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Home , Clonus, Myoclonus

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, 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 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-

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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, , escitalopram Serotonin-norepinephrine reuptake inhibitorsa: venlafaxine, duloxetine, milnacipran Tricyclic antidepressantsa: , imipramine St. John’s wort Opioidsa: meperidine, buprenorphine, , tapentadol, dextromethorphan Antiepileptics: , carbamezapine Antiemetics: ondansetron, granisetron, metoclopramide

Increased serotonin Tryptophan, , fentanyl, lysergic acid diethylamide (LSD) precursors or agonists

Increased serotonin Central 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, (meperidine, bu- serotonin include therapeutic doses, drug in- prenorphine, tramadol, tapentadol, dextro- teractions, intentional or unintentional over- methorphan), antiepileptics (, 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-

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TABLE 2 Spectrum of symptoms of serotonergic toxicity

Severity Neuromuscular excitation Altered mental status Autonomic dysfunction

Mild Hyperrefl exia Diaphoresis Restlessness Mydriasis Insomnia Tachycardia

Moderate Agitation Hypertension Spontaneous or inducible 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 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

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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 serotonin syndrome Serotonin syndrome FIGURE 1. Algorithm for clinical diagnosis of serotonin based on Hunter serotonin toxicity criteria (based on information in reference 9). rigidity in 19.5%. Other signs are spontaneous veal use of ecstasy or combined treatment or inducible clonus, ocular clonus (continuous with serotonin-potentiating agents such as rhythmic oscillations of gaze), and tremor. an antidepressant with a proserotonergic opi- Altered mental status. Confusion is pres- oid, antiepileptic, or CYP2D6 or CYP3A4 ent in 41.2% and agitation in 36.5%. Other inhibitor.15 Severe signs are anxiety, lethargy, and coma. Severe serotonin toxicity is a life-threat- serotonin Symptoms of serotonin toxicity arise with- ening condition that can lead to multiorgan in an hour of a precipitating event (eg, inges- failure within hours. It can be characterized toxicity is a tion) in approximately 28% of patients, and by muscle rigidity, which can cause the body life-threatening within 6 hours in 61%.16 Highly diagnostic temperature to elevate rapidly to over 40°C. features include hyperrefl exia and induced or This hypertonicity can mask the classic and condition that spontaneous clonus that are generally more diagnostic signs of hyperrefl exia and clonus. can lead to pronounced in the lower limbs.11 Clonus can Patients may have unstable and dynamic vital multiorgan be elicited with ankle dorsifl exion. signs with confusion or delirium and can ex- In mild toxicity, patients may present perience tonic-clonic . failure with tremor or twitching and anxiety, as well If the muscle rigidity and resulting hyper- within hours as with hyperrefl exia, tachycardia, diaphore- thermia are not managed properly, patients sis, and mydriasis. Further investigation may can develop cellular damage and enzyme uncover a recently initiated antidepressant or dysfunction leading to rhabdomyolysis, myo- a cold-and-cough medication that contains globinuria, renal failure, metabolic acidosis, dextromethorphan.15,17 acute respiratory distress syndrome, and dis- In moderate toxicity, patients present in seminated intravascular coagulation.16,18 signifi cant distress, with agitation and rest- Serotonin crisis is usually caused by the co- lessness. Features may include hyperrefl exia ingestion of multiple serotonergic agents, such and clonus of the lower extremities, opsoc- as an antidepressant with an aforementioned lonus, hyperactive bowel sounds, diarrhea, and antiemetic19; combining an SSRI nausea, vomiting, tachycardia, hypertension, and an MAOI poses the greatest risk. Alter- diaphoresis, mydriasis, and hyperthermia (< natively, patients may have recently switched 40°C, 104°F). The patient’s history may re- antidepressants without observing a safe wash-

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TABLE 3 Differential diagnosis of serotonin syndrome

Neuroleptic Serotonin syndrome malignant syndrome toxicity

Causative agent Serotonergic agent Dopamine antagonist Anticholinergic agent Withdrawal from dopa- mine agonist

Onset Within 24 hours Within days to weeks Within 1–2 hours

Resolution Within 24 hours In approximately 9 days Within hours to days

Features similar to — Hyperthermia Mydriasis those of serotonin Altered mental state Hyperthermia syndrome Diaphoresis Agitation, delirium Autonomic instability Visual hallucinations

Distinct features Myoclonus Bradyrefl exia Dry skin and mucous Hyperrefl exia Lead pipe rigidity membranes Mydriasis Extrapyramidal features Urinary retention Tremor Absence of neuromuscu- Decreased bowel Diarrhea lar excitation sounds Nausea, vomiting Normal muscle tone and refl exes

The Hunter out period, leading to an overlap of serotonin pertonia and hyperthermia criteria are levels.16 • Tremor plus hyperrefl exia. more sensitive The Sternbach criteria. The patient must ■ and specifi c HOW DO WE DIAGNOSE SEROTONIN be using a serotonergic agent, must have no SYNDROME? other causes of symptoms, must not have re- than the Serotonin syndrome is a clinical diagnosis cently used a neuroleptic agent, and must Sternbach and therefore requires a thorough review of have three of the following: criteria medications and physical examination. Serum • Mental status changes serotonin levels are an unreliable indicator • Agitation of toxicity and do not correlate well with the • Hyperrefl exia clinical presentation.16 • Myoclonus Currently, there are two clinical tools for • Diaphoresis diagnosing serotonin syndrome: the Hunter • Shivering serotonin toxicity criteria (Figure 1) and the • Tremor Sternbach criteria. • Diarrhea The Hunter criteria are based more heav- • Incoordination ily on physical fi ndings. The patient must • Fever. have taken a serotonergic agent and have one The Hunter criteria are recommended of the following: and are more specifi c (97% vs 96%) and more • Spontaneous clonus sensitive (84% vs 75%) than the Sternbach • Inducible clonus plus agitation or diapho- criteria when compared with the gold stan- resis dard of diagnosis by a clinical toxicologist.1 • Ocular clonus plus agitation or diaphoresis The Hunter criteria are also less likely to yield • Inducible clonus or ocular clonus, plus hy- false-positive results.11

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Differential diagnosis atic treatment with a and The differential diagnosis for serotonin syn- nonserotonergic antiemetics is recommended, drome includes neuroleptic malignant syn- and standard cooling measures should be im- drome, anticholinergic poisoning (Table 3), plemented for hyperthermia. Patients should metastatic carcinoma, be admitted and observed for 12 to 24 hours infection, gastroenteritis, and sepsis. to prevent exacerbation. Neuroleptic malignant syndrome, the For severe serotonin toxicity, treat- disorder most often misdiagnosed as serotonin ment should focus on management of airway, syndrome, is an idiosyncratic reaction to a do- breathing, and circulation—ie, the “ABCs.” pamine antagonist (eg, haloperidol, fl uphen- The two primary life-threatening concerns are azine) that develops over days to weeks.20 In hyperthermia (temperature > 40°C or 104°F) 70% of patients, agitated delirium with confu- and rigidity, which can lead to hypoventila- sion appears fi rst, followed by lead pipe rigidity tion.1,22 Controlling hyperthermia and rigid- and cogwheel tremor, then hyperthermia with ity can prevent other grave complications. body temperature greater than 40°C, and fi - Patients with severe serotonin toxicity should nally, profuse diaphoresis, tachycardia, hyper- be sedated, paralyzed, and intubated.21 This tension, and tachypnea.21 will reverse ventilatory hypertonia and allow Key elements that distinguish neuroleptic for mechanical ventilation. Paralysis will also malignant syndrome are the timeline of the prevent the exacerbation of hyperthermia, clinical course, bradyrefl exia, and the absence which is caused by muscle rigidity. Antipyret- of clonus. Prodromal symptoms of nausea, ics have no role in the treatment of serotonin vomiting, and diarrhea are also rare in neuro- syndrome since the hyperthermia is not caused leptic malignant syndrome. Neuroleptic ma- by a change in the hypothalamic temperature lignant syndrome typically requires an average set point.21 Standard cooling measures should of 9 days to resolve. be used to manage hyperthermia. Anticholinergic poisoning usually de- Serotonin antagonists velops within 1 to 2 hours of oral ingestion. Serotonin antagonists have had some success Symptoms include fl ushing, anhidrosis, anhi- Mainstays of in case reports, but further studies are needed drotic hyperthermia, mydriasis, urinary reten- management: to confi rm this.4,23,24 tion, decreased bowel sounds, agitated deliri- Cyproheptadine is a potent 5-HT2A an- stop the um, and visual hallucinations. In contrast to tagonist; patients usually respond within 1 to serotonergic serotonin syndrome, refl exes and muscle tone 2 hours of administration. Signs and symp- are normal with anticholinergic poisoning. toms have resolved completely within times agent and give ranging from 20 minutes to 48 hours, depend- ■ HOW CAN WE TREAT supportive care ing on the severity of toxicity. SEROTONIN SYNDROME? The recommended initial dose of cypro- The two mainstays of serotonin syndrome heptadine is 12 mg, followed by 2 mg every management are to discontinue the seroto- 2 hours if symptoms continue.16 Maintenance nergic agent and to give supportive care. Most dosing with 8 mg every 6 hours should be pre- patients improve within 24 hours of stopping scribed once stabilization is achieved. The to- the precipitating drug and starting therapy.16 tal daily dose for adults should not exceed 0.5 For mild serotonin syndrome, treatment mg/kg/day. Cyproheptadine is available only involves discontinuing the offending agent in oral form but can be crushed and adminis- and supportive therapy with intravenous fl u- tered via a nasogastric tube.21 ids, correction of vital signs, and symptom- Chlorpromazine is a 5-HT1A and 5-HT2A atic treatment with a benzodiazepine. Patients antagonist and can be given intramuscularly. should be admitted and observed for 12 to 24 Despite case reports citing its effectiveness, the hours to prevent exacerbation. risk of hypotension, dystonic reactions, and For moderate serotonin syndrome, treat- neuroleptic malignant syndrome may make it ment also involves stopping the serotonergic a less desirable option.4,25 agent and giving supportive care. Symptom- Cyproheptadine, chlorpromazine, and other

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serotonin receptor antagonists require further As use of antidepressants among an ag- investigation beyond individual case reports to ing population continues to increase, and as determine their effectiveness and reliability in physicians in multiple disciplines prescribe treating serotonin syndrome. them for evolving indications (eg, duloxetine Other agents to treat osteoarthritis, diabetic neuropathy, are considered a mainstay for fi bromyalgia, and chemotherapy-induced pe- symptomatic relief because of their anxiolytic ripheral neuropathy), healthcare providers and muscle relaxant effects.26 However, animal need to be prepared to see more cases of sero- studies showed that treatment with benzodiaz- tonin syndrome and its deleterious effects.29–31 epines attenuated hyperthermia but had no ef- Physicians should be vigilant in minimizing fect on time to recovery or outcome.27 unnecessary use of serotonergic agents and re- Neuromuscular blocking agents. The viewing drug regimens regularly to limit poly- suggested neuromuscular blocking agent for pharmacy. severe toxicity is a nondepolarizing agent such Electronic ordering systems should be de- as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis signed to detect and alert the prescriber to and hyperkalemia.21 possible interactions that can potentiate se- Dantrolene has also been suggested for its rotonin syndrome, and to not place the or- muscle-relaxing effects and use in malignant der until the prescriber overrides the alert. hyperthermia. However, this treatment has Combinations of SSRIs and MAOIs have the not been successful in isolated case reports highest risk for inducing severe serotonin syn- and has been ineffective in animal models.4,28 drome and should always be avoided. Physical restraints are ill-advised, since If a patient is transitioning between se- isometric muscle contractions can exacerbate rotonergic agents, physicians should observe hyperthermia and lactic acidosis in agitated 16,32 21 a safe washout period to prevent overlap. patients. If physical restraints are necessary Washout periods may differ among medica- to deliver medications, they should be re- If transitioning tions depending on their half-lives. For exam- moved as soon as possible. between ple, sertraline has a washout period of 2 weeks, serotonergic ■ HOW CAN WE PREVENT while fl uoxetine requires a washout period of 5 SEROTONIN SYNDROME? to 6 weeks.33 Consulting a pharmacist may be agents, observe helpful when considering half-lives and wash- Prevention of serotonin syndrome begins a safe washout with improving education and awareness in out periods. period patients and healthcare providers. Patients We believe that educating both patients should be primarily concerned with taking and physicians regarding prevention will help their medications carefully as prescribed and minimize the risk for serotonergic syndrome recognizing early of sero- and will improve effi ciency in assessment and tonin toxicity. management should toxicity develop. ■ ■ REFERENCES 1. Mojtabai R, Olfson M. National trends in long-term use of anti- ed serotonin toxicity. Ann Pharmacother 2013; 47:388–397. depressant medications: results from the US National Health and 7. Lee DO, Lee CD. Serotonin syndrome in a child associated with Nutrition Examination Survey. J Clin Psychiatry 2014; 75:169–177. erythromycin and sertraline. Pharmacotherapy 1999; 19:894–896. 2. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2002 Annual Report of 8. Gillman PK. Triptans, serotonin agonists, and serotonin syndrome the American Association of Poison Control Centers Toxic Exposure (serotonin toxicity): a review. 2010; 50:264–272. Surveillance System. Am J Emerg Med. 2003;21:353–421. 9. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical 3. Lai MW, Klein-Schwartz W, Rodgers GC, et al. 2005 Annual Report approach to diagnosis and treatment. Med J Aust 2007; 187:361– of the American Association of Poison Control Centers’ national poi- 365. soning and exopsure database. Clin Toxicol (Phila) 2006; 44:803–932. 10. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 4. Gillman PK. The serotonin syndrome and its treatment. J Psycho- Annual Report of the American Association of Poison Control Cen- pharmacol 1999; 13:100–109. ters’ National Poison Data System (NPDS): 31st Annual Report. Clin 5. Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity Toxicol (Phila) 2014; 52:1032–1283. in animals and humans: implications for diagnosis and treatment. 11. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Clin Neuropharmacol 2005; 28:205–214. Hunter serotonin toxicity criteria: simple and accurate diagnostic 6. Woytowish MR, Maynor LM. Clinical relevance of linezolid-associat- decision rules for serotonin toxicity. QJM 2003; 96:635–642.

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