- Causes of serotonin syndrome
- Clinical presentation
- Differential diagnosis
- Lab evaluation
- Diagnostic criteria
- Questions & discussion
- PDF of this chapter (or create customized PDF)
- Serotonin syndrome usually results from inadvertent interaction of several serotonergic medications.
- Most cases are mild-moderate, and will improve in about a day following cessation of medications. However, serotonin syndrome can be severe and may require ICU admission.
- The main challenge is recognition: If serotonin syndrome is recognized early and causative drugs are stopped immediately, then patients will generally do very well.
causes of serotonin syndrome
overall architecture of serotonin syndrome
- Serotonin syndrome can occur one of two ways:
- (1) Overdose of a serotonergic medication (e.g. SSRI or illicits)
- (2) Inadvertent interaction between several serotonergic medications
- 2a) Addition of drugs which are directly serotonergic
- 2b) Addition of drugs which cause drug-drug interactions, increasing the levels of other serotonergic medications (i.e. the “new” medication doesn't necessarily need to directly affect serotonin signaling).
- In practice, most episodes of serotonin syndrome result from multiple drugs interacting together.
- When in doubt, enter the whole medication list into a program such as the Medscape drug interaction program; this may reveal unexpected interactions.
- Drugs which more commonly promote serotonin syndrome are as follows…
antidepressants & psychiatric medications
- SSRIs, SNRIs (including trazodone)
- Serotonin syndrome occurs in ~15% of SSRI overdoses
- Fluoxetine has a half-life of ~1-2 weeks, so can participate in serotonin syndrome even after discontinued.
- Cyclic antidepressants (including mirtazepine)
- MAO inhibitors (may cause greater disease severity)
- Saint John's Wort
illicits & opioids
- Cocaine, amphetamine, methamphetamine
- MDMA (Ecstasy)
- Opioids: meperidine, fentanyl, tramadol, dextromethorphan, methadone, possibly oxycodone (29916050)
- In some cases, serotonin syndrome can be precipitated by non-serotonergic drugs which inhibit the metabolism of other serotonergic medications!
- inhibited by: ciprofloxacin or ritonavir
- metabolizes: methadone, venlafaxine, oxycodone
- inhibited by: fluconazole
- metabolizes: sertraline
- Linezolid (discussed further in the antibiotics chapter)
- Methylene blue
- Anti-epileptics (carbamazepine, valproate)
- Anti-emetics (ondansetron, granisetron, metoclopramide)
- Chlorpheniramine (an over-the-counter antihistamine)
- Usually occurs promptly following medication exposure or dose adjustment (within 12-24 hours).
- Will generally resolve within 24 hours following discontinuation of causitive medications.
- Rapid onset & resolution can be helpful diagnostically to distinguish from many other disorders (e.g. neuroleptic malignant syndrome, thyrotoxicosis).
overall presentation: triad of findings
- (1) Mental status change
- Anxiety, agitated delirium
- Seizure, coma
- (2) Sympathetic hyperactivity
- hypertension, tachycardia
- diaphoresis, flushing
- Nausea/vomiting, diarrhea (may occur early, as a prodrome)
- (3) Neuromuscular excitation
- Most common: elicited by dorsiflexion of foot
- Ocular clonus (ping-pong gaze)
- Spontaneous clonus in most severe cases (can mimic seizure)
- Rigidity (one of the most severe and dangerous manifestation)
- Akathisia (inability to stay still)
Ankle clonus: This is elicited by rapidly dorsiflexing the foot. One or two beats may be normal. Prolonged clonus is a hallmark of serotonin syndrome.
key finding: ankle clonus
- Clonus may be conceptualized as a form of profound hyperreflexia, wherein each muscle contraction triggers another reflexive contraction.
- Causes of clonus include:
- Upper motor neuron dysfunction (e.g. due to stroke, trauma, cerebral palsy, or multiple sclerosis).
- Serotonin syndrome
- Anticholinergic toxicity
- Baclofen withdrawal
- The hallmark finding in serotonin syndrome is clonus and hyperreflexia, generally most prominent in the legs.
- Clonus is usually inducible, meaning that it is triggered by the examiner (video above).
- In severe cases, clonus may occur spontaneously. This can resemble a seizure.
- Serotonin syndrome is strongly suggested by the following constellation:
- (1) Bilateral ankle clonus and hyperreflexia.
- (2) Lack of another obvious explanation of clonus (no known chronic neurologic abnormality).
- Lack of clonus argues strongly against the diagnosis of serotonin syndrome. However, serotonin syndrome can occur in the absence of clonus under the following circumstances:
- (1) In a patient with tremor, it may be difficult to discern the presence of clonus.
- (2) In severe cases of serotonin syndrome, clonus may progress to rigidity.
- (3) Patients with underlying neurologic disease (e.g. peripheral neuropathy) may not manifest with clonus (29207768).
The differential diagnosis will depend on the particular presenting symptoms. The following are the most common considerations:
- Serotonin syndrome can be indistinguishable from sympathomimetic intoxication (and these may be largely the same thing, because sympathomimetics increase serotonin levels)
- Alcohol or baclofen withdrawal.
- Anticholinergic toxicity
- Serotonin syndrome can be a sepsis mimic (e.g. can cause fever, elevated lactate, tachycardia).
- Meningitis or encephalitis may look a lot like serotonin syndrome.
- Neuroleptic malignant syndrome
- Malignant hyperthermia
- Brainstem stroke causing hyperthermia
- Heat stroke
- Sympathetic Storm
Labs don't help diagnose serotonin syndrome. However, they may be useful in excluding alternative diagnoses and in evaluating complications of serotonin syndrome.
lab abnormalities may include:
- Lactic acidosis
- Elevated creatine kinase (rhabdomyolysis)
- Disseminated intravascular coagulation
- Renal failure
- Liver function abnormalities
- Hyponatremia, hypomagnesemia
tests to consider (evaluation depends on presentation, but consider the following)
- Fingerstick glucose
- Chemistries, including Ca/Mg/Phos
- Creatinine kinase
- Liver function tests
- Coagulation studies
- Salicylate & acetaminophen levels
- Infectious workup (blood & urine cultures)
- CSF analysis if concern for meningitis/encephalitis
- Chest X-ray
- CT head, possibly MRI
— NEJM (@NEJM) November 4, 2016
- Among various criteria, the Hunter Criteria seem to be the best. Compared to evaluation by a medical toxicologist, these criteria are 84% sensitive and 97% specific.
- Of course, rigid application of criteria should never supersede clinical judgement.
- These criteria rightfully place clonus at the center of the diagnosis (as discussed above).
- Defining precisely whether or not a patient has serotonin syndrome is tough because this is a spectrum disorder which ranges from mild to severe. Very mild serotonin syndrome might not meet the Hunter Criteria (which are more specific than sensitive).
- Cyproheptadine is a first-generation “sedating” antihistamine with anti-serotonin activity (including activity against the 5HT-2A receptor most closely related to serotonin syndrome)(31075831).
- Contraindications: narrow-angle glaucoma, bladder obstruction.
- Potential side-effects: sedation, anticholinergic effects (e.g. tachycardia, urinary retention), hypotension.
use in serotonin syndrome?
- Seems safe and likely effective. Based also on mechanistic and cost considerations, it's arguably a front-line therapy. However, available only orally and absorption may take some hours.
- Cyproheptadine could be used in roughly two ways:
- (1) For a patient with mild to moderate agitation, oral cyproheptadine could be adequate therapy.
- (2) A patient with severe agitation may initially require IV therapy (e.g. with dexmedetomidine) and possibly intubation. In this scenario, cyproheptadine could be started following initial stabilization and could be used to wean off other agents.
- However, cyproheptadine doesn't need to be given to every patient with serotonin syndrome.
- It has never been proven to work in any RCT (no drug has been).
- The goal of cyproheptadine is primarily symptomatic improvement – so if the patient doesn't have bothersome symptoms, then there is unlikely to be any benefit from cyproheptadine.
- (1) Loading dose of 12 mg
- (2) Additional PRN doses of 2 mg q2hr until response
- (3) Maintenance dose of ~8 mg q6hr.
- Max daily dose is 32 mg
- For the sake of comparison, the dose of cyproheptadine used for urticaria is 4 mg q8hr (12 mg total daily dose).
mechanisms of action
- Two mechanisms may explain efficacy in serotonin syndrome:
- (1) Dexmedetomidine stimulates alpha-2C receptors in the striatum, thereby modulating serotonin levels (23117910). It appears that alpha-2 receptors located on serotonergic terminal axons may inhibit serotonin release (25596946).
- (2) Dexmedetomidine stimulates alpha-2A receptors in the prefrontal cortex and locus ceruleus, which causes sedation and reduced sympathetic tone.
- Thus, in addition to simply acting as a sedative agent, dexmedetomidine seems to treat the underlying pathophysiology (serotonin excess). This has been demonstrated in an animal model of serotonin syndrome, wherein dexmedetomidine was more effective than midazolam (25596946).
potential advantages of dexmedetomidine over benzodiazepines
- Traditionally, benzodiazepines have been the sedative agent used in serotonin syndrome. However, dexmedetomidine has several potential advantages over benzodizepines:
- (1) As explored above, dexmedetomidine may better address the underlying pathophysiology.
- (2) Some case reports describe success with dexmedetomidine in cases which were refractory to other sedatives (including benzodiazepines)(23117910, 25169248).
- (3) Dexmedetomidine doesn't suppress respiration, so it is less likely to precipitate intubation.
- (4) Dexmedetomidine can be titrated to effect, thereby avoiding over-sedation or under-sedation.
- (5) Some authors have suggested that there may be an increased risk of paradoxical agitation when using benzodiazepines in the treatment of serotonin syndrome (23117910). This isn't a problem with dexmedetomidine.
- (6) Dexmedetomidine is less likely than benzodiazepines to exacerbate delirium.
- (7) Dexmedetomidine can be a good choice when the diagnosis is unclear and you don't want to muddy the waters. If it is ineffective or causes adverse events, it's easily withdrawn.
potential disadvantages of dexmedetomidine compared to benzodiazepines
- (1) Dexmedetomidine may be more expensive.
- (2) Up-titration of dexmedetomidine takes some time, so it may not be an ideal agent for the patient with profoundly dangerous agitation.
- (3) Dexmedetomidine lacks anti-epileptic activity, so it would be less desirable in patients who have had a seizure.
bottom line on dexmedetomidine in serotonin syndrome?
- There is no solid evidence to establish the front-line IV sedative in serotonin syndrome.
- Limited mechanistic and clinical evidence suggests that dexmedetomidine could be superior to benzodiazepines.
- The ideal candidate for dexmedetomidine would have the following characteristics:
- Sick enough to require IV sedation, yet not so sick as to need immediate intubation.
- No prior seizure (benzodiazepine probably superior in that situation).
- Not bradycardic (not really an issue here, however, as patients with serotonin syndrome are often tachycardic)
- The strength of dexmedetomidine is that it may achieve symptom control and avoid the requirement for intubation.
basic principles of treatment
- Key principles:
- (1) The natural history of serotonin syndrome is that once causative medications are stopped, patients will improve rapidly (usually within a day). Most patients don't require anything more than high-quality supportive care. All you need to do is stop the offensive drugs and keep the patients safe, and they will recover.
- (2) The pathway whereby serotonin syndrome leads to death is hyperthermia. Hyperthermia may promote seizures, leading to a seizure-coma-death spiral.
- Primary goals of treatment:
- (1) Monitor temperature and treat/avoid hyperthermia.
- (2) Treat agitation as needed to keep patient comfortable.
- Sedation should be used only if the patient is dangerously/uncomfortably agitated or hyperthermic.
- (Note, however, that physical restraints should be avoided if at all possible or rapidly discontinued. Straining against restraints may increase fever and rhabdomyolysis.)
- From a mechanistic standpoint, front-line agents are arguably cyproheptadine and dexmedetomidine. Benzodiazepines have historically been used extensively and these are also a solid choice (particularly in a patient with seizure). For patients who are intubated, propofol might be superior to benzodiazepines (similar mechanism of action, with superior titratability).
- A general schema for how these medications may be utilized is shown above.
- For patients with mild-moderate agitation who can take oral medication, cyproheptadine may be preferred.
- For patients who are unable to take oral medication or need more immediate sedation, dexmedetomidine may be preferable.
- For patients with seizure who aren't intubated, benzodiazepines make sense.
- For an intubated patient, dexmedetomidine or propofol could be used.
- Additionally, if the patient has a source of pain (e.g. trauma), then this should be treated with appropriate analgesia.
- Avoid opioids which may increase serotonin levels (including fentanyl and oxycodone).
- Antipsychotics (e.g. haloperidol) may be undesirable, as they have anticholinergic properties which may tend to increase the temperature.
- Key treatments:
- (1) Hyperthermia needs to be controlled with physical cooling techniques (e.g. cooling blanket, Arctic Sun, fan).
- (2) Agitation should be controlled as discussed above, to prevent muscular activity that could worsen hyperthermia.
- Antipyretics won't work (these patients don't have hypothalamically mediated fever).
- For extreme hyperthermia (e.g. temperature over ~41.1 C), intubation with non-depolarizing paralysis may be considered as the fastest way to control temperature (24358002).
- May occasionally be required for the following reasons:
- (1) In extreme cases, chest wall rigidity may interfere with ventilation
- (2) Profound hyperthermia
- (3) Uncontrollable agitation
- (4) Status epilepticus
- Paralysis may be useful initially (especially in the case of profound hyperthermia).
- It this occurs, treat as described in the chapter on rhabdomyolysis.
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Failure to look for inducible ankle clonus in a patient with intoxication.
- Labeling patients with multifactorial delirium as having “serotonin syndrome,” without paying attention to diagnostic criteria.
- Insufficiently aggressive management of hyperthermia in patients with severe hyperthermia that poses a threat to vital organs.
- Use of physical restraints, which may lead to increased muscular activity that could worsen hyperthermia and rhabdomyolysis.
- Over-aggressive treatment of patients with mild serotonin syndrome who aren't hyperthermic (and who will generally improve rapidly with supportive care and cessation of serotonergic medications).
5-minute summary by Jacob Avila (EMin5)
- Differentiating serotonin syndrome and neuroleptic malignant syndrome (Jenna Otter, emDocs); Serotonin Syndrome and NMS: Pearls & Pitfalls (Brit Long, emDocs)
- Serotonin Syndrome (Taming the SRU)
- Fentanyl can cause serotonin syndrome (The Poison Review); also Methylene Blue & Serotonin Syndrome
- Serotonin Syndrome Differential Diagnosis (Mike Cadogan, LITFL)
- Hyperthermia Syndromes (Anand Swaminathan, RebelEM)