SEROTONIN SYNDROME - A MIX OF MEDICINES THAT CAN BE LETHAL

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.