Katerina is a 31 yo woman with recurrent MDD. Her depression is in full remission after taking fluoxetine 40mg daily for 6 weeks. However, the fluoxetine is causing insomnia, specifically problems with sleep maintenance. Katerina wants to keep taking fluoxetine because it is so effective for her depression, so you recommend adding trazodone 50mg at bedtime for sleep. Your clinic receives a call from the pharmacy that the combination of fluoxetine and trazodone poses a risk of serotonin syndrome and is not recommended – what do you want to prescribe instead?
Which drug combinations are high-risk for serotonin syndrome/toxicity?
A prior PsychSnap reviewed the signs, symptoms, and characteristic time course of serotonin toxicity. To summarize: serotonin toxicity is a rare, largely avoidable toxidrome caused by drugs that increase serotonin in synapses in the brain. It occurs soon (hours > days) after a recent increase in dose (or overdose) or a new exposure to a drug that increases serotonin levels. Serotonin syndrome is not an idiosyncratic, unpredictable reaction to a serotonergic drug.
This PsychSnap focuses on the specific drug combinations that increase the risk for serious serotonin toxicity.
The problem: The literature about what causes serotonin syndrome is a mess. “Serotonin syndrome [has been] applied indiscriminately to a confusing mishmash of hundreds of implausible and trivial cases as well as those with typical or life-threatening serotonin toxicity” (Chiew 2022). Most textbooks, drug interaction checkers, and even government warnings cast a wide net, including everything that could possibly contribute to serotonin syndrome. This approach minimizes harm from serotonin toxicity but generates a long list of medications that is of limited utility to clinicians.
How risky is this drug combination?
Nearly all severe serotonin toxicity relates to drug interactions (Isbister 2007). What specific drug combinations are dangerous and should never be in the body at the same time? What combinations are commonly used safely, despite being on high risk lists?
The figure below is adapted from Table 1 of Chiew’s 2022 article, “The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes.” The first five rows and columns list the same serotonin-related mechanisms of action. The row headings also include specific medication names, with a full list of MAOis and medications that decrease serotonin reuptake below the table. The colored boxes show the risk of moderate or severe serotonin toxicity when medications from two of these classes are combined, based on a synthesis of the evidence-based literature (Chiew 2022).
The column on the far right shows that serotonin agonists like buspirone, the triptans, LSD, and psilocybin, as well as lithium are unlikely to cause significant serotonin toxicity even when combined with other serotonergic medications. Similarly, although there is an FDA warning about the risk of serotonin toxicity from 5HT-3 antagonists like ondansetron (bottom row), it poses no risk of serotonin toxicity (Chiew 2022).
There are other medication combinations that should never be used–specifically those that intersect in red boxes. Severe serotonin toxicity is usually caused by the combination of a Monoamine Oxidase-inhibitor (MAOi) that inhibits serotonin metabolism and another highly serotonergic drug that decreases serotonin reuptake (like sertraline) or increases the release of stored serotonin (like ecstasy (MDMA)). These combinations pose an “Extreme Risk,” and care should be taken to allow adequate wash-out periods so that the drugs are never in the body at the same time. The combination of an MAOi and the high-risk opioids tramadol or meperidine, or dextromethorphan (which is structurally related to opioids) is also high-risk (Chiew 2022). Combinations of MAOIs with either L-tryptophan or medium-risk opioids (methadone, tepentadol, and fentanyl) have an increased risk of causing serotonin toxicity.
Linezolid has only mild MAOi properties. Avoid prescribing it in a patient taking a serotonin reuptake inhibitor, serotonin releaser, or a high-risk opioid if possible, but the risk of serotonin toxicity is low enough (<1%) that one could monitor the patient if there were truly no other alternatives (Bai 2022).
There is an increased risk (orange boxes) of serotonin toxicity from combinations of drugs that release stored serotonin (MDMA+), decrease serotonin reuptake (SSRI+), or is in the high risk opioid group (tramadol/meperidine/dextromethorphan). Moderate serotonin toxicity could be caused if enough of these medications are combined at high enough doses. Using therapeutic doses of these medications together may be reasonable if there is a sufficiently justifiable clinical indication and you monitor for the signs and symptoms of serotonin syndrome.
To summarize: if you are using an MAOi (which you probably aren’t), be very very cautious about what other serotonergic medications are used. Otherwise, notice if you are adding a third drug that decreases serotonin reuptake, releases serotonin, or is in the high risk opioid group and monitor for serotonin toxicity. Avoid tramadol, which acts as a serotonin reuptake inhibitor, a serotonin releaser, and a weak opioid agonist, particularly if your patient might benefit from an antidepressant like duloxetine or milnacipran for depression and/or pain in the future.
What drugs (that are often on the risky list) don’t cause significant serotonin toxicity?
- trazodone, nefazodone
- mirtazapine
- lithium
- buspirone
- bupropion
- modafanil
- methylphenidate
- benzodiazepines
- lamotrigine, valproate, carbamazepine
- MAO-B selective drugs like selegiline (at low dose), rasagiline, ladostigil
- antihistamines other than chlorpheniramine and brompheniramine
- antipsychotic medications other than ziprasidone or lumateperone
- triptans
- secondary tricyclic antidepressants – nortriptyline, desipramine
- low risk opioids – morphine, codeine, buprenorphine, oxymorphone, hydromorphone, oxycodone have a possible very rare interaction with MAOis only. Otherwise no risk of serotonin toxicity
- ondansetron
- LSD, psilocybin
What common drug combinations are low risk for serotonin toxicity?
(for easy reference and as a review of clinical rationales for specific drug combinations)
- Two SSRIs/SNRIs/vilazodone/vortioxetine/mirtazapine/bupropion at therapeutic doses, when cross-titrating from one to another
- SSRI + TCA (e.g. escitalopram + low-dose nortriptyline) for MDD controlled on an SSRI and a noradrenergic TCA added for chronic pain. This may be a better choice than treating pain and depression by switching the SSRI to an SNRI, or adding an SNRI to the SSRI.
- SSRI/SNRI + methadone for a patient with depression or anxiety and opioid use disorder
- SSRI + buspirone for GAD augmentation
- SSRI/SNRI + bupropion for sexual side effects from the SSRI/SNRI
- SSRI/SNRI + low-dose doxepin or mirtazapine for MDD or GAD and sleep maintenance insomnia
- SSRI/SNRI + trazodone (off-label) for SSRI/SNRI-induced insomnia or insomnia in the setting of MDD or GAD
- SSRI/SNRIs + MDMA for recreational use. The antidepressant may reduce the subjective effects from the MDMA.
- SSRI/SNRIs + moderate doses of psychedelics (LSD, psilocybin, etc) for recreational use with the exception of the psychedelic 5-MeO-DMT (Toad) (Malcolm, 2022)
Drug combinations have a higher risk of inducing serotonin toxicity in patients who take higher doses, take many medications, are older, or have liver failure or other significant medical problems.
Returning to Katerina – You call back the pharmacy and thank the pharmacy technician for their heads up. You reiterate that you did want to prescribe the fluoxetine and trazodone exactly as written given the data you learned recently about drug combinations that are unlikely to cause serotonin toxicity.
Key Points
- Do not mix an MAOi, including methylene blue, with other strongly serotonergic medications like SSRI/SNRIs, tramadol, meperidine, or dextromethorphan due to the risk of serotonin toxicity.
- Trazodone, mirtazapine, buspirone, nortriptyline, triptans, ondansetron, LSD, and psilocybin affect serotonin in the brain in ways that do not increase the risk of serotonin toxicity. They CAN be safely combined with SSRI/SNRIs.
References:
Bai, Anthony D., et al. “Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants.” JAMA Network Open 5.12 (2022): e2247426-e2247426.
Buckley, Nicholas A., Andrew H. Dawson, and Geoffrey K. Isbister. “Serotonin syndrome.” Bmj 348 (2014).
Chiew, Angela L., and Nicholas A. Buckley. “The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes.” Clinical Toxicology 60.2 (2022): 143-158.
Isbister, Geoffrey K., Nicholas A. Buckley, and Ian M. Whyte. “Serotonin toxicity: a practical approach to diagnosis and treatment.” Medical Journal of Australia 187.6 (2007): 361-365.
Malcolm, Benjamin, and Kelan Thomas. “Serotonin toxicity of serotonergic psychedelics.” Psychopharmacology 239.6 (2022): 1881-1891.
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