Important Drug Interactions with the SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychotropic medications to treat depression and anxiety. It is important to be aware of common drug interactions between them and other medications, especially because some SSRIs are competitive inhibitors of a variety of cytochrome P450 liver enzymes. Therefore, they can significantly increase the blood levels of medications that are metabolized by those liver enzymes.

Currently, six types of SSRIs are available for prescribing in the U.S.: fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa), escitalopram (Lexapro). These drugs are subject to extensive oxidative metabolism in the liver. Because these antidepressants have a wide therapeutic index, inhibition or induction of their metabolism is unlikely to be of concern. However, SSRIs may cause a clinically relevant inhibition of CYP enzymes, and care must be exercised when an SSRI is being added to a multidrug regimen.

The potency of the SSRIs as inhibitors of the metabolism of the P450-P2-D6 varies and is reported in descending order of potency as paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine. Fluoxetine and paroxetine are more likely to cause P450 drug interactions than citalopram and sertraline, particularly in combination with medications metabolized by or inhibiting the cytochrome P450 2D6 isoenzyme (e.g., certain antidepressants, phenothiazines,antipsychotics type IC antiarrhythmics).

Drug interactions with clinical consequences usually involve combinations of an SSRI with other psychotropics, especially monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. The interaction between MAOIs and SSRIs is the most important drug interaction limiting SSRI use. MAOI’s are infrequently prescribed due to other options available and the high risk of interaction with other drugs.

Sertraline, citalopram and escitalopram have the lowest potential for drug interactions among the SSRIs, and are to be preferred in patients on other drugs for general medical conditions or if consideration is given to adding an SSRI to other psychotropic medication.

With the drug interaction between fluoxetine and paroxetine and codeine-based pain medications, patients can experience reduced pain relief because the CYP2D6 inhibition will reduce conversion of codeine and related medications to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).

It is also important to be aware of the risk of serotonin syndrome (increase heart rate, sweating, myoclonus, hyperthermia, and agitation) when combining certain medications with SSRIs because it can be life threatening. MAOIs are contraindicated with SSRIs for this and other reasons (the combination can also increase the risk of hypertensive crisis). Be cautious when combining SSRIs with Tramodol, Meperidine, St. John’s Wort (an herbal supplement used for mild depression) or dextromethorphan.

Some studies suggest that NSAIDs can reduce the efficacy of SSRI medications, although the overall data is inconclusive.  This combination may lead to increased gastrointestinal side effects.

It is our hope that this discussion is helpful for providers in the primary care setting as they are prescribing SSRIs in conjuction with other medications for their patients.


Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed 12/14/12.

Albers LJ, MD et al. Handbook of Psychiatric Drugs. 2008 Edition. University of California, Irvine.

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