Aetiology
Serotonin toxicity can occur from exposure to any medication that increases the intrasynaptic serotonin concentration in the central nervous system (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-noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, or duloxetine
Some tricyclic antidepressants (e.g., clomipramine, imipramine)
Opioid analgesics (e.g., pethidine, tramadol, fentanyl, dextromethorphan)
St. John's wort
Vortioxetine
Trazodone
Monoamine oxidase inhibitors (MAOIs)
Irreversible non-selective: phenelzine, tranylcypromine
Reversible selective: moclobemide
Other: linezolid, methylene blue, isoniazid, lamotrigine
Serotonin-releasing agents
Fenfluramine
Amfetamines, methamfetamine, methylphenidate, phentermine
Synthetic stimulants - methylenedioxymethamphetamine (MDMA or ecstasy), cocaine, cathinones
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]
Pathophysiology
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 behavioural 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 hyper-reflexia, is less clear and is likely to involve multiple receptor types, including 5-HT2A and 5-HT1A receptors.[3]
Classification
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 hyper-reflexia (almost always present in patients on selective serotonin-reuptake inhibitors [SSRIs]), inducible clonus, tremor, myoclonic jerks, and diaphoresis, or sometimes more non-specific symptoms such as headache or sweating.
These patients do not meet the Hunter Serotonin Toxicity Criteria (HSTC).[4]
Moderate toxicity
Causes significant distress in the patient and requires treatment but is not life-threatening.
Characterised by anxiety and agitation. Tachycardia is also common.
Patients meet the HSTC, but hyperthermia (temperature >38.5°C [>101.3°F] or rapidly rising) and hypertonia are absent.[4]
Severe toxicity
Considered a medical emergency, as it progresses to multi-organ failure if not treated. Almost always associated with exposure to a combination of serotonergic drugs that act by different pharmacological mechanisms.
Patients meet the HSTC and have hyperthermia and hypertonia.[4]
Drugs associated with serotonin toxicity[4][5][6][7]
Serotonin-reuptake inhibitors
SSRIs such as fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline, escitalopram, or dapoxetine
Serotonin-noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, or duloxetine
Some tricyclic antidepressants (e.g., clomipramine, imipramine)
Opioid analgesics (e.g., pethidine, tramadol, fentanyl, dextromethorphan)
St. John's wort
Vortioxetine
Trazodone
Monoamine oxidase inhibitors
Irreversible non-selective: phenelzine, tranylcypromine
Reversible selective: moclobemide
Other: linezolid, methylene blue, isoniazid, lamotrigine
Serotonin-releasing agents
Fenfluramine
Amfetamines, methamfetamine, methylphenidate, phentermine
Synthetic stimulants - methylenedioxymethamphetamine (MDMA or ecstasy), cocaine, cathinones
Drugs that increase serotonin synthesis
L-tryptophan
Serotonin receptor agonists
Lysergic acid diethylamide (LSD), 2C-substituted phenylethylamines (eg. ‘NBOMe’)
Lithium
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