History and exam
Key diagnostic factors
common
exposure to a serotonergic drug
This is an essential requirement for serotonin toxicity to occur.
Drugs include: serotonin-reuptake inhibitors (e.g., selective serotonin-reuptake inhibitors, other antidepressants, opioid analgesics), monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine, moclobemide, lamotrigine), serotonin-releasing agents (e.g., amphetamines, methylenedioxymethamphetamine [MDMA], cocaine), serotonin receptor agonists (e.g., Lysergic acid diethylamide [LSD], lithium), and drugs that increase serotonin synthesis (e.g., L-tryptophan). Absence of exposure excludes serotonin toxicity.
clonus
Most common diagnostic feature of serotonin toxicity. It ranges in severity from inducible clonus (>3 beats) to spontaneous clonus and is best elicited at the ankle.
In more severe cases, clonus will be sustained or will become spontaneous and may be difficult to distinguish from hypertonia.
Ocular clonus manifests as rapid and equal movements of the eyes and is best elicited by getting the patient to fix on a finger moved rapidly to the midline.
hyperreflexia
Occurs almost universally with serotonin toxicity. It is usually more pronounced in the lower limbs.
Other diagnostic factors
common
anxiety
Symptom of moderate serotonin toxicity. Although this is nonspecific, in the presence of other features it is often one of the most distressing for the patient.
agitation
Symptom of moderate serotonin toxicity. Although this is nonspecific, in the presence of other features it is often one of the most distressing for the patient.
confusion
Symptom of severe serotonin toxicity. Although this is nonspecific, in the presence of other features it is often one of the most distressing for the patient.
tremor, shivering, muscle jerking
Tremor and shivering are abnormal regular shaking movements of the muscles that differ in frequency. Muscle jerking is sudden involuntary movements of the muscles.
sweating
Nonspecific symptom but can occur in association with other features.
headache
Nonspecific symptom but can occur in association with other features.
tachycardia
Nonspecific sign but occurs commonly in moderate serotonin toxicity and is a reasonable indicator of deterioration or improvement in the patient.
hypertonia/rigidity
Most likely due to sustained, spontaneous clonus in severe serotonin toxicity. It usually occurs in association with hyperthermia and should be considered to be diagnostic of severe toxicity requiring immediate treatment.
uncommon
diaphoresis
Nonspecific sign that can occur in all severities of serotonin toxicity.
flushing
Nonspecific sign that can occur in all severities of serotonin toxicity.
dilated pupils
May be seen but is more diagnostic of other toxidromes such as anticholinergic syndrome.[22]
hyperthermia
A mild elevation in temperature (i.e., >100.4°F [>38°C]) may occur, but this is neither diagnostic nor contributory on its own.
Hyperthermia (temperature >101.3°F [>38.5°C] or rapidly rising) is a diagnostic feature of severe toxicity and its presence necessitates urgent treatment.[4][8]
In the absence of neuromuscular features, other causes of hyperthermia should be considered.[11]
myoclonus
Patient should be observed for myoclonic movements.
startling
In moderate serotonin toxicity, patients will startle easily (e.g., at sudden sounds or changes in the environment), although this should not be elicited on exam.[23]
Risk factors
strong
exposure to a serotonergic drug
This is an essential requirement for serotonin toxicity to occur.
Drugs from many classes may be involved. Examples of some classes include the following: selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline, escitalopram, or dapoxetine); serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine, desvenlafaxine, duloxetine); some tricyclic antidepressants (e.g., clomipramine, imipramine); opioid analgesics (e.g., pethidine, tramadol, fentanyl, dextromethorphan); St. John's wort; other antidepressants with novel mechanisms of action (e.g., vortioxetine, trazodone); irreversible monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromin); reversible selective monoamine oxidase inhibitors (e.g., moclobemide); other MOAIs (e.g., linezolid, methyl blue, isoniazid, lamotrigine); serotonin-releasing agents (e.g., amphetamines, methamphetamine, methylphenidate, phentermine); synthetic stimulants (e.g., methylenedioxymethamphetamine [MDMA or ecstasy], cocaine, cathinones); drugs that increase serotonin synthesis (e.g., L-tryptophan); serotonin receptor agonists (e.g., lysergic acid diethylamide LSD, 2C-substituted phenylethylamines NBOMe, lithium).
exposure to two or more serotonergic drugs
The risk of serotonin toxicity, particularly life-threatening and severe serotonin toxicity, is much greater if there are two more agents that act via different pathways e.g. a monoamine oxidase inhibitor and a selective serotonin-reuptake inhibitor.[2] However, two or more agents with the same mode of action (e.g. two selective serotonin-reuptake inhibitors) are unlikely to increase the risk, and no more than a larger dose of a single selective serotonin-reuptake inhibitor.
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