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SSRIs Can Have Dangerous Interactions With Other Drugs

Dec 1, 2007

SSRIs Can Have Dangerous Interactions With Other Drugs


Selective serotonin reuptake inhibitors (SSRIs) are used by millions of Americans every year to treat depression, obsessive compulsive disorder and other psychiatric diseases.

In 2006 alone, 70 million prescriptions were filled in the U.S. for SSRIs. Two of these drugs were among the 10 most-prescribed drugs in that year: LEXAPRO (5th) and ZOLOFT (10th).

There are six SSRIs sold in the U.S.: citalopram (CELEXA), escitalopram (LEXAPRO), fluoxetine (PROZAC), fluvoxamine (LUVOX), paroxetine (PAXIL) and sertraline (ZOLOFT). Because they are often taken with other medications, it is important to recognize potentially dangerous drug interactions.

Do all SSRIs interact similarly with other medications?
No; the various SSRIs have different kinetic interactions, which occur when one drug causes the blood level of another drug to be abnormally high or low.

The SSRI most likely to cause a kinetic drug interaction is fluvoxamine because it inhibits several of the most important drug-metabolizing enzymes, including CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Most medications are broken down by one or more of these enzymes, so it is virtually impossible for a person taking fluvoxamine to avoid drug interactions when also taking other medications, resulting in abnormally high blood levels of these other drugs.

The one drug-metabolizing enzyme that fluvoxamine seems to have little effect on is CYP2D6, but the functions of that enzyme are markedly inhibited by other SSRIs such as fluoxetine and paroxetine.

The three other SSRIs have only mild effects or no effect on drug-metabolizing enzymes and are less likely to cause kinetic interactions.

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

Does the effect of SSRIs on serotonin cause other kinds of drug interactions?
Yes. 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. (These interactions fall into the category of “Pharmacologic Drug Interactions” described in the November 2007 issue of Worst Pills, Best Pills News.)

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 primary danger of increased serotonin levels is a side effect called “serotonin syndrome” – a rare but serious condition that occurs when drugs interact to create too much serotonin in the body. In mild forms, the condition may be simply a nuisance. In severe cases, seizures, coma and death can occur. Symptoms of severe serotonin syndrome include jerking of muscles, rigid muscles, tremor, overactive reflexes, fever, sweating, shivering, confusion and agitation.

Are there any antidepressants available that produce fewer drug interactions than SSRIs?
Yes. By and large, the older tricyclic antidepressants such as amoxapine (ASENDIN), desipramine (NORPRAMIN), doxepin (SINEQUAN), imipramine (TOFRANIL), nortriptyline (AVENTYL), protriptyline (VIVACTIL) and trimipramine (SURMONTIL) have fewer drug interactions than the SSRIs. Unlike SSRIs, tricyclic antidepressants generally do not inhibit drug metabolizing enzymes.

However, some tricyclic antidepressants have more side effects than SSRIs. An example of this is amitriptyline (ELAVIL), a long-time Do Not Use drug in Worst Pills, Best Pills, which produces more harmful side effects than any other drug in its family.

What You Can Do
Patients requiring SSRI antidepressants in addition to other drugs should provide their prescriber and/or pharmacist with a full list of drugs he or she is on to avoid potentially harmful drug interactions.

Patients taking SSRIs should tell their physician if they develop any symptoms of serotonin syndrome. This is especially important if patients develop several 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

f NSAIDs include diclofenac (VOLTAREN), diflunisal (DOLOBID), etodolac (LODINE), fenoprofen (NALFON), flurbiprofen (ANSAID), Ibuprofen (MOTRIN, ADVIL), indomethacin (INDOCIN), ketoprofen (ORUDIS), ketorolac (TORADOL), meclofenamate (MECLOMEN), meloxicam (MOBIC), nabumetone (RELAFEN), naproxen (ALEVE), oxaprozin (DAYPRO), piroxicam (FELDENE), sulindac (CLINORIL), tolmetin (TOLECTIN).

g Do Not Use until 2012 in Worst Pills, Best Pills

h Triptans include almotriptan (AXERT), eletriptan (RELPAX), frovatriptan (FROVA), naratriptan (AMERGE), rizatriptan (MAXALT), sumatriptan (IMITREX), zolmitriptan (ZOMIG).


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