A Mix of Medicines That Can Be Lethal
Personal Health
A Mix of Medicines That Can Be Lethal
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By JANE E. BRODY
Published: February 27, 2007
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 célèbre 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.
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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:
¶Cognitive-behavioral symptoms like confusion, disorientation,
agitation, irritability, unresponsiveness and anxiety.
¶Neuromuscular symptoms like muscle spasms, exaggerated reflexes,
muscular rigidity, tremors, loss of coordination and shivering.
¶Autonomic 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 using
physical restraints to control agitation because they could enforce