Important Drug Interactions with the SSRIs 11/8/2018

Selective serotonin reuptake inhibitors (SSRIs) are 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 dramatically increase the blood levels of medications that are metabolized by those liver enzymes, which include various psychotropic medications as well as other medications commonly prescribed by primary care providers.

Fluoxetine and paroxetine are potent inhibitors of cytochrome CYP2D6. Here is a partial list of affected medications:

Psychotropic Medications                Other Medications

Atypical antipsychotics                     Tramadol (increased risk of seizures)

Typical antipsychotics                      Codeine-based pain medications

Tricyclic antidepressants                 Dextromethorphan

Trazodone                                           Beta blockers

Benztropine                                        Diltiazem

Donepezil                                           Odansetron

Venlafaxine                                        Tamoxifen

Amoxetine                                          Antiarrhythmic medications

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 (hydrocodone, oxycodone) to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).

Fluoxetine and fluvoxamine are potent inhibitors of cytochrome CYP2C19 (fluvoxamine more so than fluoxetine). Sertraline is a modest inhibitor of this enzyme. Here is a partial list of affected medications:

 Psychotropic Medications                Other Medications

Tricyclic antidepressants                            Proton pump inhibitors (ex. Omeprazole)

Diazepam                                                        Proguanil


Fluvoxamine is a fairly strong inhibitor of cytochrome CYP3A4. Here is a partial list of affected medications:

Psychotropic Medications                Other Medications

Benzodiazepines                                    Calcium channel blockers

Carbamazepine                                      Proton pump inhibitors

Tricyclic antidepressants                     Fentanyl

Valproate                                                Statin medications

Nonbenzodiazepine hypnotics           Loratadine

Mirtazapine                                           Antifungal medications

Trazodone                                              Macrolide antibiotics

Hormone replacement

Fluvoxamine is a potent inhibitor of cytochrome CYP2C9, which can affect the following medications:

Psychotropic Medications                Other Medications

No significant interactions                     Glyburide/Glypizide


ARBs (ex. Losartan)



Fluvoxamine is also a potent inhibitor of cytochrome CYP1A2, which can affect the following medications:

Psychotropic Medications                Other Medications

Some antipsychotic medications          Warfarin

Tricyclic antidepressants                       Acetaminophen

Mirtazapine                                              Methadone

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 Tramadol, Meperidine, St. John’s Wort (an herbal supplement used for mild depression), 5HTP or dextromethorphan.

Some studies suggest that NSAIDs can reduce the efficacy of SSRI medications, although the overall data is inconclusive. However, the combination is also likely to 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 conjunction with other medications for their patients. It is especially important to be aware of the drug-drug interactions when prescribing fluoxetine, paroxetine and fluvoxamine.


  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed 12/14/12.
  2. Albers LJ, MD et al. Handbook of Psychiatric Drugs. 2008 Edition. University of California, Irvine.
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