Savvy Psychopharmacology

Serotonin syndrome: How to keep your patients safe

Justine E. Zick, PharmD, Suzanne S. Rettey, PharmD, MPA, Elizabeth A. Cunningham, DO, FAPA, and Christopher J. Thomas, PharmD, BCPS, BCPP

r. S, age 55, comes to your clinic the treatment team decides to send Mr. S to as a walk-in for management of urgent care for closer monitoring. M major depressive disorder, insom- nia, and . He also has tobacco use syndrome is a drug-induced disorder and . Several days ago, syndrome caused by overstimulation of Mr. S had visited the clinic because he was serotonin receptors. The syndrome is char- continuing to experience depressive symp- acterized by a classic clinical triad consisting Vicki L. Ellingrod, toms, so his sertraline was increased from of mental status changes, autonomic hyper- PharmD, FCCP 100 to 200 mg/d. His current regi- activity, and neuromuscular abnormalities. Department Editor men includes sertraline 200 mg/d, The clinical presentation is highly variable, 100 mg/d, lisinopril 10 mg/d, and sumatrip- and the severity ranges from mild to life- tan, 100 mg as needed for . He says threatening.1-3 The incidence and preva- last week he used 4 or 5 doses of lence of has not been because he experienced several migraines. well defined.3 Serotonin syndrome may be Mr. S also reports occasionally taking 2 tab- underreported because mild cases are often lets of trazodone instead of 1 on nights that overlooked due to nonspecific symptoms. he has trouble falling asleep. In addition, lack of physician awareness of Today, Mr. S presents with a low-grade drug–drug interactions, signs and symp- fever, diarrhea, internal restlessness, and a toms, and differential diagnoses may result racing heartbeat that started shortly after in underdiagnosis or misdiagnosis.1-3 his last visit. During physical examination, he exhibits slow, continuous lateral eye move- What causes it? ments. His vital signs are markedly elevated: Serotonin syndrome is usually a conse- blood pressure, 175/85 mm Hg; heart rate, quence of a drug–drug interaction between 110 beats per minute; and temperature, 2 or more agents.4 Serotonin 39°C (102.2°F). Based on his presentation, syndrome may result following medication

Dr. Zick is a PGY-2 Psychiatric Pharmacy Resident, Chillicothe VA Medical Center, Chillicothe, Ohio. Dr. Rettey is a PGY-2 Psychiatric Practice Points Pharmacy Resident, Chillicothe VA Medical Center, Chillicothe, Ohio. Dr. • Recognize the clinical manifestations Savvy Psychopharmacology Cunningham is Psychiatrist, Community Health Network, Indianapolis, of serotonin syndrome, which is produced in partnership Indiana. Dr. Thomas is Director, PGY-1 and PGY-2 Residency Programs, with the College Clinical Pharmacy Specialist in Psychiatry, Chillicothe Veterans Affairs may include agitation, diaphoresis, of Psychiatric Medical Center, Clinical Associate Professor of Pharmacology, Ohio hyperthermia, hyperreflexia, and clonus. and Neurologic University College of Osteopathic Medicine, Chillicothe, Ohio. Pharmacists • Act quickly and provide supportive cpnp.org Disclosures care for patients whom you suspect are mhc.cpnp.org (journal) This material is the result of work supported with resources and the use of facilities at the Chillicothe Veterans Affairs Medical Center in experiencing serotonin syndrome. Chillicothe, Ohio. The authors report no financial relationships with any company whose products are mentioned in this article, or with • Practice safe prescribing and minimize manufacturers of competing products. The content of this article does concomitant use of multiple Current Psychiatry not represent the view of the Department of Veteran’s Affairs of the serotonergic agents. 38 July 2019 US Government. Savvy Psychopharmacology

Table 1 associated with serotonin syndrome Class Medication(s) Mechanism of action Selective serotonin reuptake inhibitors, Serotonin reuptake inhibition serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants inhibitors Serotonin metabolism inhibition Trazodone Serotonin reuptake inhibition, serotonin receptor agonism Serotonin receptor agonism , , , , Serotonin receptor agonism , sumatriptan, Anxiolytics Serotonin receptor agonism Clinical Point Antiemetics , , Serotonin reuptake inhibition Many of the Herbal St. John’s wort Serotonin metabolism inhibition, supplements serotonin reuptake inhibition symptoms of Opioids Buprenorphine, methadone, meperidine, Serotonin reuptake inhibition serotonin syndrome tapentadol, are nonspecific, and , valproic acid Serotonin receptor agonism the severity varies Illicit substances 3,4-methylenedioxymethamphetamine, Increased release of serotonin methamphetamine, cocaine from mild to Source: References 2-5 life-threatening

misuse, overdose, initiation of a serotonergic neurons, where it can be metabolized by agent, or increase in the dose of a currently the monoamine oxidase enzyme. Finally, prescribed serotonergic agent.3,4 In addition the metabolites are excreted in the urine. to medication classes and specific agents, Serotonin syndrome results when this regu- Table 12-5 lists the drug mechanisms associ- latory system is disrupted due to hyper- ated with serotonin syndrome: stimulation of the postsynaptic serotonin • inhibition of serotonin reuptake receptors, mainly via agonism of the 5-HT2A • inhibition of serotonin metabolism and 5-HT1A receptors.1,4,5 • increased serotonin synthesis • agonism of the serotonin receptor. A nonspecific presentation The amount of serotonergic activity most Unfortunately, many of the symptoms of likely to cause serotonin syndrome is unclear.4 serotonin syndrome are nonspecific, and the severity varies among patients.2,3 The onset Pathophysiology. Serotonin, also known as of symptoms usually occurs within 6 to 8 5-hydroxytryptamine (5-HT), is a metabolite hours after ingestion of a serotonergic agent.5 of the amino acid . This neuro­ It is important to immediately recognize the transmitter is located in both the CNS and symptoms (Table 2,2-5 page 40) and formulate the periphery. Regulation of the serotonergic a differential diagnosis because sudden pro- Discuss this article at system begins in the presynaptic neurons gression of symptoms is common and may www.facebook.com/ MDedgePsychiatry with decarboxylation and hydroxylation of lead to life-threatening circumstances.1,3 tryptophan resulting in serotonin synthesis. In mild cases of serotonin syndrome, Once serotonin is produced, it is released patients may have a low-grade fever or be into the synaptic cleft, where it binds to sero- afebrile. Hyperthermia tends to be present tonin receptors.1,4,5 After receptor binding, in moderate and severe cases, with tempera- Current Psychiatry serotonin reuptake occurs in the presynaptic tures >41°C (105.8°F) during life-threatening Vol. 18, No. 7 39 Savvy Psychopharmacology

Table 2 Clinical presentation of serotonin syndrome Autonomic Neuromuscular Serious Altered mental status dysfunction abnormalities complications Agitation Hypertension Tremor Rhabdomyolysis Confusion Tachycardia Clonus Myoglobinuria Anxiety Diaphoresis Hyperreflexia Metabolic acidosis Restlessness Hyperthermia Muscle rigidity Renal failure Excitement Nausea Akathisia Respiratory failure Delirium Vomiting Coma Diarrhea Death Mydriasis Clinical Point Source: References 2-5 First review the patient’s medication cases. Diaphoresis and tachycardia may be the patient’s medication history, specifi- history, specifically present regardless of severity. Additional cally taking into account any recent expo- taking into account autonomic irregularities include hyperten- sure to serotonergic agents.3,5 It is important any recent exposure sion, tachypnea, nausea, vomiting, diarrhea, to ask about prescription medications as and hyperactive bowel sounds. In terms of well as over-the-counter products, herbal to serotonergic neuromuscular abnormalities, hyperreflexia supplements, and illicit substances.1,4 When agents is a primary concern, as well as myoclonus. reviewing the medication history, investi- As the severity progresses to life-threatening, gate whether there may have been a recent the clonus may convert from inducible to change in therapy with serotonergic agents. spontaneous and slow, continuous lateral Also, determine when the patient’s symp- eye movements may be present. Additional toms began in relation to exposure to sero- neuromuscular symptoms include tremor, tonergic agents.4 akathisia, and muscle rigidity.1,3-5 After the medication review, conduct a Common mental status changes during thorough physical and neurologic examina- mild cases include restlessness and anxi- tion to identify current symptoms and sever- ety. Abnormal mentation during moderate ity.1,3 No specific laboratory test is available cases may present as increased hypervigi- to definitively confirm the diagnosis of sero- lance and agitation, and this may advance tonin syndrome.1,4 Monitoring of serum sero- to delirium or coma in severe cases. As the tonin is not recommended because the levels severity intensifies, the risk of develop- do not correlate with symptom severity.3 ing additional physiological complications The recommended diagnostic tool is the also increases. Rhabdomyolysis may occur Hunter Serotonin Toxicity Criteria (Figure,1,3 due to muscle damage and myoglobinuria page 41).3,4 Historically, the Sternbach’s secondary to hyperreflexia, myoclonus, Diagnostic Criteria for serotonin syndrome hypertonicity, and muscle rigidity. Muscle were used for diagnosis; however, the Hunter breakdown may then progress to further Serotonin Toxicity Criteria are more sensitive complications, such as renal failure. In rare (96% vs 75%) and more specific (97% vs 84%) instances, serotonin syndrome can result in than the Sternbach’s Diagnostic Criteria for seizures or death.1,3-5 serotonin syndrome.1,3-5 In addition to using the proper diagnos- Medication history tips off tic tool, conduct a differential diagnosis to the diagnosis rule out other drug-induced syndromes, The first step in diagnosing serotonin syn- such as anticholinergic toxidrome, neuro- Current Psychiatry 40 July 2019 drome is to conduct a thorough review of leptic malignant syndrome, or malignant Savvy Psychopharmacology

hyperthermia.1,3,5 Autonomic instability, Figure including hypertension, tachycardia, tachy- Hunter Serotonin Toxicity Criteria pnea, and hyperthermia, may be present in all of the aforementioned drug-induced Exposure to a serotonergic agent 1 syndromes. As a result, the clinician must within the last 5 weeks monitor for other symptoms that may dif- ferentiate the disease states to establish a clear diagnosis. Presence of any of the following symptoms: Discontinue agents, offer 1) Spontaneous clonus supportive care 2) Tremor and hyperreflexia 3) Ocular clonus and either agitation There are no official published guide- or diaphoresis lines for managing serotonin syndrome.5 4) Inducible clonus and either Clinical Point Regardless of the severity of a patient’s agitation or diaphoresis 5) Muscle rigidity, temperature Regardless of the presentation, all serotonergic agents should >38°C (100.4°F), and either ocular severity of a patient’s be discontinued immediately. In addition, clonus or inducible clonus supportive care should be initiated for presentation, symptom management. Intravenous fluid all serotonergic replacement is recommended for hydration agents should and to treat hyperthermia. External cooling Confirmation of serotonin syndrome be discontinued may also be warranted to reduce body tem- peratures. Vital signs should be stabilized Source: References 1,3 immediately with appropriate pharmacotherapy.1,3-5 Benzodiazepines are considered a main- stay for relief of agitation during serotonin syndrome of any severity. In life-threatening with are sedation and anti- cases—which are characterized by hyper- cholinergic adverse effects.1,4,6 thermia >41°C (105.8°F)—sedation, paral- Antipsychotics, such as and ysis, and intubation may be necessary to , have been considered treat- maintain the airway, breathing, and circula- ment alternatives due to their associated tion.1,3-5 Because treatment of hyperthermia 5-HT2A receptor antagonism. However, requires elimination of hyperreflexia, paral- there is limited data supporting such use.1,4 ysis is recommended.1 Nondepolarizing Antipsychotics should be used with caution neuromuscular blocking agents, such as because neuroleptic malignant syndrome vecuronium, are preferred over depolariz- may be mistaken for serotonin syndrome. ing agents due to their decreased potential Use of antipyretics is not recommended for for rhabdomyolysis.1,3 treating fever and hyperthermia because the Cyproheptadine, a histamine-1 receptor increase in body temperature is secondary antagonist and a 5-HT2A receptor antago- to excessive muscle activity rather than dys- nist, is recommended for off-label treatment function of the hypothalamic temperature of serotonin syndrome to help decrease the set point.1,3,5 Physical restraints are also not intensity of symptoms. This should be ini- recommended because their use may pro- tiated as a single dose of 12 mg followed voke further hyperthermia and increase the by 2 mg every 2 hours until symptoms risk of rhabdomyolysis.3,5 improve.1,3,5 After stabilization, a maintenance Ultimately, the duration of treatment dose of 8 mg every 6 hours is recommended. will be influenced by the Doses should not exceed the maximum rec- of the serotonergic agents that induced the ommended dose of 0.5 mg/kg/d.1,3,6 The serotonin syndrome. Following resolution, Current Psychiatry most common adverse reactions associated retrial of the offending serotonergic agents Vol. 18, No. 7 41 Savvy Psychopharmacology

CASE CONTINUED Related Resource Upon further assessment in urgent care, • Turner AH, Kim JJ, McCarron RM. Differentiating serotonin Mr. S is found to have muscle rigidity in syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36. addition to ocular clonus and a temperature >38°C (100.4°F). Because Mr. S’s symptoms Drug Brand Names coincide with a recent increase of sertraline Almotriptan • Axert Metoclopramide • Reglan Buprenorphine • Subutex Mirtazapine • Remeron and increased use of both trazodone and • Wellbutrin, Naratriptan • Amerge sumatriptan, he meets Hunter Serotonin Zyban Olanzapine • Zyprexa Buspirone • BuSpar Ondansetron • Zofran Toxicity Criteria. Therefore, his symptoms Carbamazepine • Carbatrol, Rizatriptan • Maxalt are likely related to excessive increase in Tegretol Sertraline • Zoloft serotonergic activity. Mr. S is admitted to the Chlorpromazine • Thorazine Sumatriptan • Imitrex tablets Cyproheptadine • Periactin Tapentadol • Nucynta hospital for closer monitoring, and his ser- Clinical Point Eletriptan • Relpax Tramadol • Conzip traline, trazodone, and sumatriptan are held. Frovatriptan • Frova Trazodone • Desyrel, Oleptro He receives IV fluids for several days as well Granisetron • Kytril Valproic acid • Depakene, Patients with Lisinopril • Prinivil, Zestril Depakote as cyproheptadine, 8 mg every 6 hours after Meperidine • Demerol Vecuronium • Norcuron stabilization, until his symptoms resolve. multiple Methadone • Dolophine, Zolmitriptan • Zomig On Day 4, Mr. S no longer experiences diar- comorbidities that Methadose rhea and internal restlessness. His vital signs result in treatment return to normal, and as a result of symptom with multiple resolution, he is discharged from the hospi- serotonergic agents tal. The treatment team discusses changing should be carefully assessed. A retrial should his medication regimen to avoid multiple are at highest risk only be considered after an adequate wash- serotonergic agents. Mr. S is switched from out period has been observed, and clinicians sertraline to bupropion XL, 150 mg/d. should consider utilizing lower doses.2,5 Sumatriptan, 100 mg/d as needed, is contin- ued for acute . Trazodone Take steps for prevention is discontinued and replaced with melato- Patients at highest risk of developing sero- nin, 3 mg/d. The team also counsels Mr. S on tonin syndrome are those who have multiple the importance of proper adherence to his comorbidities that result in treatment with medication regimen. He is advised to return multiple serotonergic agents.3 Clinicians to the clinic in 2 weeks for reassessment of and patients alike need to be educated about safety and efficacy. the signs and symptoms of serotonin syn- References drome to promote early recognition. Also 1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. consider modifying your prescribing prac- 2005;352(11):1112-1120. 2. Beakley BD, Kaye AM, Kaye AD. Tramadol, pharmacology, tices to minimize the use of multiple sero- , and serotonin syndrome: a review. Pain Physician. tonergic agents. When switching between 2015;18(4):395-400. serotonergic agents, institute safe washout 3. Wang RZ, Vashistha V, Kaur S, et al. Serotonin syndrome: preventing, recognizing, and treating it. Cleve Clin J Med. periods. Encourage patients to adhere to 2016;83(11):810-817. their prescribed medication regimens. Using 4. Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017;37(1):49-54. electronic ordering systems can help detect 5. Frank C. Recognition and treatment of serotonin syndrome. drug–drug interactions.1,3 Prophylaxis with Can Fam Physician. 2008;54(7):988-992. 6. Cyproheptadine hydrochloride tablets [package insert]. cyproheptadine may be considered in high- Hayward, CA: Impax Generics; 2017. risk patients; however, no clinical trials have 7. Deardorff OG, Khan T, Kulkarni G, et al. Serotonin been conducted to evaluate using cyprohep- syndrome: prophylactic treatment with cyproheptadine. Prim Care Companion CNS Disord. 2016;18(4). doi: 10.4088/ tadine to prevent serotonin syndrome.7 PCC.16br01966.

Current Psychiatry 42 July 2019