Serotonin syndrome

Serotonin toxicity can occur from exposure to any medication that increases the intrasynaptic serotonin concentration in the CNS.[1][3] This includes medications where the therapeutic aim of using them is to increase CNS serotonin levels (e.g., antidepressants), and medications where this effect is unintended (e.g., opioid analgesics). Drugs associated with serotonin toxicity are listed below. This is not an exhaustive list, as new agents are continuously introduced to the market.[4][5][6][7][12][13][14]

Serotonin-reuptake inhibitors

Selective serotonin-reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline, escitalopram, or dapoxetine
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, or duloxetine
Some tricyclic antidepressants (e.g., clomipramine, imipramine)
Opioid analgesics (e.g., meperidine, tramadol, fentanyl, dextromethorphan)
St. John's wort
Vortioxetine
Trazodone

Monoamine oxidase inhibitors (MAOIs)

Irreversible nonselective: phenelzine, tranylcypromine
Reversible selective: moclobemide
Other: linezolid, methylene blue, isoniazid, lamotrigine

Serotonin-releasing agents

Amphetamines, methamphetamine, methylphenidate, phentermine
Synthetic stimulants - methylenedioxymethamphetamine (MDMA or ecstasy), cocaine, cathinones
Fenfluramine (not currently available in the US)

Drugs that increase serotonin synthesis

L-tryptophan

Serotonin receptor agonists

Lysergic acid diethylamide (LSD), 2C-substituted phenylethylamines (eg. ‘NBOMe’)
Lithium

A number of other agents have been implicated in causing serotonin toxicity, including some antipsychotics (i.e., those with 5-HT2A antagonist activity), triptans (5-HT1 agonists), and other antidepressants (e.g., mirtazapine).[15][16][17][18] However, there is insufficient evidence to label these drugs as causative agents.

Intrasynaptic serotonin can be increased via a number of mechanisms, including increased serotonin production, serotonin release, serotonin-reuptake inhibition, and decreased serotonin metabolism (e.g., monoamine oxidase inhibition).[1][2]

Severe serotonin toxicity is almost always the result of exposure to two serotonergic agents that act via different mechanisms. The classic combination is an SSRI plus an MAOI.[8]

The pathophysiology of serotonin toxicity in humans is still poorly understood, and much of the early literature confuses the clinical manifestations in humans with a separate behavioral syndrome defined in animals.[3] However, there is little doubt that the pathophysiology relates to increased intrasynaptic serotonin in the CNS and the effects of high concentrations of serotonin at particular serotonin (5-HT) receptor subtypes in the brain.[3] Animal studies support that, at least for life-threatening serotonin toxicity including hyperthermia, the 5-HT2A receptor subtype is the most important. 5-HT2A antagonists appeared to prevent these effects in animals.[19]

The pathophysiology of the neuromuscular effects, including increased tone, clonus, and hyperreflexia, is less clear and likely involves multiple receptor types, including 5-HT2A and 5-HT1A receptors.[3]

Serotonin toxicity severity[2][4]

The spectrum of serotonin toxicity can be divided into 3 groups of severity based on the requirement for medical intervention.

Mild toxicity

Serotonergic features that may or may not concern the patient. Such features include hyperreflexia (almost always present in patients on selective serotonin-reuptake inhibitors [SSRIs]), inducible clonus, tremor, myoclonic jerks, and diaphoresis, or sometimes more nonspecific symptoms such as headache or sweating.
These patients do not meet the Hunter Serotonin Toxicity Criteria (HSTC).[4]

Moderate toxicity

Causes significant distress in patient and requires treatment but is not life-threatening.
Characterized by anxiety and agitation. Tachycardia is also common.
Patients meet the HSTC, but hyperthermia (temperature >101.3°F [>38.5°C] or rapidly rising) and hypertonia are absent.[4]

Severe toxicity

Considered a medical emergency as it progresses to multiorgan failure if not treated. Almost always associated with exposure to a combination of serotonergic drugs that act by different pharmacologic mechanisms.
Patients meet the HSTC and have hyperthermia and hypertonia.[4]

Drugs associated with serotonin toxicity[4][5][6][7]