Is serotonin syndrome permanent?

Serotonin syndrome: Preventing, recognizing, and treating it

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.1 Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 20022 to 8,585 in 2005.3

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.4

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated 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, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.5

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,6 methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,7 ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.11 Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.5

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.14

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.15 The symptoms can range from mild to life-threatening (Table 2).16

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.16

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.16 Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.11 Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.15

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic19; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.16

According to the Centers for Medicare & Medicaid Services, approximately 1 in 10 adults in the United States is affected by depression.1 This overwhelming number of people affected are often treated with antidepressant medications. In fact, antidepressants are the prescription medications most frequently used by US adults between the ages of 20 and 59 years.1

According to the Centers for Disease Control and Prevention, antidepressant use increased nearly 65% over the course of 15 years.2 Between 2011 and 2014, 12.7% of people aged 12 years and older reported antidepressant medication use in the last month vs 7.7% from 1999 to 2002. Of people treated within the last month, a quarter of them have been using antidepressants for more than 10 years. Moreover, use increases with age, ranging from 3.4% among people aged 12 to 19 years to 19.1% among people aged 60 years and older. 2

Antidepressants are the third most frequently mentioned medications during physician office visits, with a significant proportion written by primary care physicians.3 Moreover, a significant proportion of antidepressants are not being prescribed for the approved indications (eg, depression and anxiety), but are being used off-label.4

Selective serotonin reuptake inhibitors (SSRIs) constitute the most widely used antidepressants.”5 However, they are associated with significant toxicity. According to the 2016 annual report of the National Poison Date System, SSRIs were number 10 of the top 25 substance categories associated with reported fatalities.6

In particular, SSRIs raise serotonin levels in the body, and when combined with other serotonergic agents, they can lead to a potentially fatal condition called serotonin syndrome (SS). The actual incidence of SS and associated morbidity is likely underestimated, as SS is frequently underdiagnosed and underreported and can easily be overlooked, especially when mild.7 It has been suggested that more than 85% of physicians are not familiar with the existence of SS or which drugs or drug combinations may cause it.8

“In my experience, the majority of prescribers have absolutely no idea that even exists, let alone what causes it and what to do about it,” according to Irene Campbell-Taylor, MB ChB, PhD, a clinical neuroscientist based in Nova Scotia, Canada, with a private practice focusing primarily on geriatrics.

“It is alarming because SSRIs are among the most frequently prescribed antidepressants, and patients are not usually warned about other serotonergic agents that can interact with SSRIs and induce serotonin syndrome, a condition that can be lethal,” she told Psychiatry Advisor.

Serotonin: Too Much of a Good Thing?

SS is caused by drugs that either affect serotonin metabolism or act as direct serotonin receptor agonists, or both, and takes place in the setting of excess stimulation of central and peripheral serotonin receptors.9

Decarboxylation and hydroxylation of tryptophan are responsible for producing serotonin (5-hydroxytryptamine ). After this process, 5-HT is stored in vesicles and released into the synaptic cleft when it is stimulated. Monoamine oxidase-A is responsible for metabolizing 5-HT.9

Serotonin can bind to at least 7 different families of 5-HT receptors, and no single receptor is responsible for the development of SS. However, evidence suggests that the 5HT-2A receptors are most implicated in the condition.9

Serotonin plays an essential and far-reaching role in multiple systems and acts both peripherally and centrally. Peripheral serotonin is produced primarily in gastrointestinal tract and is responsible for stimulating vasoconstriction, uterine contraction, bronchoconstriction, gastrointestinal motility, and platelet aggregation.9

Central serotonin, which is present in the midline raphe nuclei of the brainstem, functions to inhibit excitatory transmission. It also plays an important role in modulating wakefulness, attention, mood, affective and sexual behaviors, appetite, thermoregulation, motor tone, migraine, emesis, nociception, and aggression.9

Drugs that can cause SS do so by inhibiting serotonin reuptake, increasing serotonin synthesis, decreasing serotonin metabolism, increasing serotonin release, or activating serotonergic receptors.9 The inhibition of cytochrome P450 enzymes by SSRIs can result in the accumulation of certain serotonergic drugs that are usually metabolized by these enzymes, leading to an “exacerbation loop in which the SSRI inhibits the metabolism of a certain drug, which in turn increases serotonergic activity.”9 Drugs that increase serotonin concentrations and their mechanisms of action are listed in Table 1. Additional drugs with serotonergic effects that can potentiate other serotonergic agents and cause SS are listed in Table 2.

From Subtle to Serious

“Serotonin syndrome tends to be underrecognized by physicians because you have to be careful and on the lookout, since its presentation can be subtle,” Peter R. Chai, MD, MMS, from the Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, told Psychiatry Advisor.

The onset of SS can occur within hours of an exposure to a serotonergic agent, but can be delayed for as much as 24 hours.10

“It is important to note that serotonin syndrome can progress from mild to florid and serious very quickly, especially in the setting of the combination of an SSRI or and a drug of abuse, such as cocaine,” warned Dr Chai, who is also an assistant professor at Harvard Medical School in Boston.

Dr Campbell-Taylor recounted the case of a patient who was being treated with an SSRI and took over-the-counter melatonin for insomnia.

“He woke up during the night with headache, dizziness, and his ‘face on fire,’ which is typically a sign of elevated blood pressure,” she reported.

“The fact that it wasn’t lethal is likely because he took a relatively small dose of melatonin and his symptoms abated without requiring hospitalization,” she added.

Diagnosis of Serotonin Syndrome

Autonomic, cognitive, and neuromuscular derangements are common in SS, together with signs such as fever, agitation, and clonus. However, the condition varies considerably from patient to patient. Moreover, many of these manifestations are nonspecific, making the syndrome challenging to diagnose.10

It is essential to take a careful patient history, finding out what medications (prescription and over-the-counter) and dietary supplements the patient might have been using, for how long, and whether the dose was recently increased. It is also important to ascertain when the signs and symptoms began, relative to the exposure, and whether they were they rapid in onset.10

Dr Chai emphasized that it is important as well to find out whether the patient recently stopped taking a serotonergic agent and began taking another one, as many of these drugs have long half-lives and may still be in the system when a new drug is initiated.

There is no laboratory test that confirms SS and serum serotonin levels do not necessarily correlate with clinical findings. Instead, laboratory and other tests are used to rule out other diagnoses.11

Classical symptoms of SS are listed in Table 3. The Hunter Serotonin Toxicity Criteria for diagnosing serotonin syndrome has become the standard algorithm to diagnose SS and is listed in Table 4. Differential diagnoses of SS are included in Table 5.

Treating Serotonin Syndrome

“Clinicians should be aware that serotonin syndrome is treatable once you recognize the hallmark features, and that the prognosis is generally favorable,” Dr Chai said.

First-line management involves discontinuation of the offending serotonergic agents and provision of supportive care, with the intensity of treatment depending on the severity of the syndrome.11 Mild cases typically resolve in 24 to 72 hours with conservative therapy, and patients do not necessarily require hospital admission.11 In contrast, patients with moderate to severe cases involving hypertonicity, hyperthermia, autonomic instability, or progressive cognitive changes require hospitalization.11 Management of mild, moderate, and severe cases are listed in Table 6.

Prevention: The Role of Psychiatrists

Dr Campbell-Taylor and Dr Chai both emphasized the critical role that psychiatrists can plan in preventing SS.

Be vigilant about what you are prescribing.

Physicians and other prescribers should modify their prescription practices to avoid or at least minimize coprescription of drugs that have a high probability of inducing SS.11

“Do not combine 2 serotonergic agents, such as an SSRI and SNRI, in treatment, and be vigilant during initiation of the medication or when increasing the dose, especially in patients naive to these drugs,” Dr Chai warned.

A computerized ordering system and medical software can ascertain whether there are potential interactions when multidrug regimens are required.11 Physicians who do not have access to this system should verify potential interactions with a pharmacist.

Make sure you know what other agents your patient may be taking.

It is critical to inquire about every item that your patient uses, including all prescription mediations, over-the-counter remedies, dietary supplements, and drugs of abuse, Dr Campbell-Taylor emphasized.

“This requires thorough inquiring because many people don’t think to mention items taken for nonpsychiatric causes, such as cold remedies, antibiotics, or herbal supplements that the patient may regard as ‘natural’ and therefore perfectly safe,” she said.

Educate patients about serotonin syndrome

“Many drugs include instructions or warnings, such as not to take them in combination with alcohol or not to drive or use heavy equipment while being treated, but SSRIs do not carry those warnings, although there are warnings about suicidality,” Dr Campbell-Taylor pointed out. It therefore is incumbent on prescribers to inform patients about the risk for serotonin syndrome.

“I suggest that prescribers provide list of all products that patients should avoid while taking SSRIs, SNRIs, or other serotonergic agents,” she advised. “Patients should be told that if they have a cold or allergy or have difficulty sleeping, they should consult the prescriber before self-treating with an over-the-counter drug or herbal supplement.”

Part of education is educating patients and families about the risk for overdose and its associated symptoms, Dr Chai added.

Consider nonpharmacologic approaches for treatment of mood disorders

“The implications of this widespread SSRI use are staggering,” Dr Campbell-Taylor said. “It is incumbent on all medical professionals to educate themselves and their patients and avoid prescribing these drugs whenever possible.”

Evidence-based psychotherapies, such as cognitive behavioral therapy, are increasingly being regarded as potential first-line approaches to patients with mood disorders, and their use should be increased, together with other nonpharmacologic interventions, she advised.

1. Centers for Medicare and Medicaid Services (CMS). Antidepressant medications: use in adults. Accessed: February 12, 2019.

2. Centers for Disease Control and Prevention (CDC). Antidepressant use among persons aged 12 and over: United States, 2011–2014. Accessed: February 15, 2019.

3. Yuet WC, Derasari D, Sivoravong J, Mason D, Jann M. Selective serotonin reuptake inhibitor use and risk of gastrointestinal and intracranial bleeding. J Am Osteopath Assoc. 2019 Feb 1;119(2):102-111.

5. Medco Health Solutions. America’s state of mind. Accessed: February 12, 2019.

8. Brown CH. Drug-induced serotonin syndrome. US Pharm. November 17, 2010. Accessed: February 15, 2019.

9. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013 Winter;13(4):533-40.

10. Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017 Feb;37(1):49-54.

12. Patel et al. Dietary supplement-drug interaction-induced serotonin syndrome progressing to acute compartment syndrome. Am J Case Rep. 2017;18:926-930. Published 2017 Aug 25. doi:10.12659/AJCR.904375.

15. Erland LA, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275-281.

16. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-42.

Table 1

Mechanisms of Serotonin Syndrome9

Mechanism Category Drugs
Inhibition of serotonin uptake Amphetamines/weight loss drugs Phentermine
Antidepressants Bupropion, nefazodone, trazodone
Antiemetics Granisetron, ondansetron
Antihistamines Chrlopheniramine
Opiates Levomethorphan, levorphanol, meperidine, methadone, pentazocine, pethidine, tapentadol, tramadol
Drugs of abuse Cocaine, MDMA
OTC cold remedies Dextromethorphan
SNRIs Desvenlafaxine, duloxetine, venlafaxine
SSRIs Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Tricyclic antidepressants Amitriptyline, amoxapine, clomipramine, desipramine, doxepine, imipramine, maprotiline, nortriptyline, protriptyline, trimipraline
Inhibition of serotonin metabolism Anxiolytics Buspirone
Monoamine oxidase inhibitor Furazolidone, isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, Syrian rue, tranylcypromine
Triptans Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan
Increasing serotonin synthesis Amphetamines/weight loss drugs Phentermine
Dietary supplements L-tryptophan
Drugs of abuse Cocaine
Increasing serotonin release Antidepressants Mirtazapine
Amphetamines/weight loss drugs Phentermine
Opiates Meperidine, oxycodone, tramadol
Drugs of abuse MDMA
OTC cold remedies Dextromethorphan
Parkinson disease treatment/amino acid L-dopa
Activating serotonin receptors Anxiolytics Buspirone
Antidepressants Mirtazapine, trazodone
Antimigraines Dihydroergotamine, triptans
Opiates Fentanyl, meperidine
Drugs of abuse LSD
Mood stabilizers Lithium
Prokinetic agents Metoclopramide
Inhibition of various CYP450 microsomal oxidases CYP2D6 inhibitors Fluoxetine, sertraline9, 12
CYP2D6 substrates Dextromethorphan, oxycodone, phentermine, risperidone, tramadol
CYP3A4 inhibitors Ciprofloxacin, ritonavir
CYP3A4 substrates Methadone, oxycodone, venlafaxine
CYP2C19 inhibitors Fluconazole
CYP2C19 substrates Citalopram

Table 2

Additional Drugs/Supplements Associated With Serotonin Syndrome

Drug/Supplement Examples
Antimigraine medications11 Carbamazepine, valproic acid
Proton pump inhibitors13 Lansoprazole, omeprazole, pantoprazole
Angiotensin-converting enzyme inhibitors13 Benazepril, lisinopril, enalapril, captopril
Cardioselective β-adrenergic blocking drugs13 Atenolol, metoprolol, bisoprolol, esmolol
Digitalis glycoside13 Digoxin
Nonprescription product sold online as a weight-loss agent13 Sibutramine
Antibiotic13 Linezolid
Factor Xa inhibitor oral anticoagulant13 Rivaroxaban
Antiviral medications13 Ritonavir, acyclovir
Herbal/dietary supplements S-adenosyl-L-methionine14, curcumin13, ginseng13, nutmeg13, turmeric13, melatonin15 , St. John’s wort14

Table 3

Signs and Symptoms of Serotonin Syndrome10

  • Agitation
  • Akathisia
  • Ataxia
  • Clonus
  • Confusion
  • Diaphoresis
  • Diarrhea
  • Disseminated intravascular coagulation
  • Fever
  • Hyperreflexia
  • Hypertension
  • Hypomania
  • Increased bowel sounds
  • Muscular rigidity
  • Multiorgan failure
  • Mydriasis
  • Rhabdomyolysis
  • Shivering
  • Seizures
  • Tachycardia
  • Tremor

Table 4

Hunter Serotonin Toxicity Criteria: Decision Rules16

Symptom Presence of Serotonin Syndrome
Spontaneous clonus Yes
If the above is not present but there is…
Inducible clonus + agitation
OR
Inducible clonus + diaphoresis
Yes
If the above are not present but there is…
Ocular clonus + agitation
OR
Ocular clonus + diaphoresis
Yes
If the above are not present but there is…
Tremor + hyperflexia
Yes
If the above are not present but there is…
Hypertonic + temperature >38°C + ocular clonus
OR
Hypertonic + temperature >38°C + inducible clonus
Yes
If none the above are present No

Table 5

Differential Diagnosis of Serotonin Syndrome11

  • Anticholinergic syndrome (primary)
  • Malignant hyperthermia (primary)
  • Neuroleptic malignant syndrome (primary)
  • Tetanus
  • Overdose of sympathomimetic drugs
  • Meningitis
  • Encephalitis
  • Thyroid storm
  • Heat stroke
  • Delirium tremens
  • Sepsis

Table 6

Managing Serotonin Syndrome Based on Severity9

Category Symptoms Management
Mild Mild hypertension
Tachycardia
Mydriasis
Diaphoresis
Shivering
Tremor
Myoclonus
Hyperreflexia
1. Discontinue the offending agent/agents·
2. Support (ie, stabilize vital signs, initiate cooling measures)
3. For mild agitation, fever, hypertension, tachycardia: benzodiazepines (diazepam)
4. Observe for ≥6 hours
Moderate All the above plus·
Temperature of ≥40°C
Hyperactive bowel sounds
Ocular clonus
Agitation
Hypervigilance
Pressured speech
All the above plus·
1. For severe agitation/hypothermia: 5-HT antagonist (cyproheptadine)
2. Admission to hospital for cardiac monitoring/observation
Severe All the above plus·
Temperature of ≥41.1°C
Dramatic swings in pulse rate, blood pressure
Delirium
Muscle rigidity
All the above plus·
1. For severe hypertension/tachycardia: esmolol or nitroprusside
2. Sedation and paralysis with a nondepolarizing agent and intubation/ventilation
3. Admission to intensive care unit

Serotonin syndrome

Medically reviewed by Drugs.com. Last updated on Dec 10, 2019.

  • Disease Reference

Overview

Serotonin syndrome occurs when you take medications that cause high levels of the chemical serotonin to accumulate in your body.

Serotonin is a chemical your body produces that’s needed for your nerve cells and brain to function. But too much serotonin causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures). Severe serotonin syndrome can cause death if not treated.

Serotonin syndrome can occur when you increase the dose of certain medications or add a new drug to your regimen. Some illegal drugs and dietary supplements also are associated with serotonin syndrome.

Milder forms of serotonin syndrome may go away within a day of stopping the medications that cause symptoms and, sometimes, after taking drugs that block serotonin.

Symptoms

Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you’re already taking.

Signs and symptoms include:

  • Agitation or restlessness
  • Confusion
  • Rapid heart rate and high blood pressure
  • Dilated pupils
  • Loss of muscle coordination or twitching muscles
  • Muscle rigidity
  • Heavy sweating
  • Diarrhea
  • Headache
  • Shivering
  • Goose bumps

Severe serotonin syndrome can be life-threatening. Signs include:

  • High fever
  • Seizures
  • Irregular heartbeat
  • Unconsciousness

When to see a doctor

If you suspect you might have serotonin syndrome after starting a new drug or increasing the dose of a drug you’re already taking, call your doctor right away or go to the emergency room. If you have severe or rapidly worsening symptoms, seek emergency treatment immediately.

Causes

Excessive accumulation of serotonin in your body creates the symptoms of serotonin syndrome.

Under normal circumstances, nerve cells in your brain and spinal cord produce serotonin that helps regulate your attention, behavior and body temperature.

Other nerve cells in your body, primarily in your intestines, also produce serotonin. Serotonin plays a role in regulating your digestive process, blood flow and breathing.

Although it’s possible that taking just one drug that increases serotonin levels can cause serotonin syndrome in susceptible individuals, this condition occurs most often when you combine certain medications.

For example, serotonin syndrome may occur if you take an antidepressant with a migraine medication. It may also occur if you take an antidepressant with an opioid pain medication.

Another cause of serotonin syndrome is intentional overdose of antidepressant medications.

A number of over-the-counter and prescription drugs may be associated with serotonin syndrome, especially antidepressants. Illicit drugs and dietary supplements also may be associated with the condition.

The drugs and supplements that could potentially cause serotonin syndrome include:

  • Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine, paroxetine (Paxil, Pexeva, Brisdelle) and sertraline (Zoloft)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as duloxetine (Cymbalta, Drizalma Sprinkle) and venlafaxine (Effexor XR)
  • Bupropion (Zyban, Wellbutrin SR, Wellbutrin XL), an antidepressant and tobacco-addiction medication
  • Tricyclic antidepressants, such as amitriptyline and nortriptyline (Pamelor)
  • Monoamine oxidase inhibitors (MAOIs), antidepressants such as isocarboxazid (Marplan) and phenelzine (Nardil)
  • Anti-migraine medications, such as carbamazepine (Tegretol, Carbatrol, others), valproic acid (Depakene) and triptans, which include almotriptan, naratriptan (Amerge) and sumatriptan (Imitrex, Tosymra, others)
  • Pain medications, such as opioid pain medications including codeine, fentanyl (Duragesic, Abstral, others), hydrocodone (Hysingla ER, Zohydro ER), meperidine (Demerol), oxycodone (Oxycontin, Roxicodone, others) and tramadol (Ultram, ConZip)
  • Lithium (Lithobid), a mood stabilizer
  • Illicit drugs, including LSD, ecstasy, cocaine and amphetamines
  • Herbal supplements, including St. John’s wort, ginseng and nutmeg
  • Over-the-counter cough and cold medications containing dextromethorphan (Delsym)
  • Anti-nausea medications such as granisetron (Sancuso, Sustol), metoclopramide (Reglan), droperidol (Inapsine) and ondansetron (Zofran, Zuplenz)
  • Linezolid (Zyvox), an antibiotic
  • Ritonavir (Norvir), an anti-retroviral medication used to treat HIV

Risk factors

Some people are more susceptible to the drugs and supplements that cause serotonin syndrome than are others, but the condition can occur in anyone.

You’re at increased risk of serotonin syndrome if:

  • You recently started taking or increased the dose of a medication known to increase serotonin levels
  • You take more than one drug known to increase serotonin levels
  • You take herbal supplements known to increase serotonin levels
  • You use an illicit drug known to increase serotonin levels

Complications

Serotonin syndrome generally doesn’t cause any problems once serotonin levels are back to normal.

If left untreated, severe serotonin syndrome can lead to unconsciousness and death.

Prevention

Taking more than one serotonin-related medication or increasing your dose of a serotonin-related medication increases your risk of serotonin syndrome.

Be sure to talk to your doctor if you or a family member has experienced symptoms after taking a medication.

Also talk to your doctor about possible risks. Don’t stop taking any such medications on your own. If your doctor prescribes a new medication, make sure he or she knows about all the other medications you’re taking, especially if you receive prescriptions from more than one doctor.

If you and your doctor decide the benefits of combining certain serotonin-level-affecting drugs outweigh the risks, be alert to the possibility of serotonin syndrome.

Diagnosis

No single test can confirm a serotonin syndrome diagnosis. Your doctor will diagnose the condition by ruling out other possibilities.

Your doctor will likely begin by asking about your symptoms, medical history and any medications you’re taking. Your doctor will also conduct a physical examination.

To make sure your symptoms are caused by serotonin syndrome and not due to another cause, your doctor may use tests to:

  • Measure levels of any drugs you’re using
  • Check for signs of infection
  • Check body functions that may be affected by serotonin syndrome

A number of conditions can cause symptoms similar to those of serotonin syndrome. Minor symptoms can be caused by several conditions, while moderate and severe symptoms similar to those of serotonin syndrome could be caused by:

  • A serious reaction to certain medications, such as some anesthetics, antipsychotic drugs and other agents known to produce these severe reactions
  • An overdose of illegal drugs, antidepressant medications or other medications that increase serotonin levels
  • Damage associated with illegal drug use
  • Severe alcohol withdrawal

Your doctor may order additional tests to rule out other causes of your symptoms. Tests may include:

  • Blood and urine tests
  • Chest X-ray
  • CT scan
  • Spinal tap (lumbar puncture)

Treatment

Treatment of serotonin syndrome depends on the severity of your symptoms.

  • If your symptoms are minor, a visit to the doctor and stopping the medication causing the problem may be enough.
  • If you have symptoms that concern your doctor, you may need to go to the hospital. Your doctor may have you stay in the hospital for several hours to make sure your symptoms are improving.
  • If you have severe serotonin syndrome, you’ll need intensive treatment in a hospital.

Depending on your symptoms, you may receive the following treatments:

  • Muscle relaxants. Benzodiazepines, such as diazepam (Valium, Diastat) or lorazepam (Ativan), can help control agitation, seizures and muscle stiffness.
  • Serotonin-production blocking agents. If other treatments aren’t working, medications such as cyproheptadine can help by blocking serotonin production.
  • Oxygen and intravenous (IV) fluids. Breathing oxygen through a mask helps maintain normal oxygen levels in your blood, and IV fluids are used to treat dehydration and fever.
  • Drugs that control heart rate and blood pressure. These may include esmolol (Brevibloc) or nitroprusside (Nitropress) to reduce a high heart rate or high blood pressure.

    If your blood pressure is too low, your doctor may give you phenylephrine (Vazculep) or epinephrine (Adrenalin, Epipen, others).

  • A breathing tube and machine and medication to paralyze your muscles. You may need this treatment if you have a high fever.

Milder forms of serotonin syndrome usually go away within 24 to 72 hours of stopping medications that increase serotonin, and by taking medications to block the effects of serotonin already in your system if they’re needed.

However, symptoms of serotonin syndrome caused by some antidepressants could take several weeks to go away completely. These medications remain in your system longer than do other medications that can cause serotonin syndrome.

Preparing for an appointment

Because serotonin syndrome can be a life-threatening condition, seek emergency treatment if you have worsening or severe symptoms.

If your symptoms aren’t severe, you’re likely to start by seeing your family doctor or a general practitioner. Here’s some information to help you get ready for your appointment and to know what to expect from your doctor.

What you can do

  • Be aware of any pre-appointment steps you need to take. When you make the appointment, be sure to ask if there’s anything you need to do in advance, such as quitting any of the current medications or supplements you take.
  • Note down any symptoms you’re experiencing, even if they seem unrelated to the reason you have scheduled the appointment.
  • Make a note of key personal information, including things like recent life changes, or major stresses.
  • List all of the drugs, vitamins or supplements that you’re currently taking or have taken recently.
  • Take a family member or friend along, if possible. Sometimes it can be difficult to absorb all the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot.
  • Write down a list of questions to ask your doctor.

Preparing a list of questions will help you make the most of your time with your doctor. For symptoms you think may be caused by serotonin syndrome, some basic questions to ask your doctor include:

  • Is serotonin syndrome most likely causing my symptoms, or could it be something else?
  • Other than the most likely cause, what are other possible causes of my symptoms?
  • What kinds of tests do I need?
  • What is the best course of action?
  • What are the alternatives to the primary approach that you’re suggesting?
  • I have other health conditions. How can I best manage them together?
  • Can I still take the medications I’ve been prescribed, or will I need to change them or change the dose?
  • Are there any restrictions that I need to follow, such as avoiding certain drugs or supplements?

Don’t hesitate to ask your doctor any other questions you have.

What to expect from your doctor

Examples of questions your doctor may ask, include:

  • When did you begin experiencing symptoms?
  • Have your symptoms been continuous or occasional?
  • How severe are your symptoms?
  • What prescription and over-the-counter medications do you take?
  • Do you use any illicit drugs?
  • Do you take any dietary supplements?

Serotonin syndrome is the accumulation of too much serotonin in your body, resulting in a series of various signs. When an individual takes a combination of medications that contain serotonin (commonly prescribed antidepressants such as Zoloft, Lexapro, both SSRIS and Effexor, an SNRI), they are at a high risk for developing serotonin syndrome.

On occasion, taking one medication to increase serotonin levels can also result in serotonin syndrome in susceptible individuals. Before starting any medication, it is vital that you discuss all the medications you are taking with your doctor to avoid this potentially lethal condition.

What is Serotonin?

Serotonin is a chemical produced by the body that helps to regulate mood, social behavior, sexual desire, sleep, and appetite. As a neurotransmitter, serotonin carries signals between nerve cells. It is produced in the intestines and the brain, but is also present in the central nervous system (CNS) and blood platelets. As a result, serotonin is believed to influence a wide range of psychological and bodily functions.

What Does Serotonin Syndrome Feel Like?

If you start taking a serotonin-related medication, increase your dosage, or begin another in combination with one you are already taking and too much serotonin accumulates, you will feel the effects within several hours. Symptoms can range from mild to severe and depend on the level of serotonin in your body. At best, the signs and symptoms of serotonin are unpleasant; at worst, they can be extremely worrying and require intensive medical treatment.

Serotonin Syndrome Symptoms

The following symptoms are signs that you are experiencing serotonin syndrome:

  • Headaches
  • Shivering
  • Goosebumps
  • Heavy sweating
  • Restlessness
  • Agitation
  • Dilated pupils
  • Confusion
  • Diarrhea
  • Rapid heart rate
  • High blood pressure
  • Muscle rigidity
  • Loss of muscle coordination
  • Twitching muscles

If you experience these symptoms, contact your doctor as soon as possible to discuss the best course of action. However, severe serotonin syndrome can be life-threatening and if you experience any of the symptoms below you should seek emergency treatment immediately:

  • Irregular heartbeat
  • High fever (>103 F/40 C)
  • Seizures
  • Unconsciousness

How Long Does Serotonin Syndrome Last?

How long serotonin syndrome lasts is dependent on how high serotonin levels are in the body. In cases where serotonin syndrome is only present in a mild form, symptoms may be alleviated within 24 hours of discontinuing the medication causing the uptake in serotonin. However, some antidepressants can cause symptoms to last longer as serotonin levels may take weeks to return to normal.

How Common is Serotonin Syndrome?

According to the American Association of Poison Control Centers Toxic Exposure Surveillance System 8,187 people were diagnosed as having serotonin toxicity due to selective serotonin reuptake inhibitors (SSRIs) in 2004. Of these cases, 103 deaths occurred. However, given that statistics on serotonin syndrome are limited, it is likely much more common than the data indicates as those that suffer from mild to moderate serotonin toxicity often go undiagnosed or unreported.

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Serotonin syndrome most often occurs when you combine two serotonin-related medications, though, in some cases, taking one drug that increases serotonin levels may induce the condition in some individuals.

For example, serotonin syndrome could occur if you combine an antidepressant medication with an opioid medication.

Which Medications Cause Serotonin Syndrome?

Drugs and supplements that could lead to serotonin syndrome if taken together or in high doses include:

  • Selective serotonin reuptake inhibitors (SSRIs): antidepressants such as citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as trazodone, duloxetine (Cymbalta) and venlafaxine (Effexor)
  • Tricyclic antidepressants, such as amitriptyline and nortriptyline (Pamelor)
  • Anti-migraine medications
  • Pain medications: opioid medications including codeine (Tylenol with codeine), fentanyl (Duragesic), hydrocodone meperidine (Demerol), oxycodone (Oxycontin, Percocet, Percodan) and tramadol (Ultram).
  • Lithium
  • Street drugs: LSD, cocaine, ecstasy, and amphetamines
  • Anti-nausea medications
  • Cough and cold medications
  • Herbal supplements: St. John’s wort, ginseng, and nutmeg
  • Cannabinoids may also influence serotonin

Is Serotonin Syndrome Fatal?

If medical treatment is not sought when serotonin levels get too high, severe serotonin syndrome can lead to unconsciousness and death. Intentional serotonin overdose using anti-depressant medications is one instance in which serotonin syndrome is likely to be fatal without prompt medical treatment.

Can Serotonin Syndrome Be Reversed?

The symptoms of serotonin syndrome usually subside once you stop taking the medication causing the symptoms. Fortunately, there are generally no long-term or lasting complications of serotonin syndrome, though you should be conscious to avoid serotonin syndrome in the future. Talk to your doctor about prevention, especially if you are taking multiple medications that contain serotonin.

Serotonin Syndrome Treatment

Depending on where serotonin syndrome symptoms fall on a scale of mild to severe, treatment will vary in complexity. Typically, doctors will instruct the patient to stop taking the medication causing the elevated serotonin levels as the first course of action. Medications will not disappear from the body immediately and patients will be carefully monitored for any adverse reactions or withdrawal symptoms.

  • “Some patients with high body temperature or hyperthermia will need external cooling measures, similar to those used when treating someone with heat stroke,” Kyle Moylan, MD, FACP told ACP Hospitalist. “In cases where a patient’s blood pressure is very high or very low, short-acting agents should be used because changes in blood pressure can occur very quickly.” An IV and Cyproheptadine (Periactin), a drug that blocks serotonin production, may also be needed.

Finally, in some cases, benzodiazepines may also be given if the patient has severe symptoms and needs to be sedated.

Overall, it’s important to stay informed about your medications. Knowing what you are taking, the active ingredients, possible side effects, and medications that should not be mixed are important in avoiding serotonin syndrome. Pay close attention to the instructions of your medications to ensure you are taking them at correct intervals. If you have questions about your medications, reach out to your doctor to double check that you are not mixing medications that could result in serotonin syndrome.

While you should not be scared if you’ve been assigned one of the medications listed above that contains serotonin, it is vital to keep aware of the effects that mixed medications can have on one another.

Article Sources Last Updated: Mar 19, 2019

Serotonin syndrome warnings magnify its rare probability

Serotonin syndrome.

What do those words make you think of? A rare neurological condition? The differential diagnosis you got at 2:00 a.m. from an overly enthusiastic resident? Or a fax from a pharmacy that you get a few times a week?

I’ll say the last.

megaflopp/Thinkstock SSRIs and SNRIs are everywhere out there. Sometimes it seems like the majority of the population is on them. I’m not knocking that at all – mental health is often overlooked, but critically important.

Triptans are not as common, but are still out there in large numbers. To date, they’re the most effective migraine treatment we have.

Inevitably, these roads will cross, especially because SNRIs, and their older cousins the tricylic antidepressants, are commonly used for migraine prevention. And that’s where the fun begins. There’s a suspected incidence of serotonin syndrome when the two are combined, which became widespread knowledge following a 2006 Food and Drug Administration alert. This is a fact drilled into us by multiple call-backs and faxes from pharmacies, terrified patients who use Google, and electronic prescribing systems that flag our attempts to combine them to make sure we know THIS IS DANGEROUS!

But a study published Feb. 26 in JAMA Neurology found that it’s rarer than anyone suspected (JAMA Neurol. 2018 Feb 26. doi: 10.1001/jamaneurol.2017.5144). Breaking down 14 years’ worth of patient data with more than 19,000 patients on both triptans and serotonergic drugs, there were only two cases (0.01%) that clearly met criteria for serotonin syndrome.

Dr. Allan M. Block

That ain’t much. Of course, you can always make the argument that if you’re one of those cases the incidence goes up to 100%, but it certainly puts the overall frequency into perspective. Prescribing the combination is far from being overtly dangerous.

I also understand where the warnings come from. When things go bad, medicine becomes a blame game as each side points at another. The pharmacy wants to say they warned us. The e-prescribing system company wants to say they warned us. The patients want to know why no one warned them when a Google search makes it sound common. And the malpractice lawyers want to blame everyone.

But there are more serious side effects out there. Dilantin has been linked to lymphoma. Sinemet (possibly) to melanoma. But do you remember the last time you had to click or sign off on a pharmacy warning for those? Me neither.

Using any drug is a balance of risks and benefits. We make our judgments, discuss concerns with the patients, and roll the dice every day. Side effects aren’t uncommon. Most serious side effects are rare. But warnings that magnify issues with a rare probability don’t help the situation and can keep patients from receiving the help they need.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Serotonin Syndrome and Other Serotonergic Disorders

  • 10)

    Conversely, the action of certain SSRIs that directly inhibit P450 enzyme subtypes, including fluoxetine, paroxetine, sertraline, and nefazodone, may increase methadone levels, making standard dosing conversions from other opioids to methadone unreliable in these circumstances .

  • 11)

    Finally, although these medications are generally thought to be safe, with many years in the field with millions of users, the longer term consequences of chronic SSRI use are still unknown and may include dyskinesias and EPS. Whether these risks warrant that future guidelines for long-term use of SSRIs include AIMS testing, in the same way is done for patients on neuroleptics, is yet to be determined.

  • Conclusions

    Although SSRIs are widely considered to be safe with little established toxicity, there appear to be several side effects associated with their use that may be generally unrecognized and therefore under-reported. All clinicians should be aware of the risk for psychiatric, neurological and medical side effects to ensure proper caution in prescribing combinations of drugs affecting serotonin and to ensure early detection and proper management of the conditions associated with serotonergic excess and toxicity. Prompt recognition of the most severe condition, serotonin syndrome, can be life saving. Use of medication combinations that induce serotonin toxicity could potentially result in morbidity and mortality, so physicians should consider the potential for these effects when using such combinations. Further studies should seek prevalence rates of serotonin excess in various illness populations, starting in groups at higher risk for exposure, such as patients with comorbid pain and depression, to identify both prevalence and incidence rates of toxicity. The problem of the variability of drug–drug interactions within the patient population and the prediction of health risk for using polypharmacy in settings such as geriatric or pain clinics calls for the introduction of a predictive pharmacotherapy model. Pharmacogenetics is a promising new field of basic and clinical research that should provide practitioners with useful information about risks in individual patients and groups of patients to reduce the risk of drug interactions and to allow for a more effective and safer polypharmacy.

    Acknowledgments

    Colleen Healy helped with referencing and typing of several iterations of this manuscript. We dedicate this article to our families.

    1 Gallagher RM Verma S . Managing pain and comorbid depression: A public health challenge Semin Clin Neuropsychiatry. 1999;4:203–20. 2 Gerson SC Baldessarini RJ . Motor effects of serotonin in the central nervous system Life Sci. 1980;27:1435–51. 3 LoCorto MJ . The serotonin syndrome Emerg Med Clin North Am. 1997;15:665–75. 4 Bradley PB Engel G Feniuk W et al. Proposals for the classification and nomenclature of functional receptors for 5-hydroxytriptamine Neuropharmacology. 1986;25:563–76. 5 Bodner RA Lynch T Lewis L et al. Serotonin syndrome Neurology. 1995;45:219–23. 6 Mills KC . Serotonin syndrome Am Fam Phys. 1995;52:1475–82. 7 Gillman PK . The serotonin syndrome and its treatment J Psychopharmacol. 1999;13:100–9. 8 Kapur S Zipursky RB Jones C et al. Ciproheptadine: A potent in vivo serotonin antagonist Am J Psychiatry. 1997;154:884–884. 9 Jacobs BL Klemfuss H . Brain stem and spinal cord mediation of a serotonergic behavioral syndrome Brain Res. 1975;100:450–7. 10 Jacobs BL Fornal CA . 5-HT and motor control: A hypothesis Trends Neurosci. 1993;16:346–52. 11 Siriwardena A Kellum JMJr. A 5-HT2 receptor mediates serotonin-induced electrolyte transport in rat left colon J Surg Res. 1993;55:323–9. 12 Mege J . Serotonin syndrome Pa Med. 2000;103:8–9. 13 Waters CH . Fluoxetine and selegiline—lack of significant interaction Can J Neurol Sci. 1994;21:259–61. 14 Jermain DM Hughes PL Follender AB . Potential fluoxetine-selegiline interaction Ann Pharmacother. 1992;26:1300. 15 Suchowersky O DeVries JD . Interaction of fluoxetine and selegiline Can J Psychiatry. 1990;35:571–2. 16 Graham PM Potter JM Paterson J . Combination monoamine oxidase inhibitor/tricyclic antidepressants interaction Lancet. 1982;2:440. 17 Marley E Wozniak KM . Clinical and experimental aspects of interactions between amine oxidase inhibitors and amine re-uptake inhibitors Psychol Med. 1983;13:735–49. 18 Sternbach H . The serotonin syndrome Am J Psychiatry. 1991;148:705–13. 19 Gardner DM Lynd LD . Sumatriptan contraindications and the serotonin syndrome Ann Pharmacother. 1998;32:33–8. 20 Skop BP Finkelstein JA Mareth TR et al. The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease Am J Emerg Med. 1994;12:642–4. 21 Nielsen DA Goldman D Virkkunen M et al. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism Arch Gen Psychiatry. 1994;51:34–8. 22 Van Kempen GM Notten P Hengeveld MW . Repeated measures of platelet MAO activity and 5-HT in a group of suicidal women Biol Psychiatry. 1992;31:529–30. 23 Brown TM Skop BP Mareth TR . Pathophysiology and management of the serotonin syndrome Ann Pharmacother. 1996;30:527–33. 24 Brosen K Hansen JG Nielsen KK et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine Eur J Clin Pharmacol. 1993;44:349–55. 25 Gerber PE Lynd LD . Selective serotonin-reuptake inhibitor-induced movement disorders Ann Pharmacother. 1998;32:692–8. 26 Rosenberg PB Pearlman CA . NMS-like syndrome with a lithium/doxepin combination J Clin Psychopharmacol. 1991;11:75–6. 27 Lane RM . SSRI-induced extrapyramidal side-effects and akathisia: Implications for treatment J Psychopharmacol. 1998; 12192–214. 28 Black B Uhde TW . Acute dystonia and fluoxetine J Clin Psychiatry. 1992;53:327. 29 Steinbusch HW . Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals Neuroscience. 1981;6:557–618. 30 Daniel DG Randolph C Jaskiw G et al. Coadministration of fluvoxamine increases serum concentrations of haloperidol J Clin Psychopharmacol. 1994;14:340–3. 31 Meltzer HY Young M Metz J et al. Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant J Neural Trans. 1979;45:165–75. 32 Bouchard R Poucher E Vincent P . Fluoxetine and EPS effects Am J Psychiatry. 1989;146:1352–3. 33 Jacobs BL Azmitia EC . Structure and function of the brain serotonin system Physiol Rev. 1992;72:165–229. 34 Fishbain DA Dominguez M Goldberg M et al. Dyskinesia associated with fluoxetine use Neuropsychiatry Neuropsychol Behav Neurol. 1992;5:97–100. 35 Hammer RP Margulies JE Lynn AB et al. Chronic fluoxetine treatment upregulates dopamine receptors in the mesolimbic forebrain of the rat Depression. 1993;1:82–7. 36 Lipinski JFJr Mallya G Zimmerman P et al. Fluoxetine-induced akathisia: Clinical and theoretical implications J Clin Psychiatry. 1989;50:339–42. 37 Goldstein J Litwin L Malick J . Ritanserin increases spontaneous activity of A9 and A10 dopaminergic neurons Fed Proc. 1987; 946–66. 38 Lane R Baldwin D . Selective serotonin reuptake inhibitor-induced serotonin syndrome: Review J Clin Psychopharmacol. 1997;17:208–21. 39 Murphy DL Mueller EA Hill JL et al. Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers Psychopharmacology (Berl). 1989;98:275–82. 40 Committee on Safety of Medicines (CSM). Dystonia and withdrawal symptoms with paroxetine (seroxat) Current Problems in Pharmacovigilance. 1993;19:1. 41 Choo V . Paroxetine and extrapyramidal reactions Lancet. 1993;341:624. 42 Armstrong M Daly AK Cholerton S et al. Mutant debrisoquine hydroxylation genes in Parkinson’s disease Lancet. 1992;339:1017–8. 43 Smith CA Gough AC Leigh PN et al. Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease Lancet. 1992;339:1375–7. 44 Steiger MJ Lledo P Ouinn NP et al. Debrisoquine hydroxylation in Parkinson’s disease Acta Neurol Scand. 1992;86:159–64. 45 Arthur H Dahl ML Siwers B et al. Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia J Clin Psychopharmacol. 1995;15:211–6. 46 Pollock BG Mulsant BH Sweet RA et al. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia Psychopharmacol Bull. 1995;31:327–31. 47 Armstrong M Daly AK Blennerhassett R et al. Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype Br J Psychiatry. 1997;170:23–6. 48 Andreassen OA MacEwan T Gulbrandsen AK et al. Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients Psychopharmacology (Berl). 1997;131:174–9. 49 Serebruany VL O’Connor CM Gurbel PA . Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary artery disease Am J Cardiol. 2001;87:1398–400. 50 Fricchione GL Woznicki RM Klesmer J et al. Vasoconstrictive effects and SSRIs J Clin Psychiatry. 1993;54:71–2. 51 Fishman SM Wilsey B Mahajan G et al. Methadone reincarnated: Novel clinical applications with related concerns Pain Med. 2002;3:339–48. 52 Robertson JA Brody B Buchanan A Kahn J McPherson E . Pharmacogenetic challenges for the health care system Health Aff (Millwood). 2002;2:155–67. 53 Guttmacher AE Collins FS . Genomic medicine—A primer N Engl J Med. 2002;347:1512–20.

    How Common or Significant Is Serotonin Syndrome?

    Question

    We are seeing more patients who are taking multiple antidepressants of different classes. All drug interaction programs cite drug-drug interactions leading to the potentially severe toxicity known as serotonin syndrome. Just how common and clinically significant is serotonin syndrome?

    Response

    Joel Lamoure, RPh, BSP, FASCP

    Assistant Professor, Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Mental Health Pharmacist, London Health Sciences Centre, London, Ontario, Canada

    The Toxic Exposure Surveillance System reviewed cases from office-based practices, inpatient settings, and emergency departments and found that during 2004, selective serotonin reuptake inhibitors (SSRIs) caused significant toxic effects in 8187 persons, leading to 103 deaths. The true incidence of serotonin syndrome and associated morbidity are likely to be much greater. This syndrome may be underdiagnosed given the fact that SSRIs are not the only contributing class of agents. Moreover, it has been suggested that more than 85% of physicians are unaware that the syndrome even exists.

    Serotonin syndrome is a condition caused most often by the concurrent use of 2 or more agents that enhance synaptic serotonin levels. A triad of clinical changes — cognitive, neuromuscular, and autonomic — characterizes this syndrome. Specific changes may include confusion, delirium, agitation, restlessness, muscular spasms, hyperpyrexia, diaphoresis, tachycardia, blood pressure fluctuations, mydriasis, nausea, or diarrhea. Symptoms often develop within 2 hours of the increase in the synaptic level of serotonin. The clinician must be proactive to identify the early symptoms, such as cognitive changes, when they occur.

    Confusion about symptoms may be responsible for the difficulty in assessing the actual incidence of serotonin syndrome. Agitation, a cardinal symptom of serotonin syndrome, is clinically similar to activation, an adverse effect associated with SSRI use.

    Polypharmacy is pandemic, and the incidence of serotonin syndrome may be on the rise. Both drug factors and patient factors can contribute to the toxicity of SSRIs in some individuals. A wide range of medications can increase serotonin levels in the body. When these agents are combined, the risk of serotonin syndrome increases. Drug classes implicated include anti-migraine agents (eg, triptans); antidepressants (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors, buspirone, tricyclic antidepressants, monoamine oxidase inhibitors); antipsychotics; anticonvulsants; anti-Parkinsonian agents; analgesics (eg, meperidine, tramadol); over-the-counter products (eg, medications containing dextromethorphan); herbal products (eg, St. John’s Wort); and antibiotics (eg, linezolid).

    Concurrent use of medications that interact with serotonergic drugs through the inhibition of the cytochrome P450 pathway can also contribute to serotonin syndrome. For example, extra caution should be observed if a patient is taking an SSRI in addition to a cytochrome P450 2D6 (CYP2D6) inhibitor because SSRIs are extensively hepatically metabolized by this isozyme.

    Susceptibility to the serotonin syndrome can also be conferred by patient factors, such as the capacity to metabolize certain drugs. One of the key enzymes related to adverse drug reactions, the CYP2D6 system, has a high degree of genetic polymorphism. An example of this was reported in a study of 4 elderly patients who ostensibly developed serotonin syndrome as a result of an interaction between tramadol and mirtazapine. The patients had auditory and visual hallucinations, myoclonus, hypertension, and changes in behavior. Tramadol may be subject to genetic polymorphism; about 7% of whites are poor metabolizers of CYP2D6. Consequently, these patients would have higher serum levels of tramadol and be at increased risk for serotonin syndrome when a second serotonergic agent is added.

    Although rare in monotherapy, serotonin syndrome is more prevalent with polypharmacy, even across medication classes. When a computer flags this interaction, the clinician should consider the whole patient: What medications has the patient taken previously? What adverse reactions have previously been experienced? When making an evidence-based recommendation, it is essential to apply the therapeutic thought process and carry out a sound risk-benefit assessment. Awareness of serotonin syndrome and education about its effects are vital. All of these factors must be considered, lest all the “holes in the Swiss cheese line up” and the patient comes to harm.

    The author acknowledges Jessica Stovel, pharmacist, and Katherine Bateman, pharmacy resident at London Health Sciences Centre, for their research and contributions to this article.

    Serotonin Syndrome Causes

    Serotonin syndrome can occur if you are taking medications, particularly antidepressants that affect the body’s level of serotonin. The greatest risk of serotonin syndrome occurs if you are taking two or more drugs and/or supplements together that influence serotonin. The condition is more likely to occur when you first start a medicine or increase the dose.

    Other prescription and over-the-counter drugs that can raise serotonin levels alone or in combination to cause serotonin syndrome include:

    • Serotonin and norepinephrine reuptake inhibitors (SNRIs), a class of antidepressants including desvenlafaxine (Khedezla), desvenlafaxine succinate (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), and venlafaxine (Effexor).
    • Monoamine oxidase inhibitors (MAOIs), a class of antidepressants including isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), and transdermal selegiline (EMSAM)
    • Buspirone (BuSpar), a drug used to treat anxiety disorders
    • Desyrel ( Trazodone ), a drug prescribed for depression or insomnia
    • Migraine treatments such as almotriptan (Axert), Amerge (naratriptan), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig)
    • Certain pain medications, including fentanyl (Sublimaze, Fentora), fentanyl citrate (Actiq), meperidine (Demerol), pentazocine (Talwin), and tramadol (Ultram)
    • Dextromethorphan , a cough suppressant found in many over-the-counter and prescription cough medicines or cold medicines
    • Certain medications prescribed for nausea, such as granisetron (Kytril), metoclopramide (Reglan), and ondansetron (Zofran)
    • Antidepressants that affect multiple serotonin receptors, such as vortioxetine (Trintellix -formerly Brintellix) and vilazodone (Viibryd)

    US Pharm. 2010;35(11):HS-16-HS-21.

    A potentially lethal condition, serotonin syndrome (SS) is caused most often when certain antidepressant agents are taken concurrently with other drugs that modulate synaptic serotonin levels.1,2 When patients take two or more antidepressants from different pharmacologic classes, drug-drug interactions may occur; these interactions may lead to potentially severe serotonin toxicity, or SS. This syndrome was first described during the 1960s in studies of monotherapy and combination therapy with antidepressant medications.

    In a review of suspected SS cases from physician office-based practices, inpatient hospital visits, and emergency room visits, the Toxic Exposure Surveillance System found that selective serotonin reuptake inhibitors (SSRIs) caused significant toxic effects in more than 8,000 people, leading to more than 100 deaths.2 One notable case that garnered national attention was that of Libby Zion, an 18-year-old college freshman with a history of depression who was being treated with phenelzine.3 She was admitted to Manhattan’s New York Hospital on the evening of October 4, 1984, with agitation, disorientation, fever, and jerky body motions. Libby was prescribed an injection of meperidine to calm her and control her shaking, and, later, when her agitation increased, an injection of haloperidol. She eventually fell asleep, but when her temperature was taken at 6:30 am, it was 107°F. Emergency measures were undertaken to lower her temperature, but Libby experienced cardiac arrest and died.3

    The incidence of adverse drug reports with SSRIs has continued to increase as more serotonergic drugs have become available.4,5 The true incidences of SS and associated morbidity are likely unknown. Also, SS may be underdiagnosed. Some reasons for this are that SSRIs are not the only contributing class of drugs; SS symptoms can range from mild to severe and may be nonspecific; diagnostic criteria vary; and some clinicians are unfamiliar with the condition. It has been suggested that more than 85% of physicians are unaware of the existence of SS or of which drugs or drug combinations are capable of causing it.5 In addition, mild SS symptoms may be ignored or not attributed to drug therapy. Polymedicine is pandemic in our society, and the incidence of SS may be on the rise. A wide variety of medications have the potential to elevate serotonin levels in the body. When these agents are combined, the risk of SS increases.

    Causative Agents

    SS may occur when central and peripheral serotonin receptors are overstimulated through the action of antidepressant medications or drugs of abuse.4 Both drug factors and patient factors can contribute to the toxicity of SSRIs in some individuals. Drug classes implicated include antimigraine agents; triptans (e.g., sumatriptan); antidepressants (e.g., SSRIs, serotonin norepinephrine reuptake inhibitors , buspirone, tricyclic antidepressants, monoamine oxidase inhibitors ); antipsychotics; anticonvulsants; antiparkinsonian agents; analgesics (e.g., meperidine, tramadol); OTC products (e.g., cough and cold medication containing dextromethorphan); herbal products (e.g., St. John’s wort ; and the antibiotic linezolid.6-13 Mild SS episodes have been reported when St. John’s wort or triptans have been used concurrently with SSRIs, SNRIs, or tricyclic antidepressants (e.g., amitriptyline). More severe SS episodes have been reported with the use of an MAOI with other serotonergic drugs (e.g., SSRIs, SNRIs).14,15 See TABLE 1 for a more comprehensive list of drugs commonly associated with SS.6-13

    SS typically occurs when a patient takes two or more drugs that elevate serotonin levels through different mechanisms, but the syndrome can occur with the use of individual agents.16 Mechanisms that cause SS include increased serotonin production, inhibition of serotonin reuptake, inhibition of serotonin metabolism, increased serotonin release, and stimulation of serotonin receptors.16 Certain drugs may affect serotonin levels through more than one mechanism. Mechanisms of action and their causative agent(s) include the following:

    Increased Serotonin Production: One substance that increases serotonin production is the dietary supplement L-tryptophan. This serotonin precursor has been implicated in SS.4,17,18

    Inhibition of Serotonin Reuptake: Drugs that inhibit serotonin reuptake include chlorpheniramine; cyclobenzaprine; dextromethorphan (e.g., Robitussin DM); meperidine; methadone; pentazocine; sibutramine; SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); St. John’s wort; tramadol; trazodone; and tricyclic antidepressants (e.g., clomipramine, imipramine). Clomipramine and imipramine have relatively high serotonergic activity compared with amitriptyline, which inhibits serotonin reuptake to a lesser degree.4,5,16,18-21

    Inhibition of Serotonin Metabolism by MAO: This category includes isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, and tranylcypromine.4,17-19,22,23

    Increased Serotonin Release: Some drugs that increase serotonin release are dextromethorphan, meperidine, methadone, methylenedioxymethamphetamine (also known as MDMA or ecstasy), and mirtazapine.4,19,21,24

    Stimulation of Serotonin Receptors: Drugs that stimulate serotonin receptors include buspirone; dihydroergotamine; lithium; lysergic acid diethylamide (LSD); meperidine; metoclopramide; and triptans (e.g, sumatriptan).4,19,24,25 SS also can occur when the metabolism and elimination of a serotonergic drug are altered; e.g., some SSRIs inhibit the metabolism of tramadol by CYP2D6 inhibition and may increase serotonergic activity.26

    Clinical Signs and Symptoms

    Clinical symptoms of SS typically develop within 2 hours of an increase in dose or the addition of a serotonergic drug.19,27 About 67% of affected patients present with symptoms within 6 hours of medication initiation, change in dose, or overdose. Approximately 75% of affected patients experience symptoms within 24 hours.4,28 The clinician must be proactive to identify early symptoms of SS–e.g., cognitive changes–when they occur. Confusion about symptoms may be responsible for the difficulty in assessing the actual incidence of SS.24 Agitation is a cardinal symptom of SS, and it occurs to some degree with most SSRIs.27 The Hunter Serotonin Toxicity Criteria are recommended for diagnosing SS (TABLE 2).11,28

    A triad of clinical features characterize SS: 1) cognitive or mental-status changes (e.g., agitation, confusion, delirium, hallucinations, hyperactivity, hypervigilance, hypomania, pressured speech); 2) neuromuscular abnormalities (clonus , hyperreflexia, increased muscle tone and spasms, restlessness, rhabdomyolysis, rigidity, shivering, tremor); and 3) autonomic hyperactivity symptoms (diaphoresis, diarrhea, fever, flushing, hypotension or hypertension, increased bowel sounds, mydriasis, increased respiratory rate, tachycardia, tearing).4,17,29,30

    Mild SS may have a more subacute or even chronic presentation. In such cases, symptoms might be dismissed by clinicians or not attributed to the medication.4 A patient who presents with rapidly increasing temperature and muscle rigidity should probably be considered a medical emergency, as progression to multiorgan failure can occur within hours.27

    Two serotonergic drugs do not need to be administered concurrently to cause SS; the syndrome can occur up to 6 weeks after discontinuation of just one such drug with a long-acting dosage form, like fluoxetine (Prozac, Sarafem) or an MAOI (e.g., isocarboxazid, phenelzine).17

    Concurrent use of medications that interact with serotonergic drugs, thereby resulting in inhibition of the CYP450 metabolic pathway, can also contribute to SS.31 In this regard, caution should be observed when a patient is taking an SSRI in addition to a CYP2D6 inhibitor or a CYP3A4 inhibitor: SSRIs are extensively metabolized in the liver by these isozymes, and some patients lack the capacity to metabolize certain drugs.

    One of the key enzymes involved in adverse drug reactions–the CYP2D6 system–has a high degree of genetic polymorphism.32 A study reported on four elderly patients who apparently developed SS as a result of an interaction between tramadol and mirtazapine.33 These patients presented with auditory and visual hallucinations, myoclonus, hypertension, and behavioral changes. Tramadol is reported to be subject to genetic polymorphism, and about 7% of white patients are poor metabolizers of drugs metabolized by CYP2D6.34,35 Consequently, these patients would have higher serum levels of tramadol and would be at increased risk for SS if a second serotonergic agent were added to the drug regimen.34

    In general, treatment of SS first involves discontinuing the offending drug(s) and providing the patient with supportive care. Many mild-to-moderate SS cases are self-limiting and usually resolve within 24 to 72 hours.19 Resolution of more severe cases will likely take much longer. In such cases, supportive care, drug discontinuation, and administration of medication (e.g., diazepam 5 mg IV to reduce hypertonicity and neurologic excitability) may be sufficient to resolve mild symptoms.2,13,36 Patients with severe symptoms may need sedation, paralyzation, and intubation.

    Administration of drugs with serotonin antagonist properties, such as cyproheptadine and chlorpromazine, has been utilized in a few patients.4,16,18 Cyproheptadine 4 mg orally is the most widely used antidote for SS.36 Although increased body temperature is common in patients with severe SS, antipyretic therapy usually is not recommended. This is because the fever that occurs with SS is caused by excessive muscular activity, not a change in the hypothalamic temperature set point.2

    Role of the Pharmacist

    Severe episodes of SS are generally considered rare with monotherapy; SS is more prevalent with polymedicine, even across medication classes. The pharmacist should be knowledgeable about individual drugs and drug combinations with the propensity to cause SS (TABLE 1), the mechanism of action associated with the syndrome, and common signs and symptoms of SS. With this information, the pharmacist is better prepared to advise a patient having this reaction or to advise physicians about necessary drug changes to assure patient safety.

    When a pharmacy’s computer sounds an alert of a potential drug-drug interaction, the clinician should thoroughly examine the patient’s medication history: What medication has the patient taken previously? What adverse drug reactions have been previously experienced? When making drug therapy recommendations, it is essential for the pharmacist to apply knowledge of pharmacology and pharmacokinetics of causative drugs and to carry out a sound risk-benefit assessment. Awareness of SS and education about its effects are vital. All of these factors must be considered to avoid harm to the patient.37

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