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SSRIs: Drug interactions

Serotonin syndrome: patient’s being treated with SSRI’s are at risk for serotonin syndrome, a potentially fatal condition due to increased serotonergic activity in the central nervous system. Symptoms classically associated with this would be mental status changes, neuromuscular abnormalities, and autonomic hyperactivity.

Taking multiple serotonergic compounds is a common way to precipitate this reaction. Examples of drugs that can participate in this would be: drugs causing increase serotonin release such as MDMA, cocaine, Amphetamines, levodopa-carbidopa. Drugs that cause decreased serotonin reuptake: cocaine, MDMA, tramadol, trazodone, SNRIs, bupropion, TCAs, St John’s Wort, ondansetron, valproic acid and cylclobenzaprine and others. Drugs that inhibit Monoamine oxidase such as linezolid, tedizolid, methylene blue, procarbazine, selegiline and rasagiline are also associated with increased risk of serotonin syndrome. Other drugs that work as direct serotonin agonists such as Buspar, fentanyl, the triptans, LSD and ergots have also been associated with serotonin syndrome. Lithium has also been known to induce increased postsynaptic receptor sensitivity to serotonin.

Many SSRIs inhibit enzymes in the p450 system. Fluoxetine is known to be a potent inhibitor of CYP2D6. Fluvoxamine is a potent inhibitor of both CYP 2C19 and CYP 1A2, Paroxetine is a potent inhibitor of both CYP2D6, and 2B6, Sertaline is also known to be a potent inhibitor of CYP 2D6 at concentrations > 200 mg/day. Amongst the SSRIs citalopram and Escitalopram are least likely to impact the p450 system. These two drugs are not known to be potent inhibitors of any specific cytochrome.

Tamoxifen is processed by CYP 2D6 to its active metabolite. In light of the known inhibition of this enzyme by both fluoxetine and paroxetine it is no surprise that these medications are known to decrease the efficacy of this drug. Concurrent use of these medications is generally avoided.

SSRIs have been associated with an increase in the QT interval. The SSRI most associated with this is citalopram. Caution should be used when treating patient on these medications with other substances known to prolong the QT. is a website which curates a list of QT prolonging medications. You will need to provide an email address and set up an account to use this though.

Specific drug interactions can be found in up-to-date using the Lexi-Interact Online tool. This tool will allow you to search for specific drug-drug interactions. This tool provides a list of drug interactions, and also a risk estimate, and an assessment on the level of evidence used to make that estimate.