Serotonin Syndrome: Preventing, Recognizing, and Treating It
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REVIEW ROBERT Z. WANG, MD VISHAL VASHISTHA, MD SUKHDEEP KAUR, MBBS NATHAN W. HOUCHENS, MD Department of Family Medicine, Department of Internal Medicine, Dayanand Medical College and Department of Internal Medicine, State University of New York Downstate Cleveland Clinic Hospital, Ludhiana, India University of Michigan, Ann Arbor Medical Center, Brooklyn Serotonin syndrome: Preventing, recognizing, and treating it ABSTRACT ith a substantial increase in antide- W pressant use in the United States over the As the use of serotonergic agents to treat depression last 2 decades, serotonin syndrome has become has increased, so too has the incidence of serotonin an increasingly common and signifi cant clini- syndrome. We identify the common agents implicated in cal concern. In 1999, 6.5% of adults age 18 and serotonin syndrome and the clinical tools to diagnose, older were taking antidepressants; by 2010, the manage, and prevent serotonergic toxicity. percentage had increased to 10.4%.1 Though the true incidence of serotonin syndrome is dif- KEY POINTS fi cult to determine, the number of ingestions of Serotonin syndrome is caused by elevated serotonin lev- selective serotonin reuptake inhibitors (SSRIs) els in the central and peripheral nervous systems. associated with moderate to major effects re- ported to US poison control centers increased from 7,349 in 20022 to 8,585 in 2005.3 The classic presentation is the triad of autonomic dys- Though the clinical manifestations are of- function, neuromuscular excitation, and altered mental ten mild to moderate, patients with serotonin status. These symptoms vary based on the severity of syndrome can deteriorate rapidly and require serotonergic toxicity and often do not present concomi- intensive care. Unlike neuroleptic malignant tantly. syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic re- Early recognition is critical to ensure appropriate resusci- action to medication, but rather a progression of serotonergic toxicity based on increasing tative measures and to limit further use of drugs that can concentration levels that can occur in any pa- exacerbate symptoms. tient regardless of age.4 Because it has a nonspecifi c prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or ex- acerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome. ■ WHAT IS SEROTONIN SYNDROME? Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromus- cular excitation, and altered mental status. doi:10.3949/ccjm.83a.15129 These symptoms are a result of increased se- 810 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 11 NOVEMBER 2016 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. WANG AND COLLEAGUES TABLE 1 Drug mechanisms associated with serotonin syndrome Mechanism Specifi c agents Decreased serotonin Monoamine oxidase inhibitorsa: phenelzine, tranylcypromine, isocarboxazid, moclobemide, breakdown selegiline, rasagiline Antibiotics: linezolid, tedizolid Others: methylene blue, procarbazine, Syrian rue Decreased serotonin Antidepressants: reuptake Selective serotonin reuptake inhibitorsa : fl uoxetine, fl uvoxamine, paroxetine, citalopram, sertraline, escitalopram Serotonin-norepinephrine reuptake inhibitorsa: venlafaxine, duloxetine, milnacipran Tricyclic antidepressantsa: clomipramine, imipramine St. John’s wort Opioidsa: meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan Antiepileptics: valproate, carbamezapine Antiemetics: ondansetron, granisetron, metoclopramide Increased serotonin Tryptophan, lithium, fentanyl, lysergic acid diethylamide (LSD) precursors or agonists Increased serotonin Central nervous system stimulants: amphetaminesa release Anorecticsa: fenfl uramine, dexfenfl uramine, phentermine Drugs of abuse: methylenedioxymethamphetamine (ecstasy),a cocaine CYP2D6 and CYP3A4 Antibiotics: erythromycin, ciprofl oxacin inhibitors Antifungal: fl uconazole Antiretroviral: ritonavir a Confi rmed to precipitate serotonin syndrome. The others have not been reliably confi rmed and are based on case reports or expert opinion. rotonin levels affecting the central and pe- (MAOIs), linezolid,6 methylene blue, procar- ripheral nervous systems. Serotonin affects a bazine, and Syrian rue. family of receptors that has seven members, of Drugs that decrease serotonin reup- which 5-HT1A and 5-HT2A are most often take include SSRIs, serotonin-norepineph- responsible for serotonin syndrome.5 rine reuptake inhibitors (SNRIs), tricyclic Conditions that can alter the regulation of antidepressants, opioids (meperidine, bu- serotonin include therapeutic doses, drug in- prenorphine, tramadol, tapentadol, dextro- teractions, intentional or unintentional over- methorphan), antiepileptics (carbamazepine, doses, and overlapping transitions between valproate), and antiemetics (ondansetron, medications. As a result, drugs that have been granisetron, metoclopramide), and the herbal associated with serotonin syndrome can be preparation St. John’s wort. classifi ed into the following fi ve categories as Drugs that increase serotonin precursors shown below and in Table 1: or agonists include tryptophan, lithium, fen- Drugs that decrease serotonin break- tanyl, and lysergic acid diethylamide (LSD). down include monoamine oxidase inhibitors Drugs that increase serotonin release in- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 11 NOVEMBER 2016 811 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. SEROTONIN SYNDROME TABLE 2 Spectrum of symptoms of serotonergic toxicity Severity Neuromuscular excitation Altered mental status Autonomic dysfunction Mild Hyperrefl exia Anxiety Diaphoresis Tremor Restlessness Mydriasis Myoclonus Insomnia Tachycardia Moderate Opsoclonus Agitation Hypertension Spontaneous or inducible clonus Hyperthermia (< 40°C, < 104°F) Hyperactive bowel sounds Diarrhea, nausea, vomiting Severe Rigidity Coma Severe hyperthermia Respiratory failure Delirium (≥ 40°C, ≥ 104°F) Tonic-clonic seizure Confusion Dynamic blood pressure clude fenfl uramine, amphetamines, and meth- adults and non-Hispanic whites.1,12,13 Intui- ylenedioxymethamphetamine (ecstasy). tively, as the risk for depression increases dra- Drugs that prevent breakdown of the matically in patients with chronic medical agents listed above are CYP2D6 and CYP3A4 conditions, serotonin syndrome should be inhibitors, eg, erythromycin,7 ciprofl oxacin, more prevalent among the elderly. In addi- fl uconazole, ritonavir, and grapefruit juice. tion, patients with multiple comorbidities Serotonin However, the only drugs that have been take more medications, increasing the risk of 14 syndrome reliably confi rmed to precipitate serotonin polypharmacy and adverse drug reactions. syndrome are MAOIs, SSRIs, SNRIs, and Although the epidemiology of serotonin can easily serotonin releasers. Other listed drug interac- syndrome has yet to be extensively studied, be overlooked, tions are based on case reports and have not the combination of age and comorbidities may been thoroughly evaluated.6–9 increase the risk for this condition. misdiagnosed, Currently, SSRIs are the most commonly or exacerbated prescribed antidepressant medications and, ■ HOW DOES IT PRESENT? consequently, they are the ones most often if not carefully 1,10 Serotonin syndrome characteristically pres- implicated in serotonergic toxicity. An es- ents as the triad of autonomic dysfunction, assessed timated 15% of SSRI overdoses lead to mild 11 neuromuscular excitation, and altered mental or moderate serotonin toxicity. Serotonergic status. However, these symptoms may not oc- agents used in conjunction can increase the cur simultaneously: autonomic dysfunction is risk for severe serotonin syndrome; an SSRI present in 40% of patients, neuromuscular ex- and an MAOI in combination poses the great- 5 citation in 50%, and altered mental status in est risk. 40%.15 The symptoms can range from mild to Ultimately, the incidence of serotonin syn- life-threatening (Table 2).16 drome is diffi cult to assess, but it is believed to Autonomic dysfunction. Diaphoresis is be underreported because it is easy to misdiag- present in 48.8% of cases, tachycardia in 44%, nose and mild symptoms may be dismissed. nausea and vomiting in 26.8%, and mydriasis ■ in 19.5%. Other signs are hyperactive bowel WHO IS AT RISK sounds, diarrhea, and fl ushing.16 OF SEROTONIN SYNDROME? Neuromuscular excitation. Myoclonus is Long-term antidepressant use has dispropor- present in 48.8%, hyperrefl exia in 41%, hy- tionately increased in middle-aged and older perthermia in 26.8%, and hypertonicity and 812 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 11 NOVEMBER 2016 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. WANG AND COLLEAGUES Currently on serotonergic agent or within washout period? No Yes Not serotonin syndrome Is at least one of the following fi ve conditions present? 1 Spontaneous clonus 2 Inducible clonus and Agitation or diaphoresis 3 Ocular clonus and Agitation or diaphoresis 4 Inducible clonus and Hypertonia and or ocular clonus hyperthermia 5 Tremor and Hyperrefl exia No Yes Not