SEROTONIN SYNDROME

DANA BARTLETT, RN, MA, MSN

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevire, Lippincott, and Thieme. He has written widely on the subject of toxicology and was recently named a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Connecticut Poison Control Center and is actively involved in lecturing and mentoring nurses, emergency medical residents and pharmacy students.

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ABSTRACT

Drugs can react to cause the body to have too much serotonin and lead to serotonin syndrome, which is a potentially life threatening condition.Serotonin syndrome is caused by therapeutic doses, drug interactions, or overdoses of medications that directly or indirectly affect the serotonergic system. An excess stimulation of the serotonergic receptors is what causes serotonin syndrome. The stimulation is excitatory and causes symptoms, such as tachycardia, hypertension, agitation, excessive muscular activity. There is no proven antidote for serotonin syndrome that is effective and safe.The best treatment is supportive care.Health care professionalsmust consider the possibility of serotonin syndrome in the setting of serotonergic medications where mental status changes and neurological hyperexcitability occur.

Continuing Nursing Education Course Director & Planners

William A. Cook, PhD, Director, Douglas Lawrence, MS, Webmaster

Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner

Accreditation Statement

NurseCe4Less.com is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

Credit Designation

This educational activity is credited for 2hours. Pharmacology content 30 minutes. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.

Course Author & Planner Disclosure Policy Statements

It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities. All authors and course planners participating in the planning or implementation of a CNE activity are expected to disclose to course participants any relevant conflict of interest that may arise.

Statement of Need

Nursing knowledge to identify serotonin syndrome and to help patients avoid it is imperative to avoid complications. Patients that are prescribed serotonergic medications need to be educated and warned about the possibility of serotonin syndrome and subtle changes that could lead to severe adverse outcomes.

Course Purpose

This course will help nurses identify signs and symptoms of serotonin syndrome andrecommended treatment.

Learning Objectives

  1. Provide a basic definition of serotonin syndrome.
  2. Correctly identify the causes of serotonin syndrome.
  3. Name two drug classes that inhibitserotonin reuptake; and, two drugs that can cause excessive release serotonin.
  4. List three illicit drugs that may cause serotonin syndrome.
  5. List the three categories of signs/symptoms that are diagnostic of serotonin syndrome.
  6. Identify the diagnostic sign that is most reliably noted in cases of serotonin syndrome.
  7. Identify autonomic, cognitive, and neuromuscular changes seen in serotonin syndrome.
  8. Identify the name of the criteria that are used to diagnose serotonin syndrome.
  9. List three clinical conditions that may be mistaken for malignant hyperthermia.
  10. Identify the usual time of onset of the signs and symptoms of serotonin syndrome.
  11. Identify three serious complications of serotonin syndrome.
  12. Identify the best therapy,three specific treatments, and three drugs that may help in serotonin syndrome.
  13. Identify three drugs that may be helpful in treating serotonin syndrome.
  14. List drugs that should not be used to treat serotoninsyndrome.

Target Audience

Advanced Practice Registered Nurses, Registered Nurses, Licensed Practical Nurses, and Associates

Course Author & Director Disclosures

Dana Bartlett, RN, BSN, MSN, MA, William S. Cook, PhD,

Douglas Lawrence, MS, Susan DePasquale, CGRN, MSN, FPMHNP-BC –

All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Activity Review Information

Reviewed by Susan DePasquale, CGRN, MSN, FPMHNP-BC.

Release Date: 3/3/2014 Termination Date: 3/3/2017

Please take time to complete the self-assessment Knowledge Questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

  1. Which of the following is the correct definition of serotonin syndrome?
  1. Signs and symptoms caused by excessive stimulation of the serotonergic system.
  2. Signs and symptoms caused by an overdose of serotonergic drugs.
  3. A clinical condition that closely resembles neuroleptic malignant syndrome.
  4. A clinical condition characterized hyperthermia, clonus, and agitation.
  1. The causes of serotonin syndrome are:
  1. Prolonged use of drugs that affect the serotonergic system.
  2. Therapeutic use, overdose, or drug interaction
  3. Improper tapering of medications that affect the serotonergic system.
  4. It is an inevitable consequence for some people who take serotonergic drugs.
  1. Which of these classes of drugs that inhibits the reuptake of serotonin?
  2. Common analgesics
  3. Illicit drugs
  4. Sympathomimetics
  5. SSRIs
  1. Three illicit drugs that may cause serotonin syndrome are:
  2. Methamphetamine, heroin, marijuana
  3. Cocaine, LSD, ecstasy
  4. Marijuana, ecstasy, cocaine
  5. Dextromethorphan, LSD, methamphetamine
  1. The three categories of signs/symptoms that are diagnostic of serotonin syndrome are:
  2. Cardiovascular, autonomic, cognitive
  3. Metabolic, neuromuscular, cognitive
  4. Cognitive, neuromuscular, autonomic
  5. Psychiatric, metabolic, cardiovascular
  1. The diagnostic signs that is most reliably noted in cases of serotonin syndrome is:
  2. Hyperthermia
  3. Hallucinations
  4. Tremor
  5. Clonus
  1. The criteria used to diagnose serotonin syndrome are:
  1. Sternbach’s criteria
  2. Hunter’s criteria
  3. Modified Glasgow scale
  4. Romberg criteria
  1. Two clinical conditions that may be mistaken for serotonin syndrome are:
  2. Cholinergic syndrome, syndrome, malignant hyperthermia
  3. Anticholinergic syndrome, Stevens-Johnson syndrome
  4. Neuroleptic malignant syndrome, anticholinergic syndrome
  5. Sympathomimetic syndrome, drug-induced hypothermia
  1. The best therapy for serotonin syndrome and three specific treatments include:
  1. Supportive care: intubation, fluids, dantrolene
  2. Supportive care: aggressive cooling, benzodiazepines, cyproheptadine
  3. Antidotal therapy: cyproheptadine, chlorpromazine
  4. Discontinuation of the drug: supportive care
  1. Drugs that should not be used to treat serotonin syndrome are:
  2. Cyproheptadine, bromocriptine, acetaminophen, propranolol
  3. Dopamine, succinylcholine, epinephrine, chlorpromazine
  4. Olanzapine, tramadol, phenylephrine
  5. Bromocriptine, dantrolene, propranolol, succinylcholine

INTRODUCTION

Serotonin syndrome is a group of signs and symptoms caused by excessive stimulation of the serotonin receptors. Serotonin syndrome is caused by therapeutic doses, drug interactions, or overdoses of medications that directly or indirectly affect the serotonergic system. The first case of diagnosed serotonin syndrome occurred in the late 1950s, but case reports of unrecognized serotonin syndrome predate that by at least 20 years.

The clinical presentation of serotonin syndrome can be intense and dramatic, but it can also be mild and subtle. Serotonin syndrome can be mistaken for an infectious or metabolic disorder or for the clinical syndromes caused by anticholinergic or sympathomimetic poisoning, or for the neuroleptic malignant syndrome or malignant hyperthermia. Although it is unusual for the serotonin syndrome to cause a fatality, a severe case of serotonin syndrome is a medical emergency that can rapidly cause multi-system organ failure.

Nurses must be aware of serotonin syndrome because drugs that can cause it are in common use, and intentional overdoses with drugs that can cause the serotonin syndrome are being seen with increasing frequency, which make it difficult to detect and easily mistaken serotonin syndrome for other pathologies.

SEROTONERGIC SYSTEM

Serotonin (also called 5-hydroxytryptamine) is a monoamine neurotransmitter that acts centrally and peripherally. It is synthesized in the central nervous system and in enterochromaffin cells in the gastrointestinal tract. Serotonin has many complex functions, and the full range and activity of these is not known. It inhibits gastric secretion, acts as a smooth muscle stimulant, promotes platelet aggregation, affects vascular tone, and is a central and peripheral neurotransmitter. In the brain, serotonin is involved in mood, personality, affect, appetite, motor function, temperature regulation, sexual activity, pain perception, and sleep induction.

Serotonin is stored in vesicles in presynaptic neurons. It is released into the synaptic cleft and binds to a serotonin receptor on the postsynaptic neuron. There are seven families of serotonin receptors (5-HT1 to 5HT7) and several of these have different subtypes, for example, 5-HT1A. Serotonin binding to a 5-HT receptor initiates a wide variety of effects on the post-synaptic neuron (decreasing or increasing intracellular cAMP levels, causing Na+ and Ca2+ influx and depolarization action),however the basic effect of serotonin is excitatory. After binding to the receptor, serotonin is transported back to the presynaptic neuron where it reenters the vesicles or is broken down by monoamine oxidase.1,2

Learning Break:

Neurotransmitters such as serotonin, dopamine, and glycine, function by binding to receptors on the membranes of post-synaptic neurons. These receptors are ligand-gated ion channels or G protein receptors. When a neurotransmitter binds to a ligand-gated ion channel, the channel opens and ions enter or leave the cell: depending on which ions enter or leave, the effect of the neurotransmitter can be excitatory (causing cell depolarization) or inhibitory (preventing cell depolarization). When a neurotransmitter binds to a G protein, the same effects occur.

Example: When serotonin binds to G proteins of the 5-HT1 receptors, potassium ions channels open, potassium leaves the cell – increasing membrane potential and inhibiting depolarization – and cAMP concentrations are decreased, and the effect is inhibitory. It is important to remember that the terms inhibition and excitation refer to how the neurotransmitter affects the cell. The physiological action produced by excitation may be a decrease in a particular function (e.g., decreased peristalsis) and the physiological action produced by inhibition may be an increase in a particular function (e.g., muscle tremor or hyperreflexia).

SEROTONIN SYNDROME: EPIDEMIOLOGY

Serotonin syndrome is not a recent phenomenon. It was first recognized in animals, and the first case described in a human was reported in 19593The term serotonin syndrome was first used by Insel et al in 1982 to describe a patient who developed serotonin syndrome from a combination of an monoamine oxidase (MAO) inhibitor and a tricyclic antidepressant.4

The exact incidence of serotonin syndrome is not known. One author noted that 14-16% of all patients who took an overdose of a selective serotonin reuptake inhibitor (SSRI) had signs and symptoms of serotonin syndrome.5 Fatality rates have been reported to be between 2-12%, but death from serotonin syndrome is considered to be an unusual event.6 Serotonin syndrome has been described in all ages groups, including neonates, children, and the elderly.7-9

SEROTONIN SYNDROME: HOW IT HAPPENS AND THE

CLINICAL PRESENTATION

The essential cause of serotonin syndrome is an excess stimulation of the serotonergic receptors. The stimulation is excitatory and causes the tachycardia, hypertension, agitation, and excessive muscular activity. and the other signs and symptoms of the syndrome. The excess stimulation occurs by one of the followingsix mechanisms:10-13

  • Direct stimulationof the serotonergic receptors:

Such as occurs with the medications buspirone, carbamazapine, lithium, as well as with LSD.

  • Excessive releaseof serotonin:

Such as occurs with amphetamines, cocaine, dextromethorphan, levodopa, monoamine oxidase inhibitors, reserpine, as well as with ecstasy/MDMA.

  • Decreased breakdownof serotonin:

Such as occurs with monoamine oxidase inhibitors and St. John’s wort.

  • Enzyme inhibition:

Cytochrome P450 enzymes that metabolize certain serotonergic drugs can be inhibited by these drugs, e.g., dextromethorphan, methadone, oxycodone, tramadol, venlafaxine.

  • Increase in serotonin precursors:

The essential amino acid, Tryptophan.

  • Decreased serotonin reuptake:

Selective serotonin-reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; as well as, dextromethorphan, monoamine oxidase inhibitors, methadone, and trazadone.

It is not known exactly which families and subtype of serotonin receptors are involved in the serotonin syndrome,which could be one of the factors accounting for the variability of the clinical presentation of this pathology.14Some authors, however, have identified the 5-HT1cand the 5-HT2 receptors as the ones affected in the serotonin syndrome.15

Although there is a wide range of signs and symptoms that are possible, serotonin syndrome is definitely characterized and diagnosed by abnormal autonomic, cognitive, and neuromuscular changes.16-18 These are further outlined below:

  • Autonomic:

Autonomic changes include hyperthermia, hypertension, tachycardia, diaphoresis, flushing, increased bowel sounds, diarrhea, and mydriasis. The hyperthermia can be very severe with a body temperature ≥ 38.5° C and higher.

  • Cognitive:

There are many cognitive changes associated with serotonin syndrome such as agitation, drowsiness, coma, hypomania, anxiety, confusion, hallucinations, and delirium.

  • Neuromuscular:

Akathisia, clonus, hyperreflexia, myoclonus, rigidity, shivering, and tremor.

Learning Break:

Clonus- inducible, ocular, or spontaneous - is the most reliable finding when diagnosing serotonin syndrome. Clonus is defined as alternate muscular contraction and relaxation in rapid succession. This will be discussed in more detail later in the module.

These are the signs and symptoms that have been observed in patients who have serotonin syndrome.The clinical presentation and the severity of signs and symptoms are quite variable: the serotonin syndrome can be mild and quite subtle in presentation or severe and life threatening.

Patients with a mild case of serotonin syndrome may feel restless and anxious, they may have a low-grade fever, and mild, intermittent tremors, and it is easy to overlook or misdiagnose these types of cases. A severe case of serotonin syndrome is a medical emergency. These patients may have a body temperature > 41° C. Coma, metabolic acidosis, renal failure, rhabdomyolysis, and disseminated intravascular coagulation(DIC) may occur and all of this can develop very rapidly.19,20

Serotonin syndrome typically begins very quickly: the onset of effects can be within minutes after exposure. In most cases the patient will develop signs and symptoms within six hours after exposure to a drug or drugs,21,22but a delay of up to 24 hours is possible.23-25Most cases resolve within 24 hours, but there have been reports of the serotonin syndrome lasting for several days.26

DRUGS THAT CAUSE SEROTONIN SYNDROME

Certain classes of medications have been definitely identified as drugs that can cause serotonin syndrome, and this makes sense because their therapeutic effect is based on their action on the serotonergic system. The SSRIs such as fluoxetine and sertraline, and monoamine oxidase inhibitors(MAOIs) such as phenelzine and moclobemide, are common examples of these drugs.

Other drugs may cause serotonin syndrome;however, the connection between the syndrome and the drug is not as obvious because many drugs affect uptake or metabolism of multiple neurotransmitters that does not always translate to a measurable or observable clinical effect. Two such examples are bromocriptine and tramadol. Both drugs do have an in vivo effect on the serotenergic system; however, the therapeutic effect of bromocriptine is caused by dopamine receptor agonist activity, and the therapeutic effect of tramadol is caused by agonism of the mu opioid receptors. Yet, both bromocriptine and tramodol can cause serotonin syndrome.

Drugs and supplements that have been identified as causing, being associated with, or suspected of causing serotonin syndrome include:27-32

  • Sympathomimetics:

Fenfluramine, phentermine, phenylpropanolamine

  • 5-HT1 agonists:

Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan

  • Monoamine oxidase inhibitors: Isocarboxazid,moclobemide, phenelzine, selegiline, and tranylcypromine
  • Selective serotonin reuptake inhibitors:

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

  • Tricyclic antidepressants:

Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine

  • Opiates/analgesics:

Buprenorphine, codeine, levomethorphan, levorphanol, meperidine, methadone, oxycodone, pentazocine, pethidine, tapentadol, tramadol

  • Illicit drugs:

Amphetamine, bath salts, cocaine, ecstasy/MDMA, LSD (Unconfirmed)

  • Antidepressants and anxiolytics:

Bupropion, buspirone, duloxetine, mirtazapine, nefazodone, trazodone, venlafaxine.

  • Antiemetics:

Droperidol, granisetron, metoclopramide, ondansetron

  • Dietary supplements/herbal product:

Ginseng, St. John’s wort, tryptophan, yohimbe

  • Other drugs:

Amantadine, bromocriptine, carbamazapine, carisoprodol, chlorpheniramine, dextromethorphan, dihydroergotamine, fluconazole, levodopa, linezolid, lithium, methylene blue, olanzapine, reserpine, ritonavir, and 5-methoxydiisopropyltryptamine (a.k.a. foxy methoxy).

An increased dose of a serotenergic drug, or the addition of a sertonergic drug to the medication regimen of a patient already taking a SSRI, MAO, or others (discussed further below) usually causes serotonin syndrome. It can also be a consequence of overdose. Serotonin syndrome after a single dose of a serotonergic drug is unusual, but this has been reported;33-35and, it is far more common for serotonin syndrome to be caused by a combination of drugs that act at different 5-HT receptor sites.

Drug interactions can also be a cause of serotonin syndrome, even if one of the drugs does not affect the serotonergic system. If a patient who is taking an SSRI is prescribed a medication that inhibits the cytochrome P450 enzyme that metabolizes the SSRI, serotonin syndrome is possible.36

Further, discontinuedserotonergic medications can cause serotonin syndrome if there is an insufficient period of time between the discontinuation of one medication and beginning therapy with another.37An example is Norfluoxetine, which is a metabolite of fluoxetine that has a half-life of approximately 2.5 weeks. Because of the long half-life of this drug and its metabolite, fluoxetine may cause serotonin syndrome if a patient is given another serotonergic drug within several weeks of the discontinuation of fluoxetine.38

The drug combinations in the list below have been reported to cause, or be associated with the serotonin syndrome.38-41It’s important for health care providers to continuously review an approved drug database for current information when prescribing or administering any form of mono- or combination drug therapy. Drug-drug interactions are one possible cause of serotonin syndrome; underlying medical conditions must also be considered. The list below is complete as of this writing, but there are new reports added all the time in the medical literature about drug combinations that can cause serotonin syndrome.