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Day # 33: Serotonin Syndrome

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.


•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


•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


  • 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


•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.


•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


•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


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.

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