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Jan 1, 2000

Parker Waichman LLP – Newsletter – December 2007


Interactions Between SSRIs and Other Drugs Can Be Dangerous


Many prescription drugs have potentially dangerous side-effects when used alone, while others that may not be as risky on their own become problematic when taken with other medications (prescription or over-the-counter), by smokers (see December Newsletter), or with certain foods.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              

Selective serotonin reuptake inhibitors (SSRIs), however, are a class of drugs that pose serious risks when taken alone and as a result of dangerous interactions with other medications.


SSRIs are widely prescribed to millions of Americans as a treatment for depression, obsessive compulsive disorder, and other psychiatric problems. Some 70 million prescriptions for SSRIs were filled in the U.S. in 2006, with LEXAPRO (5th) and ZOLOFT (10th) both being in the top ten.

Currently, six SSRIs are marketed in the U.S. these include: citalopram (CELEXA), escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine (LUVOX), paroxetine (PAXIL) and sertraline (ZOLOFT).

Many studies have noted serious side-effects to SSRIs and they have been linked to dangerous adverse reactions in adolescents, including suicide. Thus, SSRIs are already the target of consumer watchdog organizations (like Public Citizen) that strongly challenge the safety and even the usefulness of these powerful psychotropic drugs.    

Since people who take SSRIs often take other medications, the interactions that may occur become extremely important since some are potentially dangerous. The different SSRIs have diverse kinetic interactions. A kinetic reaction is when one drug causes the blood level of another drug to be abnormally high or low.

In addition, certain liver enzymes break down drugs to help eliminate them from the body. Thus, anything that causes these enzymes to become overactive can reduce the blood levels of medications to the point where they do not work. This process is a metabolic change called enzyme induction.


Fluvoxamine is the SSRI most likely to cause a kinetic drug interaction since it inhibits several key drug-metabolizing enzymes, including CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Most medications are broken down by one or more of these enzymes, so it is practically impossible for a person taking fluvoxamine to avoid drug interactions. Thus, this will result in abnormally high blood levels of these other drugs.

Although fluvoxamine appears to have little effect on the drug-metabolizing enzyme CYP2D6, the functions of that particular enzyme are noticeably inhibited by other SSRIs such as fluoxetine and paroxetine. The remaining three SSRIs have little or no effect on these enzymes and, thus, are less likely to cause kinetic interactions.

The following tables were compiled by Public Citizen as part of their Worst Pills, Best Pills publication at   “Table 1 shows the enzymes affected by each of the SSRIs and the differing degrees of kinetic interactions of these drugs. Citalopram, escitalopram and sertraline have the lowest potential for kinetic interactions among SSRIs because they have a weak affect on only one drug-metabolizing enzyme. However, these drugs are not necessarily preferred to other SSRIs – especially if the patient is either not taking any other drug or the specific SSRIs do not interact with other drugs a patient is taking.”

Table 1. Risk of Kinetic Interactions with SSRIs


SSRI Enzymes Inhibited by the SSRI

Overall Kinetic Interaction Risk

Citalopram (CELEXA)

CYP2D6 (weak)


Escitalopram (LEXAPRO)*

CYP2D6 (weak)


Fluoxetine (PROZAC)

CYP2D6, CYP2C19, CYP3A4 (weak)


Fluvoxamine (FLUVOX)



Paroxetine (PAXIL)



Sertraline (ZOLOFT)

CYP2D6 (weak)


* Do Not Use drug in Worst Pills, Best Pills

The effect of SSRIs on serotonin causes other kinds of drug interactions. “The desired effect of SSRIs is to increase the level of serotonin in the brain. Unfortunately, this action can result in excess serotonin elsewhere in the body, especially if SSRIs are used along with other drugs that also increase serotonin levels.” (See “Pharmacologic Drug Interactions” described in the November 2007 issue of Worst Pills, Best Pills News.)

According to Public Citizen: “All SSRIs have similar effects on serotonin levels, but their serotonin-related interactions vary. Some of the serotonin-related drug interactions of SSRIs are life-threatening, while others are less dangerous (See Table 2, which lists both kinetic and the serotonin-related interactions).”

The foremost danger of increased serotonin levels is known as “serotonin syndrome” – an infrequent but potentially severe condition caused when a drug interaction creates too much serotonin in the body. The condition may range from no more than an annoyance to possible seizures, comas, and death in the most severe cases, which are accompanied by symptoms such as jerking of muscles, rigid muscles, tremor, overactive reflexes, fever, sweating, shivering, confusion and agitation.

For the most part, the older “tricyclic” antidepressants including amoxapine (ASENDIN), desipramine (NORPRAMIN), doxepin (SINEQUAN), imipramine (TOFRANIL), nortriptyline (AVENTYL), protriptyline (VIVACTIL) and trimipramine (SURMONTIL) display fewer drug interactions since tricyclic antidepressants, in general, do not inhibit drug metabolizing enzymes.

Some tricyclic antidepressants, however, have more side effects than SSRIs. For instance, amitriptyline (ELAVIL) has consistently been designated as a “Do Not Use drug” in Worst Pills, Best Pills, since it produces more harmful side effects than any other tricyclic.

Because of the potential for harmful interactions, patients on any SSRI should provide their physician and/or pharmacist with a complete list of drugs they are taking and immediately inform their physician if they develop one or more of the symptoms of serotonin syndrome.

Table 2. Drugs with Documented Interactions with SSRIs a


Side Effect When Used with SSRIs

Alprazolam (XANAX)b

Increased risk of alprazolam toxicity with fluoxetine or fluvoxamine

Aripiprazole (ABILIFY)c

Increased risk of aripiprazole toxicity with fluoxetine and paroxetine

Atomoxetine (STRATTERA)c

Increased risk of atomoxetine toxicity with fluoxetine and paroxetine

Buspirone (BUSPAR)

Possible increased risk of serotonin syndrome


Increased caffeine effect with fluvoxamine

Carbamazepine (TEGRETOL)

Increased risk of carbamazepine toxicity with fluoxetine and possibly fluvoxamine

Clomipramine (ANAFRANIL)

Possible increased risk of serotonin syndrome

Clozapine (CLOZARIL)d

Increased risk of clozapine toxicity with fluvoxamine or fluoxetine


Possible decreased analgesic effect of codeine, especially with fluoxetine and paroxetine

Desipramine (NORPRAMIN)

Increased risk of desipramine toxicity with fluoxetine and paroxetine

Dextromethorphan (DELSYM)*

Possible increased risk of serotonin syndrome, especially with fluoxetine or paroxetine

Diazepam (VALIUM)*

Increased risk of diazepam toxicity with fluoxetine or fluvoxamine


Possible increased risk of serotonin syndrome, especially with fluvoxamine

Imipramine (TOFRANIL)

Possible increased risk of serotonin syndrome

Itraconazole (SPORANOX)e

Possible increased risk of fluoxetine toxicity

Linezolid (ZYVOX)

Possible increased risk of serotonin syndrome

Lithium (LITHOBID)

Possible risk of lithium toxicity or serotonin syndrome

Meperidine (DEMEROL)

Possible increased risk of serotonin syndrome

Methadone (METHADOSE)

Increased risk of methadone toxicity with fluvoxamine

Metoclopramide (REGLAN)

Possible increased risk of metoclopramide toxicity with fluoxetine

Mexiletine (MEXITIL)

Increased risk of mexiletine toxicity with fluvoxamine

Mirtazapine (REMERON)

Possible increased risk of mirtazapine toxicity or serotonin syndrome

NSAIDs (see list below)f

Increased risk of gastrointestinal bleeding

Olanzapine (ZYPREXA)

Possible increased risk of olanzapine toxicity with fluoxetine and fluvoxamine

Phenelzine (NARDIL)

Risk of fatal serotonin syndrome: AVOID COMBINATION

Phenytoin (DILANTIN)

Increased risk of phenytoin toxicity with fluoxetine or fluvoxamine

Propafenone (RHYTHMOL)

Increased risk of propafenone toxicity with fluoxetine or paroxetine

Quinidine (QUINIDEX)

Possible increased risk of quinidine toxicity with fluvoxamine

Ramelteon (ROZEREM)g

Marked increase in ramelteon levels with fluvoxamine: AVOID COMBINATION

Rasagiline (AZILECT)

Possible increased risk of serotonin syndrome

Sibutramine (MERIDIA)*

Possible increased risk of serotonin syndrome

Tacrine (COGNEX)*

Increased risk of tacrine toxicity with fluvoxamine


Increased risk of theophylline toxicity with fluvoxamine: AVOID COMBINATION

Thioridazine (MELLARIL)*

Serious risk of heart arrhythmias with fluoxetine, fluvoxamine, or paroxetine: AVOID COMBINATION

Tizanidine (ZANAFLEX)

Increased risk of tizanidine toxicity with fluvoxamine: AVOID COMBINATION

Tramadol (ULTRAM)*

Possible increased risk of serotonin syndrome

Triptans (see list below)h

Increased risk of serotonin syndrome, but many people have taken SSRIs and triptans without developing symptoms of serotonin syndrome

Tranylcypromine (PARNATE)

Risk of fatal serotonin syndrome: AVOID COMBINATION

Trazodone (DESYREL)

Increased risk of trazodone toxicity with fluoxetine or paroxetine

Warfarin (COUMADIN)

Possible increased risk of bleeding

* Do Not Use drug in Worst Pills, Best Pills

a Interactions based on isolated case reports or interactions that are otherwise poorly documented are not included in the table.

b Do Not Use (except for panic disorder) in Worst Pills, Best Pills

c Do Not Use until 2010 in Worst Pills, Best Pills

d Last Choice drug in Worst Pills, Best Pills

e Do Not Use (except for serious fungal infection) in Worst Pills, Best Pills

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