Demystifying serotonin syndrome (or serotonin toxicity)

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Figure 1.
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Figure 2.
Serotonin physiology: Serotonin is formed in the presynaptic terminal from tryptophan. Once packaged into vesicles, it is released into the synaptic cleft where it can bind to serotonin receptors on the postsynaptic neuron to exert its action. Serotonin is transported through a transporter to the presynaptic terminal where it is broken down by monoamine oxidase.¹⁵ The 3 classes of drugs that increase serotonin in synapses are highlighted in red.
5HT—5-hydroxytryptamine.

Table 1.

Evidence supporting the key considerations for practice

CLINICAL CONSIDERATIONS	EVIDENCE RATING	REFERENCES
The best available evidence for the clinical presentation of toxicity is from the Hunter Area Toxicology Service in Australia	Level II^*	1
Serotonin toxicity most often happens when 2 serotonin-elevating drugs are used together. The use of an MAOI with an SSRI, an SNRI, or another MAOI is the most concerning drug combination	Level III^†	1,3
Some drugs thought to cause serotonin toxicity do not (eg, triptans, ondansetron)	Level III^†	1,4,7–11
Prevention of serotonin toxicity through good prescribing practices and monitoring is important	Level III^†	2,12

MAOI—monoamine oxidase inhibitor, SNRI—serotonin-norepinephrine reuptake inhibitor, SSRI—selective serotonin reuptake inhibitor.
↵* Level II: Comparison trials other than randomized controlled trials, systematic reviews, or meta-analyses; non-randomized, cohort, case-control, or epidemiologic studies; and preferably more than 1 study.
↵† Level III: Expert opinion or consensus statements.

Table 2.

Signs and symptoms of serotonin toxicity

CATEGORY	SIGNS AND SYMPTOMS
Neuromuscular	Tremor Hyperreflexia (increased reflexes)^* Clonus (rhythmic muscle spasms that can be spontaneous, inducible, or ocular)^*
Autonomic	Mydriasis (dilated pupils) Diaphoresis (sweating) Tachycardia (increased heart rate) Tachypnea (increased breathing rate)
Mental status	Agitation Excitement Restlessness Confusion Delirium

Data from Dunkley et al,¹ Boyer and Shannon,² Ables and Nagubilli,¹² and Isbister et al.¹³
↵* Hyperreflexia and clonus are often worse in the legs than in the arms.