Today we are going to continue our discussion on antidepressant medications and cover serotonin syndrome. Serotonin syndrome is a dangerous potential complication particularly when using more than one medication that affects serotonin levels. We will discuss why this happens, the presenting symptoms, an evidence-based rating scale, and how to treat your patients that may develop this reaction.
Todays Content Level: All levels (Beginner, Intermediate, Advanced)
INTRODUCTION
•Serotonin syndrome (SS) is a potentially life-threatening toxic drug reaction that is caused by excessive levels of serotonin in both the central nervous system (CNS) and peripheral nervous system (PNS). This is why the syndrome includes neuromuscular abnormalities, autonomic hyperactivity, and mental state changes.
•The exact pathophysiology is unclear, however it is thought to reflect 5-HT1A overstimulation (hyperactivity, hyperreflexia, anxiety) and 5-HT2A overstimulation (hyperthermia, poor coordination, and neuromuscular excitability). 1
•The primary risk associated with SS is using more than one "serotonergic" agents or an overdose of these medications. It can also, more rarely, occur in patients on only one of these medications.
•"Serotonergic" = any medication, drug, or supplement that:
Decreases serotonin breakdown
Decreases serotonin re-uptake from the synapse
Increases serotonin precursors
Agonists at serotonin receptors
Increases serotonin release
Serotonin antagonism (particularly 5HT2A receptors) may also play a role (2)
Inhibits the enzymes that metabolize other serotonergic drugs (CYP2D6 and CYP3A4)
•The classic "textbook" case of serotonin syndrome involves the combination of an MAOI and another serotonergic agent but rarely seen today due to lower usage of MAOIs in general.
•The highest incidence is in those prescribed >5 serotonergic agents or a combination of MAOI and serotonergic agent. 3
SPECIFIC DRUGS
•Common offenders include SSRIs, SNRIs, TCAs, St John’s wort, linezolid, opioids, antiepileptics, antiemetics, stimulants.
•The following is not completely exhaustive, but includes most of the common serotonergic medications broken down by mechanism. 4
Decreases serotonin breakdown
MAOIs
Linezolid
St. Johns wort
Buspirone
Decreases serotonin re-uptake from the synapse
SSRIs/SNRIs
TCAs
DNRIs (including buspirone)
Opioids including tramadol
Ondansetron
Amphetamines
Cocaine
MDMA
St. John's wort
Dextromorphan
Agonists at serotonin receptors
Triptans
Ergot derivatives
Mirtazapine
Lithium
Trazodone
LSD
Increases serotonin release
MDMA
Dextromorphan
Amphetamines
Serotonin antagonism (particularly 5HT2A receptors) may also play a role
Second Generation Antipsychotics
CLINICAL FEATURES
•Symptoms tend to have a quick onset (less than 24 hours) and a quick resolution (<24 hours after removing the offending agent).
•As mentioned above, the symptoms of serotonin syndrome can be broken down into 1) Autonomic hyperactivity 2) Neuromuscular abnormalities and 3) Mental status changes.
Autonomic hyperactivity can include:
Increased temperature and excessive sweating (diaphoresis)
Increased heart rate and blood pressure
Dilated pupils (mydriasis)
Increased bowel sounds and diarrhea
Flushing
Neuromuscular abnormalities can include:
Myoclonus = muscle jerk/spasm that is sudden, brief, irregular, and involuntary
Clonus = muscle contractions that are rhythmic, rapid, repetitive, and involuntary.
Hyperreflexia = overactive or overresponsive reflexes
Hypertonicity = increased muscle tone/tension
Rigidity = stiffness, increased muscle tone that occurs throughout the entire range of motion of a limb
Mental status changes can include:
Delirium
Agitation
Anxiety
Lethargy
Symptoms of catatonia (stuporous or excited) often present
Coma
•I find it easy to remember the clinical features when you break it down into the three categories above, however if you are a fan of mnemonics here is one for the manifestations of serotonin syndrome: HARMED.
Hyperthermia
Autonomic instability
Rash (flushing)
Myoclonus/Clonus
Encephalopathy
Diarrhea
•The severity of SS, like many things, lies along a spectrum. There can be relatively minor causes, but severe cases can lead to rhabdomyolysis, disseminated intravascular coagulation (DIC), and death.
•If you remember back to a prior session this may sound an awful lot like neuroleptic malignant syndrome (NMS). Some of the best clues in differentiating serotonin syndrome from NMS is by the offending agent (serotonergic vs antidopaminergic), acute onset (SS has quicker onset), hyperreflexia, and clonus (clonus vs tremor). Having said that, there may be significant overlap in these two syndromes and is not always easy to distinguish.
EVALUATION
•Serotonin syndrome is diagnosed based on clinical findings. Most guidelines recommend the use of Hunter's criteria to assist with the diagnosis, however it may miss mild/moderate cases.
Hunter's criteria -> Patient must have taken a serotonergic agent + at least one of the following:
Spontaneous clonus
Inducible clonus PLUS agitation or diaphoresis
Ocular clonus PLUS agitation or diaphoresis
Tremor PLUS hyperreflexia
Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus
Laboratory tests used to assist the diagnosis and guide management decisions of serotonin toxicity may include the following:
Complete Blood Count (CBC)
Blood cultures
Basic Metabolic Panel (BMP) + Calcium (Ca)
Liver Function Tests (LFTs)
Creatinine Kinase (CK) (uncommonly elevated)
Urine myoglobin
Arterial Blood Gas (ABG)
Coags
Serum and urine tox screen
EKG
TREATMENT
•As discussed above, serotonin syndrome is typically has a quick onset and quick resolution (within 24 hours of onset). The syndrome is self-limited so the priority in treatment is to remove the serotenergic agents and provide supportive care.
•If at home or in the clinic patient should be urgently sent to the emergency department for expedited evaluation, monitoring, and supportive measures. If patient is on a psychiatric inpatient unit then we recommend a medicine consult (transfer to medical floor?) or RRT depending on acuity and severity.
•Remove the offending agent. Discontinue all serotonergic medications until at least all symptoms of SS have abated.
•Provide supportive care. This may include IV fluids, cooling blankets and antipyretics (often tylenol). If the syndrome is severe and patients respiratory status is compromised escalate respiratory support as clinically indicated (oxygen -> high flow -> BIPAP -> intubation).
•Medication interventions. Administer benzodiazepines as needed for the management of rigidity or agitation. May administer antihypertensives if patients blood pressure remains dangerously elevated after providing supportive measures. Administer anticonvulsants if patient has a seizure.
•Cyproheptadine is a medication that also needs to be addressed. Cyproheptadine is a serotonin receptor and histamine receptor antagonist that also has weak anticholinergic activity. Due to the fact that it theoretically binds serotonin receptors to block additional serotonergic toxicity you can see its theoretical utility in serotonin syndrome. Unfortunately, as there has been no clear efficacy established and it is not FDA approved, it is not recommended. 5
CONCLUSION
Nice work today. Serotonin syndrome is very important for all of us to understand and is critical to provide this information to patients so they can recognize these warning signs early and seek treatment quickly. Next lesson we will jump back into antidepressant classes as we discuss the atypical/novel class of antidepressants.
Resources for todays post include Stahl’s Essential Psychopharmacology, The Maudsley Prescribing Guidelines in Psychiatry, First Aid for the Psychiatry Clerkship, and Pocket Psychiatry.
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