Drug-induced Serotonin Syndrome

Charles H. Brown, MS Pharm, RPh, CACP


US Pharmacist 

In This Article

Causative Agents

SS may occur when central and peripheral serotonin receptors are overstimulated through the action of antidepressant medications or drugs of abuse.[4] Both drug factors and patient factors can contribute to the toxicity of SSRIs in some individuals. Drug classes implicated include antimigraine agents; triptans (e.g., sumatriptan); antidepressants (e.g., SSRIs, serotonin norepinephrine reuptake inhibitors [SNRIs], buspirone, tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs]); antipsychotics; anticonvulsants; antiparkinsonian agents; analgesics (e.g., meperidine, tramadol); OTC products (e.g., cough and cold medication containing dextromethorphan); herbal products (e.g., St. John's wort [Hypericum perforatum]; and the antibiotic linezolid.[6–13] Mild SS episodes have been reported when St. John's wort or triptans have been used concurrently with SSRIs, SNRIs, or tricyclic antidepressants (e.g., amitriptyline). More severe SS episodes have been reported with the use of an MAOI with other serotonergic drugs (e.g., SSRIs, SNRIs).[14,15] See Table 1 for a more comprehensive list of drugs commonly associated with SS.[6–13]

SS typically occurs when a patient takes two or more drugs that elevate serotonin levels through different mechanisms, but the syndrome can occur with the use of individual agents.[16] Mechanisms that cause SS include increased serotonin production, inhibition of serotonin reuptake, inhibition of serotonin metabolism, increased serotonin release, and stimulation of serotonin receptors.[16] Certain drugs may affect serotonin levels through more than one mechanism. Mechanisms of action and their causative agent(s) include the following:

Increased Serotonin Production

One substance that increases serotonin production is the dietary supplement l-tryptophan. This serotonin precursor has been implicated in SS.[4,17,18]

Inhibition of Serotonin Reuptake

Drugs that inhibit serotonin reuptake include chlorpheniramine; cyclobenzaprine; dextromethorphan (e.g., Robitussin DM); meperidine; methadone; pentazocine; sibutramine; SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); St. John's wort; tramadol; trazodone; and tricyclic antidepressants (e.g., clomipramine, imipramine). Clomipramine and imipramine have relatively high serotonergic activity compared with amitriptyline, which inhibits serotonin reuptake to a lesser degree.[4,5,16,18–21]

Inhibition of Serotonin Metabolism by MAO

This category includes isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, and tranylcypromine.[4,17–19,22,23]

Increased Serotonin Release

Some drugs that increase serotonin release are dextromethorphan, meperidine, methadone, methylenedioxymethamphetamine (also known as MDMA or ecstasy), and mirtazapine.[4,19,21,24]

Stimulation of Serotonin Receptors

Drugs that stimulate serotonin receptors include buspirone; dihydroergotamine; lithium; lysergic acid diethylamide (LSD); meperidine; metoclopramide; and triptans (e.g, sumatriptan).[4,19,24,25] SS also can occur when the metabolism and elimination of a serotonergic drug are altered; e.g., some SSRIs inhibit the metabolism of tramadol by CYP2D6 inhibition and may increase serotonergic activity.[26]


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