Detecting and Managing Serotonin Syndrome

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 [SS] 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 [5-HT]). 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 [serotonin-norepinephrine reuptake inhibitor (SNRI)] 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.

References

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.

4. Vijay A, Becker JE, Ross JS. Patterns and predictors of off-label prescription of psychiatric drugs. PLoS One. 2018;13(7):e0198363.

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

6. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th annual report. Clin Toxicol (Phila). 2017;55(10):1072-1252.

7. Prakash S, Patel V, Kakked S, Patel I, Yadav R. Mild serotonin syndrome: A report of 12 cases. Ann Indian Acad Neurol. 2015;18(2):226-30.

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.

11. Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1;81(9):1139-42.

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.

13. Warner ME, Naranjo J, Pollard EM, Weingarten TN, Warner MA, Sprung J. Serotonergic medications, herbal supplements, and perioperative serotonin syndrome. Can J Anaesth. 2017 Sep;64(9):940-946.

14. Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine (same) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.

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 or ACE 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