SEROTONIN SYNDROME

• EPIDEMIOLOGY

• The overall incidence of serotonin syndrome is unknown
• In one study, the incidence of serotonin syndrome in patients taking nefazodone was 0.4 case per 1000 patients taking nefazodone for a month
• Serotonin syndrome occurs in 14 - 16% of SSRI overdoses [1]

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• MECHANISM

• Serotonergic neurons in the central nervous system are located primarily in the raphe nuclei. These neurons are involved in the regulation of processes such as wakefulness, thermoregulation, motor tone, and sexual behavior to name a few.
• In the periphery, serotonin is involved in the regulation of vascular tone and gastrointestinal motility
• Serotonin syndrome occurs when there is an excessive amount of serotonergic stimulation from medications that potentiate the serotonergic system
• A single serotonergic drug may precipitate serotonin syndrome, or two or more drugs with serotonergic activity may interact to cause serotonin syndrome. Drug interactions involving drug metabolism may also cause serotonin syndrome. For example, a strong Cytochrome P450 inhibitor may inhibit the metabolism of an antidepressant thereby potentiating its serotonergic activity.

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• SYMPTOMS

• Overview
• The symptoms or serotonin syndrome reflect hyper-stimulation of the serotonin systems
• There is no single symptom that establishes the diagnosis of serotonin syndrome
• A study published in 2016 reviewed 299 cases of serotonin syndrome. The prevalence of symptoms in those cases is presented in the table below.

• Reference [5]

Symptom	Prevalence
Tachycardia / Bradycardia	85%
Hypertension / Hypotension	76%
Confusion / Consciousness impairment	64%
Fever (Temp > 38°C or 100.4°F)	60%
Tremor	59%
Hyperreflexia	57%
Agitation / Restlessness	56%
Diaphoresis	53%
Rigidity / Hypertonicity	45%
Myoclonus	42%
Mydriasis (pupil dilation)	34%
Clonus	Spontaneous (27%) Inducible (7%)
Dyspnea (RR > 20 or hypoxia)	26%
Diarrhea	15%
Rhabdomyolysis	14%
Insomnia	10%
Hyperthermia (Temp > 41.1°C or 106.0°F)	9%

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• DIAGNOSIS

• Overview
• Serotonin syndrome is a clinical diagnosis meaning there is no objective lab, test, or singular symptom that can be used to establish its presence
• Serotonin syndrome can range from mild to severe. Patients with mild cases may only experience tremor, akathisia, or rapid heart rate, while more severe cases may have clonus, fever, sweating, delirium, seizures, and shock.
• Serotonin syndrome may develop within hours after an increase or addition of a serotonergic drug, or it may take longer. In a review of 236 cases, 28% of patients presented within 6 hours of a drug change and 45% presented after 24 hours. Overdoses and cases where medications were titrated rapidly were more likely to present earlier.
• Three different sets of criteria for diagnosing serotonin syndrome have been proposed. Since serotonin syndrome lacks a "gold standard" measure to validate the criteria, the sensitivity and specificity of the criteria are generally unknown. In one review, all three sets of criteria performed equally when they were compared in 299 cases of suspected serotonin syndrome. The criteria are detailed in the table below. [1,5]

• Reference [5]

Sternbach diagnostic criteria
Serotonin syndrome is diagnosed if ≥ 3 of the below symptoms are present Symptoms must occur with the addition of, or an increase in a known serotonergic agent Other etiologies (e.g. infectious, metabolic, drugs) must be ruled out If a neuroleptic agent was started or increased prior to the onset of symptoms, neuroleptic malignant syndrome is a possibility Symptoms Mental status changes Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhea Incoordination Fever
Radomski diagnostic criteria
Serotonin syndrome is diagnosed if ≥ 4 major criteria or 3 major criteria + 2 minor criteria are present Symptoms must occur with the addition of, or an increase in a known serotonergic agent Other etiologies (e.g. infectious, metabolic, drugs) must be ruled out If a neuroleptic agent was started or increased prior to the onset of symptoms, neuroleptic malignant syndrome is a possibility Major criteria Consciousness impairment Elevated mood Semicoma/coma Myoclonus Tremor Shivering Rigidity Hyperreflexia Fever Sweating Minor criteria Restlessness Insomnia Incoordination Dilated pupils Akathisia Tachycardia Tachy/dyspnea Diarrhea Hyper/hypotension
Hunter diagnostic criteria
Serotonin syndrome is present if any one of the following criteria is met Symptoms must occur in the presence of a serotonergic agent Criteria Spontaneous clonus Inducible clonus + agitation or diaphoresis Ocular clonus + agitation or diaphoresis Tremor + hyperreflexia Hypertonic + temperature > 38°C (100.4°F) + ocular clonus or inducible clonus

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• TREATMENT

• Overview
• The treatment of serotonin syndrome depends on the severity of symptoms. Results from randomized controlled trials are not available to help guide management, so treatment recommendations are mostly based on theory and case reports.
• In all cases of serotonin syndrome, the offending medication(s) should be stopped
• Mild cases (hyperreflexia, tremor and no fever) often resolve in 2 - 3 days, and treatment with benzodiazepines may suffice. In more significant cases (fever, hypertension, etc.), the administration of serotonin antagonists may be needed. Cyproheptadine, a 5-HT_2A antagonist, is the serotonin antagonist most often cited in case reports. The antipsychotics olanzapine and chlorpromazine have also been used, but are less studied. In extreme cases, muscular paralysis and intubation may be necessary. [1,6,7]


• In reviews, the following dosing was cited:
• Cyproheptadine: 12 mg initially followed by 2 mg every 2 hours for as long as symptoms persist (not exceeding 32 mg in 24 hours) then 8 mg every 6 hours for maintenance therapy
• Olanzapine: 10 mg sublingually
• Chlorpromazine: 50 - 100 mg IM

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• MOST COMMON CAUSES OF SEROTONIN SYNDROME

• ^✝Other serotonergic agent includes dextromethorphan, triptans, antiemetics, SNRIs, and agents inhibiting the metabolism of antidepressants
• Reference [5]

Most common cause of serotonin syndrome in a review of 299 cases
Suspected cause	Proportion of cases
Combination of antidepressant and opiate	16%
Overdose	15%
Combination of antidepressant and other serotonergic agent✝	13%
Combination of different antidepressants	8%
Combination of antidepressant and linezolid	7%
Changing antidepressants	5%
Combination of antidepressant and methylene blue	5%
Start of antidepressants	5%
Start/stop second generation antipsychotic in the presence of another serotonergic agent✝	3%

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• MEDICATIONS WITH SEROTONERGIC ACTIVITY

• Overview
• The medications listed here do not represent a complete list of drugs with serotonergic activity. Other drugs with serotonergic activity exist. Consult your health professional if you are concerned about an interaction.

• Reference [1,2]

Medications with serotonergic activity
Antibiotics Linezolid (Zyvox®) - through MAO inhibition Tedizolid (Syvextro®) - through MAO inhibition
Anticonvulsants Carbamazepine (Tegretol®) - based on case reports Valproate (Depakote®) - based on case reports
Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram (Celexa®) Escitalopram (Lexapro®) Fluoxetine (Prozac®) Fluvoxamine (Luvox®) Paroxetine (Paxil®) Sertraline (Zoloft®) Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Desvenlafaxine (Pristiq®) Duloxetine (Cymbalta®) Venlafaxine (Effexor®) Norepinephrine-Dopamine Reuptake Inhibitors Bupropion (Wellbutrin®) - based on case reports Tricyclic antidepressants (TCAs) Amitriptyline (Elavil®) Clomipramine (Anafranil®) Desipramine (Norpramin®) Doxepin Imipramine (Tofranil®) Nortriptyline (Pamelor®) Serotonin modulators Trazodone (Desyrel®) Vilazodone (Viibryd®) Other Mirtazapine (Remeron®) Vortioxetine (Trintellix®)
Antianxiety medications Buspirone (Buspar®)
Antinausea / vomiting (Antiemetics) Granisetron (Granisol®, Sancuso®) Metoclopramide (Reglan®) Ondansetron (Zofran®)
Bipolar medications Lithium
Cough Suppressants Dextromethorphan (DM) - in over-the-counter cough suppressants
Dietary supplements (herbal products) Ginseng Tryptophan St. John's wort - Hypericum perforatum
HIV medications Ritonavir (Kaletra®) - through CYP3A4 inhibition
Illicit drugs Amphetamines Cocaine Ecstasy - MDMA LSD - lysergic acid diethylamide Foxy Methoxy - 5-methoxy diisopropyltryptamine Syrian rue
Migraine medications Almotriptan (Axert®) Dihydroergotamine (Migranal®, D.H.E.-45®) Eletriptan (Relpax®) Ergotamine (Cafergot®) Frovatriptan (Frova®) Naratriptan (Amerge®) Rizatriptan (Maxalt®) Sumatriptan (Imitrex®) Zolmitriptan (Zomig®)
Monoamine oxidase inhibitors (MAOI) Isocarboxazid (Marplan®) - nonselective [type A and B] Linezolid (Zyvox®) - nonselective [type A and B] Moclobemide - selective [type A] Methylene blue Ozanimod (Zeposia®) - primarily type B Phenelzine (Nardil®) nonselective [type A and B] Procarbazine (Matulane®) Rasagiline (Azilect®) selective [type B] Selegiline (Eldepryl®) selective [type B] at normal doses, nonselective at higher doses Tedizolid (Sivextro®) Tranylcypromine (Parnate®) nonselective [type A and B]
Muscle relaxers Cyclobenzaprine (Flexeril®) Metaxalone (Skelaxin®) [3,4]
Pain medications Fentanyl (Duragesic®, Actiq®) Meperidine (Demerol®) Pentazocine (Talwin®) Tramadol (Ultram®)
Parkinson's medications Levodopa-carbidopa (Sinemet®) - based on case reports
Stimulants / ADHD medications Amphetamine-dextroamphetamine (Adderall®) Dexmethylphenidate (Focalin®) Dextroamphetamine (Dexedrine®) Methylphenidate (Ritalin®, Concerta®)
Weight loss medications (appetite suppressants) Appetite suppressants Lorcaserin (Belviq®) Sibutramine (Meridia®)

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• BIBLIOGRAPHY

• 1 - PMID 15784664 - NEJM review
• 2 - Manufacturer's Package Insert for various medications
• 3 - PMID 25671244 - Metaxalone OD with SSRI
• 4 - PMID 24805103 - Metaxalone OD
• 5 - PMID 27406219 - SS case review
• 6 - PMID 20433130 - AFP review
• 7 - PMID 18625822 - CMAJ review