CLINICAL REVIEW Syndrome/Serotonin Cynthia Wright Talton, DNP, FNP-BC

Objective: This review of or serotonin combinations of commonly prescribed used to toxicity covers the years 2014 to 2019, including information treat both veteran and nonveteran patients and includes the on pathophysiology, etiology, and diagnosis, 3 criteria for latest information on offending medications. diagnosing serotonin syndrome, and criteria for neuroleptic Conclusions: Prevention of serotonin toxicity includes malignant syndrome. informed clinicians, patient education, careful prescribing Importance: The review highlights the potential lethal and monitoring, and avoidance of multidrug regimens.

Cynthia Talton is a Nurse erotonin, or 5-hydroxytryptamine This paper reviews the potential lethal Practitioner in the Outpatient (5-HT), is a chemical neurotransmit- combinations of commonly prescribed Mental Health Clinic at the ter in the central and peripheral ner- medications used to treat both veteran and Veterans Affairs Medical S 1 Center in Salem, Virginia. vous systems that was discovered in 1940s. nonveteran patients and includes the lat- Correspondence: One of the most widely studied chemical est information on offending medications; Cynthia Talton ([email protected]) messengers, serotonin influences many a presentation of symptoms from in utero physiologic functions in humans, including to adult; diagnostic criteria; and recom- Fed Pract. 2020;37(10):452-459 regulation of mood, sleep-wake cycle, ap- mended treatments. doi:10.12788/fp.0042 petite suppression, memory, emesis, breath- The Veterans Health Administration ing, cognition, blood coagulation, libido, (VHA) and non-VHA health care providers and many other functions.2 In 1992, Insel can play a key role in identifying and pre- and colleagues first documented the toxic venting serotonin syndrome/ST by keeping symptoms produced from too much sero- abreast of the latest updates of potentially tonin in the central and peripheral nervous lethal drug combinations. Commonly pre- systems, naming it serotonin syndrome.3,4 scribed medications with the potential for a reaction include , anxiolytics, SEROTONIN SYNDROME pain medications, antinausea medications, Experts in the fields of , pharmacy, herbal medications, and over-the-counter and refer to these symptoms as (OTC) medications, such as cough suppres- serotonin toxicity, because the symptoms sants. Patients may be at increased risk for ST result from the toxic effects of too much sero- due to the growth of polypharmacy manage- tonin.5-9 The term toxicity instead of syndrome ment of comorbidities. “clarifies that it is a form of , just as toxicity is a form of poisoning.”6 Antidepressants Therefore, serotonin toxicity (ST) can de- Over the past decade, use velop with administration of any serotonin- has increased substantially in the US, enhancing , including therapeutic United Kingdom, and Canada.14 Also the use, polypharmacy, or accidental/intentional types of antidepressants prescribed has . changed and been replaced with the newer The incidence of ST has increased over agents. The selective serotonin reuptake the past decade.5,6,10,11 Several reasons ex- inhibitors (SSRIs) and selective norepi- plain this increase: (1) ST mirrors the nephrine reuptake inhibitors (SNRIs) have increase in in the US popula- replaced the older tricyclics (TCAs) and tions10,12,13; (2) There has been an increase inhibitors (MAOIs) in off-label antidepressant prescribing by as first-line treatments for depression due both primary care and mental health pro- to their improved comparative efficacy, re- viders14-16; (3) the increased use of illicit duced mortality following overdose, ad- drugs13; (4) an increase in suicide attempts verse effects (AEs) that are more tolerable with antidepressants17; and (5) increased for most patients, and the SSRIs have no use of for pain management, in- properties (except parox- cluding both prescription and illicit use.11,14 etine) (Table 1).18

452 • FEDERAL PRACTITIONER • OCTOBER 2020 mdedge.com/fedprac TABLE 1 Serotonin-Elevating Medications SRIs SGA Opioids Illicit Drugs OTC/Herbals Disputeda

SSRIs Ziprasidone Meperidine MDMA/Ecstasy St. John’s Wort Antidepressants (es) Methadone L- Mirtazepine Ginseng S-adenosyl-L-methionine Antiemetics SNRIs (SAMe) (des) LSD (lysergic acid diethylamide) Chlorpheniramine (levo) Tryptans Brompheniramine TCAs Imipramine

MAOIs Lithium (weak) Isoniazid (weak) Metaxolone (weak)

Abbreviations: LSD, lysergic acid diethylamide; MAOIs, monoamine oxidase inhibitors; MDMA, methylenedioxymethamphetamine; OTC, over-the-counter; SGA, second-generation ; SNRIs, selective reuptake inhibitors; SRI, serotonin reuptake inhibitor; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. aDisputed-experts disagree on these medications causing serotonin syndrome/toxicity because of their mechanisms of action.

In 2017 the National Institute of Mental patient visits in a western portion of the Health reported that about 17 million adults US found 12.9% of the prescriptions filled and 3 million adolescents (aged 11-18 years) were off-label.15 In Minnesota, off-label pre- experienced at least 1 episode of major de- scribing of antidepressants was found to pression.19 About 40% of US veterans will ex- contribute to an increase in drug interac- perience depression, which is 3 times higher tions in elderly nursing home residents.24 than the rate of the general US population.12 An investigation by the Military Times A random sampling survey conducted of of the military community revealed off- about 17,000 active-duty service members by label prescribing occurs not only with an- the US Department of Defense (DoD) from tidepressant medications, but also with an- November 2015 to April 2016 revealed 9.4% ticonvulsants, antipsychotics, anti- reported depression.20 Antidepressant usage drugs, and antiepileptic medications.14 in the US and among veterans continues to A case report that brought ST to the fore- increase.12,16 In 2018, the list of top US pre- front occurred in the 1980s and involved a scribed drugs, included sertraline (14th), college student.25 She was initially diagnosed citalopram (21st), trazodone (24th), and es- with the flu. Her symptoms progressed over a citalopram (26th).21 Antidepressant prescrib- 24-hour period despite treatment, leading to ing in the US increased 18% from 2012 to , , generalized , 2017.22 This trend also continues within the muscle rigidity, respiratory failure, and death military with a 40% increase of antidepres- because of unrecognized ST. Her combina- sant use in the past decade.16 tion of serotonin-elevating drugs included One reason for the increase in antide- meperidine, phenelzine, chlorpheniramine, pressant use is off-label prescribing.14,23 A and haldol. On autopsy, there were traces of sampling of about 2 billion psychiatric out- cocaine found in some of her tissue samples.

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TABLE 2 Drugs Causing Moderate to Severe ST Symtoms4 depression with SSRIs, SNRIs, TCAs, and MAOIs.29 Three of the most studied receptors Drug Classes Drug Combinations include 5-HTIA,5-HT1B, and 5-HT2A.

MAOIs MAOIs + SSRIs or SNRIs or TCAs or Etiology Imipramine + tranylcypromine Phenelzine + meperidine Most serotonin-induced drug fatalities occur Methylene blue + clomipramine or paroxetine when combining drugs that work through different pathways (Table 2).30 SSRIs SSRIs + MAOIs or TCAs or SNRIs or opiates or tryptans The most toxic combination of serotonin- Fluoxetine + or phentermine or fentanyl enhancing drugs includes MAOIs taken SNRIs SNRIs + TCAs or MAOIs or opiates or with SSRIs or SNRIs, or a combination of Fluoxetine + or phentermine or fentanyl 2 MAOIs.5-9 Other potentially lethal combinations may Other antidepressants Mirtazapine + SSRIs Trazodone + amitriptyline + lithium include polypharmacy with antidepressants, pain medications, OTC medications, and il- Opiates Opiates + MAOIs or SSRIs or SNRIs or triptans licit drugs. Linezolid, a new synthetic anti- microbial, is considered to be a weak MAOI. Cold remedies Dextromethorphan + SSRIs or TCAs or atypical Therefore, prescribing it with other sero- antipsychotics tonin-elevating agents has been reported to 18 Atypical antipsychotics Olanzapine + citalopram and lithium precipitate ST. + paroxetine or fluoxetine Most cases of ST do not require - ization and can be managed by stopping the Antibiotics/antifungals Linezolid + SSRIs or medication or decreasing the dose. Thera- Fluconazole + citalopram Ciprofloxacin + methadone + venlafaxine peutic doses of a single drug are highly un- likely to cause toxicity, although there have Abbreviations: MAOIs, monoamine oxidase inhibitors; SNRIs, selective norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; ST, serotonin toxicity; been reported cases of patients who are sen- TCAs, tricyclic antidepressants. sitive or more susceptible and develop symp- toms after administration of a single agent Pathophysiology and/or a dosage increase. Tryptophan is a precursor of serotonin and Delayed ST reactions have occurred be- must be ingested from foods, including cause of a prolonged half-life of a drug, iron meats, dairy, fruits, and seeds. About 90% of deficiency anemia, and coingestion of shorter all serotonin is made in the gastrointestinal acting serotonin antagonists.31 Most antide- epithelium and is the major component of pressants have a short half-life (< 24 hours) the brain-gut axis.26 Serotonin cannot cross except for fluoxetine. A decrease in iron may the blood-brain barrier; therefore, it is syn- contribute to ST because iron is needed to thesized and stored in presynaptic termi- process serotonin from tryptophan. An ex- nals around the midline of the .1,26 ample of 2 shorter-acting serotonin antago- Transport of serotonin is provided by sero- nists include and olanzapine. tonin transporter (SERT).1,26,27 Once released, Cyproheptadine is used in the treatment of serotonin can either stimulate postsynap- ST, and olanzapine is an . neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI anti- SYMPTOMS depressants, such as citalopram and parox- Symptoms of ST range from mild to severe etine inhibit the reuptake of serotonin by and include a combination of neuromuscu- binding to 2 different sites on the SERT thus lar, autonomic, and mental status changes allowing more available serotonin to be ac- (Table 3).5,10 Mild symptoms of ST can start cessible to other neurons.27 There are 7 fam- within 1 to 2 hours after ingesting a med- ilies of serotonin receptors, 5-HT1 to 5-HT7 ication that increases serotonin to a toxic and at least 15 mammalian subtypes.28,29 The state unless the drug has a long half-life (eg, majority of these receptors have been impli- fluoxetine). Sometimes mild symptoms of cated in depression or depressive-like behav- ST can be difficult to distinguish from com- ior as evidenced by the efficacy of increasing mon drug AEs, flu symptoms, or . extracellular serotonin for the treatment of Patients taking therapeutic doses of SSRIs

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can experience serotonin symptoms, such TABLE 3 Serotonin Toxicity Signs/Symptoms5,10 as lower limb or a few beats of ankle clonus without being toxic. One Mild Moderate Severe thing to remember is that not all patients Hyperreflexia Hyperthermia will start with mild symptoms and may pres- (> 101.3°F) Incoordination Clonus: lower extremities with ent in moderate or severe distress. generalized progression Hyper/hypotension Moderate-to-severe ST symptoms require Restlessness (muscle jerks) Sustained clonus or rigidity hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses Ocular clonus from the lower extremities to the upper body with teeth chattering and becomes more generalized. Ocular clo- nus can be continuous, intermittent, or have Agitation Tonic-clonic seizures a ping pong effect (short cycle, periodic, al- Diaphoresis Respiratory depression ternating lateral gaze). Clonus of lower Severe ST is life threatening and leads to extremities multiorgan failure within hours if not treated. Dyspnea The patient is intubated to assist with breath- Dilated pupils ing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the < 24 hours; therefore, reducing or elimi- symptoms reach the severe state. Of note, nating the offending drug(s) will result in a hyperthermia is due to a noninfectious ele- steady reduction of symptoms. Exceptions in- vation of body temperature from hypertonic- clude medications with a longer activity, such ity, agitation, and muscle rigidity. A true core as the irreversible MAOIs (eg, phenelzine, temperature > 105.8°F causes irreversible isocarboxazid) and drugs with a longer half- cell damage, cerebral injury, and death.32,33 life, such as fluoxetine. These types of medi- The patient can develop seizures and a . cations may have been stopped weeks earlier Multiorgan failure occurs, including rhabdo- and may prolong reduction of symptoms. myolysis, myoglobinuria, renal failure, meta- When initiating or increasing SSRIs or bolic acidosis, acute respiratory distress, and SNRIs, there are common nontoxic AEs that disseminated intravascular coagulation. are not consistent with ST, including anxi- ety, restlessness, and irritability that may last DIAGNOSIS for 2 weeks. The difference in toxic vs non- The diagnosis of ST is clinical and based on a toxic reactions are the timing and rapid pro- history of ingesting serotonin-elevating med- gression of symptoms. The toxic symptoms ications and physical findings as per Hunter will start within hours of ingesting the of- Serotonin Toxicity Criteria34 (Table 4). An in- fending agents(s) and progress rapidly to se- depth history needs to include previous and vere symptoms within 24 hours. Therefore, it current prescriptions, indications of the pre- is imperative to review AEs with the patient scriptions (eg, therapeutic, increase in dos- and or caregiver, so they may act as their own age, suicide intent), OTC medications, and advocate and seek immediate assistance. illicit drug use. Early recognition of symp- toms, identification of serotonergic medica- Differentials tions, and appropriate resuscitative measures There are symptoms specific to ST that can lead to more successful outcomes. A sero- be used to differentiate it from other condi- tonin drug level is ineffective and does not tions. These include hyperthermia, bilateral correlate with the dosage since serotonin symmetric clonus (inducible, spontaneous, does not cross the blood-brain barrier. ocular), and hyperreflexia. These criteria The type of drug determines the length form the basis for Hunter criteria. and response of the episode. The drug(s) Differential diagnoses to consider in- elimination half-lives need to be calculated clude neuroleptic malignant syndrome; along with the pharmacokinetic or pharma- antidepressant initiation AEs; antidepres- codynamics; , antagonist, reuptake sant discontinuation syndrome; malig- inhibitor, etc. Many drugs have half-lives of nant hyperthermia; anticholinergic toxicity;

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TABLE 4 Hunter Criteria (Need 3 to Diagnose)27 mask tachycardia that can be used to monitor the effectiveness of treatment.10 Bromocrip- Criteria Descriptions tine is a serotonin agonist and may exacer- 1 Spontaneous clonus bate symptoms. Dantrolene has no effect on 10 2 Inducible clonus AND agitation OR diaphoresis survival in animal models. Droperidol and 3 Ocular clonus AND agitation OR diaphoresis haloperidol can worsen hyperthermia by in- 4 AND hyperreflexia hibiting sweating.38 5 Hypertonic AND temperature > 100.4°F AND Mechanical ventilation should be consid- ocular clonus OR inducible clonus ered especially if muscle rigidity progresses and depressed respiratory function occurs. /; sepsis; drug over- If the temperature starts to rise, immediate dose; / withdrawal; sedation, paralysis, mechanical ventilation, and preeclampsia. Neuroleptic malignant and cyproheptadine are administered. The syndrome (NMS) is the disorder most often overall goal is prevention of hyperthermia, misdiagnosed as ST. Key elements that dis- which leads to multiorgan failure. A core tinguish ST from NMS include the timing of temperature of ≥ 104°F is associated with the clinical course (NMS develops over days neurologic cell death, and recovery is min- to weeks); the medications ingested (NMS imal.32 Consultation with an experienced from dopaminergic drugs); and the symp- toxicologist is strongly recommended. An- toms of NMS (bradyreflexia, bradykinesia, tipyretics should not be used, because el- bradyphrenia, and no clonus). According to evated temperature is centrally mediated Gillman, serotonin toxicity is a manifesta- from muscle rigidity. If presentation occurs tion of toxicity that is predictable and com- within 1 hour, activated charcoal can be mon with specific drug combinations, while used for detoxification of potentially lethal NMS is a “rare idiosyncratic reaction to es- amounts. sentially normal doses and very rarely occurs after overdoses.”35 Preeclampsia is a preg- Warning Label Controversies nancy that can mimic ST with In 2006, the US Food and Drug Adminis- symptoms of , clonus, and hy- tration (FDA) issued an advisory warning perreflexia. It has been estimated to compli- against concurrently using a tryptan antimi- cate 2% to 8% of pregnancies and remains a graine drug and serotonin-mediated medica- principle cause of maternal and fetal morbid- tions.39 In 2018, a research team conducted a ity and mortality.36,37 14-year retrospective analysis on 20,000 pa- tients who were coprescribed a tryptan drug TREATMENT with SSRIs or SNRIs.40 The study reported Mild-to-moderate symptoms usually resolve that the risk of ST was rare and suggested on their own 1 to 3 days after decreasing or that the FDA reconsider their advisory. There stopping the offending drug. The timing will are several other controversial medications depend on the half-life or active metabolites with a ST FDA warning label due to their of the drug. Treatment is largely supportive mechanisms of action and inaccurate case and may require treatment for control of agi- reports.41 tation with and IV fluids for /hypotension.14 In cases not re- Human sponding to supportive care, treatment with Consistent with the 2017 American Asso- oral cyproheptadine is recommended.14 ciation of Control Centers Toxic Ex- There are other medications that have posure report, antidepressants continue to been used in treatment such as olanzapine, be in the top 5 substance classes most fre- , , bromocrip- quently involved in human exposures.42 Most tine, dantrolene, droperidol, and haloperi- accidental ingestions of antidepressants occur dol, but their efficacy is unproven and not in toddlers, whereas intentional ingestions recommended.10 Chlorpromazine can cause are usually done by adolesents.43 Over the hypotension and increase hyperthermia. Pro- past 10 years, antidepressants are the No. 1 pranolol has a long duration of action, may fastest growing category of human exposures cause a prolonged hypotension, and can in all age groups.42

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ST in the Pediatric Population strument.46 Treatment with antidepressants ST in the pediatric population mirrors that in is controversial. “Current evidence is gener- adults. Differences include the inability of the ally reassuring and indicates that the absolute child to report symptoms, lack of clinician risks of negative infant outcomes are small awareness, and reluctance of adolescents to except for PNAS [poor neonatal adaptation disclose . Management syndrome], which largely appears to be self- is the same as for adults, including discon- limited.”47 Antidepressants cross the human tinuing the offending drug, supportive care, placenta and fetal blood-brain barrier.48 Sev- adequate sedation, , IV fluids, and eral cases of infant toxicity from SSRIs have continuous cardiac monitoring. Sedation is been reported with citalopram and escitalo- weight based for benzodiazepines. Mild-to- pram.49,50 Symptoms included severe muscle moderate reactions require admission for ob- rigidity, lethargy, tachycardia, QTc prolonga- servation. Severe reactions require admission tion, altered consciousness, hypertonia, and to the ICU. seizures at birth. These mothers had taken an There have been at least 4 published SSRI during pregnancy. case reports of children aged < 6 years with moderate-to-severe ST secondary CONCLUSIONS to acute vilazodone ingestion.44 The dos- This article highlights some of the latest in- ages included 5.5 to 37 mg/kg. All 4 pa- formation on ST. Increased awareness of tients had altered mental status, seizures, all clinicians and their patients may help hyperthermia, mild clonus, tachycardia, decrease unnecessary comorbidities and and hypertension. They all survived with death. Early identification of ST symptoms intensive care treatment, including in- will increase the chances for survival, be- tubation, sedation, cyproheptadine in cause of the rapid progression of symptoms 2 cases, activated charcoal and IV lorazepam within 24 hours. Most fatal reactions occur in the other cases. when combining MAOIs with SSRIs, SNRIs, Direk and colleagues reported a case of or another MAOI. Overdose with an SSRI a 12-year-old girl who was brought to the does not progress to the severe symptoms emergency department by her stepmother unless combined with another serotonin- for seizurelike activity and was diagnosed elevating medication. with and .45 In the Education of all patients who are pre- pediatric ICU she developed tachycardia, scribed antidepressants must include aware- , agitation, dilated pupils, tremors, in- ness of the potential for serotonergic drug creased deep tendon reflexes, spontaneous interactions, particularly from OTC medica- clonus, and horizontal ocular movements. tions, herbal medications, and illicit drugs. A detailed clinical history was retaken and The diagnosis of ST is based on clinical find- revealed that the child had been prescribed ings and there must be a history of ingesting risperidone 1 week before by the psychiat- serotonin-elevating drug(s). Hunter Sero- ric clinic due to behavioral problems, includ- tonin Toxicity Criteria is the gold standard ing stealing money, lying, and running away for diagnosing symptoms along with consult- from home and school. On further investi- ing a toxicologist. Prevention of ST includes gation, the stepmother was taking clomip- informed clinicians, patient education, care- ramine and discovered 9 missing pills. ful prescribing and monitoring, and avoid- ance of multidrug regimens. Pregnancy and Lactation The American College of Obstetricians and Author disclosures The author reports no actual or potential conflicts of interest Gynecologists recommends that clinicians with regard to this article. screen patients at least once during the peri- natal period for depression and anxiety Disclaimer symptoms, using a standardized, validated The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline tool and complete a full assessment of mood Medical Communications Inc., the US Government, or any and emotional well-being during the post- of its agencies. This article may discuss unlabeled or inves- tigational use of certain drugs. Please review the complete partum, including screening for postpartum prescribing information for specific drugs or drug combina- depression and anxiety with a validated in- tions—including indications, contraindications, warnings, and

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