Pubdate: Tue, 27 Feb 2007
Source: New York Times (NY)
Section: Pg F7
Copyright: 2007 The New York Times Company
Author: Jane E. Brody


The death of Libby Zion, an 18-year-old college student, in a New 
York hospital on March 5, 1984, led to a highly publicized court 
battle and created a cause celebre over the lack of supervision of 
inexperienced and overworked young doctors. But only much later did 
experts zero in on the preventable disorder that apparently led to 
Ms. Zion's death: a form of drug poisoning called serotonin syndrome. 
Skip to next paragraph Stuart Bradford

Ms. Zion, who went to the hospital with a fever of 103.5, had been 
taking a prescribed antidepressant, phenelzine (Nardil). The 
combination of phenelzine and the narcotic painkiller meperidine 
(Demerol) given to her at the hospital could raise the level of 
circulating serotonin to dangerous levels. When she became agitated, 
a symptom of serotonin toxicity, and tried to pull out her 
intravenous tubes, she was restrained, and the resulting muscular 
tension is believed to have sent her fever soaring to lethal heights.

Now, with the enormous rise in the use of serotonin-enhancing 
antidepressants, often taken in combination with other drugs that 
also raise serotonin levels, emergency medicine specialists are 
trying to educate doctors and patients about this not-so-rare and 
potentially life-threatening disorder. In March 2005, two such 
specialists, Dr. Edward W. Boyer and Dr. Michael Shannon of 
Children's Hospital Boston, noted that more than 85 percent of 
doctors were "unaware of the serotonin syndrome as a clinical diagnosis."

In their review in The New England Journal of Medicine, Dr. Boyer and 
Dr. Shannon cited a report based on calls to poison control centers 
around the country in 2002 showing 7,349 cases of serotonin toxicity 
and 93 deaths. (In 2005, the last year for which statistics are 
available, 118 deaths were reported.)

The experts fear that failure to recognize serotonin syndrome in its 
mild or early stages can result in improper treatment and an abrupt 
worsening of the condition, leading to severe illness or death. Even 
more important, in hopes of preventing it, they want doctors -- and 
patients -- to know just what drugs and drug combinations can cause 
serotonin poisoning.

A Diagnostic Challenge

Serotonin syndrome was first described in medical literature in 1959 
in a patient with tuberculosis who was treated with meperidine. But 
it wasn't given its current name until 1982.

Recognizing the early signs is tricky because it has varying symptoms 
that can be easily confused with less serious conditions, including 
tremor, diarrhea, high blood pressure, anxiety and agitation. The 
examining physician may regard early symptoms as inconsequential and 
may not think to relate them to drug therapy, Dr. Boyer and Dr. Shannon noted.

In its classic form, serotonin syndrome involves three categories of symptoms:

PCognitive-behavioral symptoms like confusion, disorientation, 
agitation, irritability, unresponsiveness and anxiety.

PNeuromuscular symptoms like muscle spasms, exaggerated reflexes, 
muscular rigidity, tremors, loss of coordination and shivering.

PAutonomic nervous system symptoms like fever, profuse sweating, 
rapid heart rate, raised blood pressure and dilated pupils.

Widespread ignorance of the syndrome is another diagnostic 
impediment. But even when doctors know about it, the strict 
diagnostic criteria may rule out "what are now recognized as mild, 
early or subacute stages of the disorder," Dr. Boyer and Dr. Shannon wrote.

Perhaps adding to the diagnostic challenge is the fact that a huge 
number of drugs -- prescription, over the counter, recreational and 
herbal -- can trigger the syndrome. In addition to selective 
serotonin reuptake inhibitors like Zoloft, Prozac and Paxil and 
serotonin/norepinephrine reuptake inhibitors like Effexor, the list 
includes tricyclic antidepressants and MAOIs (for monoamine oxidase 
inhibitors); narcotic painkillers like fentanyl and tramadol; 
over-the-counter cough and cold remedies containing dextromethorphan; 
the anticonvulsant valproate; triptans like Imitrex used to treat and 
prevent migraines; the antibiotic Zyvox (linezolide); antinausea 
drugs; the anti-Parkinson's drug L-dopa; the weight-loss drug Meridia 
(sibutramine); lithium; the dietary supplements tryptophan, St. 
John's wort and ginseng; and several drugs of abuse, including 
ecstasy, LSD, amphetamines, the hallucinogens foxy methoxy and Syrian rue.

Although serotonin poisoning can be caused by an antidepressant 
overdose, it more often results from a combination of an S.S.R.I. or 
MAOI with another serotonin-raising substance. Patients at particular 
risk, some experts say, are those taking combinations of 
antidepressant and antipsychotic drugs sometimes prescribed to treat 
resistant depression. All it may take is a small dose of another 
serotonin-inducing drug to cause the syndrome.

One patient, a 45-year-old Bostonian, had been taking four drugs to 
treat depression when he had surgery on an ankle last December. He 
developed several classic signs of serotonin syndrome while in the 
recovery room, where he had been given fentanyl when the anesthetic wore off.

As described by his wife, he suddenly developed tremors and violent 
shaking and started cracking his teeth. He was moved to the intensive 
care unit, where he thrashed and flailed, was oblivious to those 
around him, and had to be restrained to keep from pulling out his 
tubes. Two weeks later, he was still in intensive care and still very 
confused, despite being taken off all medications that could have 
caused his symptoms.

Serotonin syndrome can occur at any age, including in the elderly, in 
newborns and even in dogs. Since 1998, the poison control center at 
the American Society for the Prevention of Cruelty to Animals has 
gotten more than a thousand reports of the ingestion of 
antidepressant medications by dogs, which can develop symptoms 
rapidly and die. The syndrome can also occur weeks after a 
serotonin-raising drug has been discontinued. Some drugs remain 
active in the body for weeks, and the MAOIs disable an enzyme 
involved in serotonin metabolism that does not recover until weeks 
after the drugs are stopped.

Prevention and Treatment

Most cases of serotonin syndrome are mild and resolved within 24 
hours. But if the doctor fails to recognize them and prescribes 
either a larger dose of a serotonin enhancer or another 
serotonin-raising drug, the consequences can be rapid and severe.

Most important to preventing the syndrome is for patients to give 
each of their doctors a complete list of drugs they regularly take -- 
including prescriptions, over-the-counter medication, dietary 
supplements and recreational drugs -- before a doctor prescribes something new.

Indeed, if you are taking any of the drugs described above, you might 
ask whether a new prescription is safe. And when filling a new 
prescription, it's not a bad idea to also ask the pharmacist whether 
the medication, or an over-the-counter remedy you are considering, is 
safe to combine with any other drugs you take.

Once the syndrome develops, the first step is to stop the offending 
drugs. It is crucial to seek immediate care, preferably in a 
hospital. Most cases require only treatment of symptoms like 
agitation, elevated blood pressure and body temperature, and a 
tincture of time.

More severe cases are treated with drugs that inhibit serotonin and 
chemical sedation. Dr. Boyer and Dr. Shannon cautioned against 
usingphysical restraints to control agitation because they could 
enforce isometric muscle contractions that cause a severe buildup of 
lactic acid and a life-threatening rise in body temperature.
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MAP posted-by: Beth Wehrman