agonist, and it could theoretically contribute to SS; therefore, it should be administered with caution.20 However, no good evidence has shown that buspirone causes SS when administered with SSRIs and MAOIs.21 Linezolid is an oxazolidinone antibiotic drug that was originally found to have psychotropic effects through mild reversible nonselective inhibition of monoamine oxidase.12 This drug was also found to have activity against drugresistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. When linezolid is taken with serotonin agonists, a small risk of SS exists. Quinn and Stern12 and Lawrence et al14 concluded that decisions about discontinuing or not initiating SSRIs with linezolid need to be based on risks versus benefits of need for this antibiotic versus the risk of SS. 5-Hydroxytryptamine receptor agonists (triptans) are antimigraine agents that activate the 5-HT1B and 5-HT1D receptors in the brain. When used in combination with an SSRI or SNRI, SS can occur. However, the evidence supporting this association is controversial. In July 2006, the US Food and Drug Administration (FDA) issued a warning that SS can occur when a triptan is taken with an SSRI or SNRI. Evans et al22 concluded that only class IV evidence (uncontrolled studies, case series, case reports, expert opinions) is provided in the literature and through the FDA registration of adverse events to support the July 2006 FDA statement. They also concluded that data were conflicting and that no evidence-based recommendations could be made. Sclar et al23 reviewed the number of patients who were prescribed triptan and an SSRI or SNRI after the FDA warning in 2006 Dextromethorphan Serotonin-norepinephrine reuptake inhibitors: venlafaxine Selective serotonin reuptake inhibitors: citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline St. John’s wort Tricyclic antidepressants: amitriptyline, desipramine, clomipramine, imipramine, doxepin, nortriptyline Trazodone, nefazodone Inhibitors of serotonin metabolism (decreased serotonin degradation) Linezolid Monamine oxidase inhibitors: isocarboxazid, phenelzine, rasagiline, selegiline, tranylcypromine Increased serotonin release Amphetamines Cocaine Codeine Dextromethorphan Fenfluramine Levodopa MDMA (Ecstasy) Meperidine Methadone Mirtazapine Pentazocine Reserpine Direct serotonin receptor agonists 5-HT1 agonists: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan Buspirone Dihydroergotamine Indirect serotonin receptor agonist Lithium a Based on data from references 10 to 15. 18 Copyright © 2013 American Association of Critical-Care Nurses. Unauthorized reproduction of this article is prohibited. NCI200251.indd 18 16/01/13 7:31 AM V O LU ME 24 • N U M BER 1 • JANUARY–M ARCH 2013 Drug Update (1.8% of patients). They concluded that not enough literature is available as to the number of cases of SS resulting from the concomitant use of triptan with SSRI or SNRI. Note that ergotamine and its analogs do not seem to cause SS as reported in the literature.21 Table 4: Treatment Options for Serotonin Syndromea Severity Mild Treatment Remove causative agents Intravenous fluids for hydration and diuresis Other Agents Benzodiazepines for agitation MDMA (Ecstasy) is a recreational drug that is an amphetamine derivative and directly releases serotonin from the nerve terminals, which can induce SS when used alone or facilitated by high temperatures and dehydration. Lysergic acid diethylamide does not seem to cause SS in either usual doses or overdoses.21 Synthetic cathinones, also known as bath salts, have been associated with SS. Bath salts increase the synaptic concentration of serotonin and inhibit monoamine uptake transporters.24 Hypericum perforatum, commonly known as St. John’s wort, is an herb available over the counter that is used to treat depression. St. John’s wort has been associated with SS when taken with 5-HT reuptake inhibitors.13 Moderate Above therapy Cyproheptadine Dosing: 12 mg PO/NG initially followed by 2 mg every 2 h if symptoms continue Maintenance dose: 8 mg PO/NG every 6 h once the patient is stabilized Chlorpromazine (not first choice) Dosing: 50-100 mg IM 1⫻ Use with caution in patients who are hypotensive Olanzapine (not first choice) Dosing: 10 mg SL 1⫻ Severe Treatment of SS Early recognition of SS is crucial. If a patient is taking multiple agents that can cause SS, clinicians should counsel him or her on the signs and symptoms of SS. The treatment of SS is summarized in Table 4. First-line treatment includes withdrawal of the serotonergic drugs. Benzodiazepines, such as diazepam, can be used to control agitation in mild, moderate, and severe cases. Mild cases are typically managed by supportive care, withdrawal of causative agents, and treatment with benzodiazepines.1 Moderate cases include cardiorespiratory and thermal abnormalities, and these patients may benefit from an antidote such as cyproheptadine. Cyproheptadine is a 5-HT2A antagonist; however, evidence is inconclusive on its effectiveness in SS. Cyproheptadine is available only in oral form, but tablets may be crushed and administered via a nasogastric tube.1 Chlorpromazine or olanzapine can also be used, but they have adverse and toxic effects. Chlorpromazine can cause hypotension, lower the seizure threshold, and cause dystonic reactions.18,26 Olanzapine has a potential to lower the seizure threshold as well. Severe cases caused by hyperthermia may require intubation, neuromuscular paralysis, and sedative agents.25 Antipyretic agents do not help with hyperthermia in these cases, because hyperthermia in SS is caused by muscle Above therapies Cooling blankets Muscle relaxants (dantrolene) Paralysis (vecuronium) Intubation Sedative agents Abbreviations: IM, intramuscularly; NG, nasogastric; PO, by mouth; SL, sublingual. a Based on data from references 1, 2, 7, 10, 18, and 25 to 27. hypermetabolism and not by central nervous system effects. Muscle relaxants can be used for muscle rigidity and hyperthermia caused by SS; however, the use is controversial, because no controlled trials support it.1,10,28 In severe cases, nondepolarizing agents, such as vecuronium, can be used in conjunction with intubation and ventilation. 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