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The Serotonin Syndrome: A Potentially Life-Threatening Adverse Drug Reaction — Fluoxetine (PROZAC), Escitalopram (LEXAPRO), Sibutramine (MERIDIA) And Other Drugs

Worst Pills, Best Pills Newsletter article September, 2003

Canadian drug regulatory authorities reviewed reported cases of serotonin syndrome in the July 2003 issue of the Canadian Adverse Reaction Newsletter. The serotonin syndrome is a potentially life-threatening adverse drug reaction involving an excess of serotonin, a naturally occurring nerve transmitter. It usually occurs when two or more drugs that have an effect on serotonin are given together. Drugs that have an effect on serotonin are referred to as serotonergic drugs.

The table...

Canadian drug regulatory authorities reviewed reported cases of serotonin syndrome in the July 2003 issue of the Canadian Adverse Reaction Newsletter. The serotonin syndrome is a potentially life-threatening adverse drug reaction involving an excess of serotonin, a naturally occurring nerve transmitter. It usually occurs when two or more drugs that have an effect on serotonin are given together. Drugs that have an effect on serotonin are referred to as serotonergic drugs.

The table accompanying this article lists drugs that have an effect on serotonin or have been linked to the serotonin syndrome.

Serotonin levels can be increased in a number of ways. For example, increased production, increased release, inhibition of reuptake at nerve endings, and inhibition of breakdown. Interactions in which drugs, foods or herbal products inhibit the breakdown and elimination of serotonergic drugs may also precipitate serotonin syndrome by increasing the concentration of these drugs in the body.

The manifestations of the serotonin syndrome fall into three general areas:

  1. Cognitive or behavioral changes such as confusion, agitation, lethargy, and coma.
  2. A condition that is referred to as autonomic instability that includes elevated temperature, rapid heart rate, sweating, nausea, vomiting, diarrhea, and dilated pupils.
  3. Neuromuscular changes that include spasm or twitching a muscle or group of muscles, exaggerated reflexes, and tremor.

Serotonin syndrome is often self-limited with a good outcome, particularly if it is recognized early, treatment with the suspected drug or drugs is stopped, and supportive care is given.

Between January 1, 1998 and December 30, 2002 the Canadian authorities had received 53 reports of suspected serotonin syndrome. Serotonin syndrome was most often reported with the use of the selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (PROZAC) or escitalopram (LEXAPRO), with 33 reports. The monoamine oxidase inhibitor (MAOI) antidepressants accounted for 10 reports. Tranylcypromine (PARNATE) is an example of an MAOI antidepressant. Venlafaxine (EFFEXOR), also a very popular antidepressant, was cited nine times in association with the serotonin syndrome.

The Canadian Adverse Reaction Newsletter paid particular attention to reports of serotonin syndrome in association with the use of the dangerous diet drug sibutramine (MERIDIA). The Health Research Group petitioned the Food and Drug Administration (FDA) in March 2002 to remove sibutramine from the market (see Worst Pills, Best Pills News May 2002).

Sibutramine has an effect on both serotonin and norepinephrine, another nerve transmitter. The Canadian authorities had received 87 adverse reaction reports associated with the use of sibutramine from February 2001, when it was first marketed in Canada, to December 31, 2002. In three of the 87 cases serotonin syndrome was reported.

In the first of these cases, sibutramine was taken together with fluoxetine (PROZAC). In the second case, sibutramine was taken with sertraline (ZOLOFT) but the sertraline was stopped two days before the symptoms of serotonin syndrome appeared. In the third case, the use of other drugs was reported. There were no reports of a fatal outcome.

The Drug Interaction section of the U.S.professional product label, or package insert, for sibutramine carries the following warnings:

In patients receiving monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions (“serotonin syndrome;” see below). Because MERIDIA inhibits serotonin reuptake, MERIDIA should not be used concomitantly with an MAOI. At least 2 weeks should elapse between discontinuation of an MAOI and initiation of treatment with MERIDIA. Similarly, at least 2 weeks should elapse between discontinuation of MERIDIA and initiation of treatment with an MAOI.

The rare, but serious, constellation of symptoms termed “serotonin syndrome” has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex (sumatriptan succinate) and dihydroergotamine; certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl; and lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention.

What You Can Do

If you are taking one of the drugs in the table abelow and develop any of the symptoms of serotonin syndrome, contact your physician immediately.

DRUGS THAT AFFECT SEROTONIN OR HAVE BEEN ASSOCIATED WITH THE SEROTONIN SYNDROME

GENERIC NAME

BRAND NAME

Analgesics/Painkillers

codeine

 

dextropropoxyphene

DARVON

fentanyl

ACTIQ, DURAGESIC

meperidine

DEMEROL

entazocine

TALWIN

Antidepressants – Monoamine Oxidase Inhibitors (MAOIs)

moclobemide

not available in U.S.

phenelzine

NARDIL

tranylcypromine

PARNATE

Antidepressants – Selective Serotonin Re-uptake Inhibitors (SSRIs)

citalopram

CELEXA

escitalopram

LEXAPRO

fluoxetine

PROZAC

fluvoxamine

LUVOX

paroxetine

PAXIL

sertraline

ZOLOFT

Antidepressants - Tricyclic

amitriptyline

ELAVIL

clomipramine

ANAFRANIL

desipramine

NORPRAMIN

doxepin

SINEQUAN

imipramine

TOFRANIL

nortriptyline

AVENTYL

Antidepressants - Other

bupropion

WELLBUTRIN, ZYBAN

mirtazapine

REMERON

nefazodone

SERZONE

trazodone

DESYREL

venlafaxine

EFFEXOR

Anti-Nausea Drugs

dolasetron

ANZEMET

granisetron

KYTRIL

ondansetron

ZOFRAN

Antipsychotics

clozapine

CLOZARIL

olanzapine

ZYPREXA

risperidone

RISPERDAL

Parkinson’s Disease Drugs

amantadine

SYMMETREL

bromocriptine

PARLODEL

levodopa

SINEMET

selegiline

ELDEPRYL

Illegal Drugs

cocaine

 

MDMA ("ectasy")

 

LSD

 

mescaline

 

Migraine Headache Drugs

dihydroergotamine

DHE 45

almotriptan 

AXERT

eletriptan

RELPAX

frovatriptan

FROVA

naratriptan

AMERGE

rizatriptan

MAXALT

sumatriptan

IMITREX

zolmitriptan

ZOMIG

Other Drugs

brompheniramine

ingredient in cold preparations

buspirone

BUSPAR

carbamazepine

TEGRETOL

dextroamphetamine

DEXEDRINE

dextromethorphan

over the counter cough suppressant

droperidol

INAPSINE

L-tryptophan

dietary supplement

lithium

LITHOBID

linezolid

ZYVOX

metoclopramide

REGLAN

phentermine

IONAMIN

reserpine

SALUTENSIN

sibutramine

MERIDIA

St. John'swort

dietary supplement