Great Article but long!

[Guest guest]

December 16, 2003

British Ignite Debate in U.S. on Drugs and Suicide

By ERICA GOODE

Many American psychiatrists were taken by surprise last week when

British drug regulators told doctors to stop writing prescriptions

for all but one of a newer generation of antidepressant drugs to

treat depressed children under 18.

Now the psychiatrists are trying to figure out how to advise the

parents of the young patients who come to them for help. Some

parents, the doctors say, are calling to ask if the drugs their

children are taking are really safe.

" The news has certainly generated anxiety, concern and questions, "

said Dr. Flemming Graae, the chief of child and adolescent

psychiatry at Westchester Medical Center in Valhalla, N.Y.

For parents and psychiatrists alike, the issue is not an easy one to

sort out.

The British regulators said that for adults, the benefits of the

antidepressants, most belonging to the class called selective

serotonin reuptake inhibitors or S.S.R.I.'s, clearly outweigh their

risks.

But after reviewing 11 studies of the drugs in treating depressed

children and adolescents, the regulators concluded that for most of

the medications, the potential for harmful side effects — including

suicidal thoughts and behavior, as well as hostility — was greater

than the evidence for their effectiveness. Doctors should not

prescribe the medications except in certain circumstances, the

regulators said.

The drugs included Paxil, from GlaxoKline; Zoloft, from Pfizer;

Effexor, from Wyeth; Celexa and Lexapro, from Forest Laboratories

Inc.; and Luvox, from Solvay. Prozac, by Eli Lilly, was exempted

from the advisory. (Effexor is a serotonin-norepinephrine inhibitor.)

Few psychiatrists dispute that little is known about how well the

drugs work and how they affect the developing brain: the number of

large-scale studies of S.S.R.I.'s in children is small, many of the

findings are less than impressive, and some drugs have yet to be

tested.

And some mental health professionals believe that, given the limited

knowledge, antidepressants are being prescribed too widely and too

casually by doctors, many of them general practitioners rather than

psychiatrists.

But medical experts have sharply divergent opinions on whether

governments should intervene in the way that Britain did.

Dr. Harrington, a professor of child and adolescent

psychiatry at the University of Manchester in England, said he

thought that, on balance, the British regulators did the right thing.

" The broad story seems to be that the drugs don't work and they have

some side effects, " Dr. Harrington said. " If we're going to practice

evidence-based medicine and if the basic evidence is negative, then

why prescribe them? "

But some American psychiatrists say the British regulators acted

hastily and went too far.

" Everybody — scientists, parents and advocates — needs an answer to

this question, " said Dr. March, the chief of child and

adolescent psychiatry at Duke University Medical Center. But the

British regulators, he said, " prematurely closed the story. "

Dr. March and other experts argue that the cost of leaving depressed

children and teenagers untreated is high: depression itself can be a

lethal illness. And some psychiatrists say that they have

seen " indisputable proof " in their practices that the drugs help

seriously ill children.

Most of the experts said they would continue to use S.S.R.I.'s to

treat children and teenagers. But they added that doctors and

parents should closely monitor children for signs of restlessness,

agitation, recklessness, unusual behavior or thoughts of suicide,

especially during the first weeks of drug treatment and after any

increase in dosage. Some anecdotal evidence suggests that suicidal

or aggressive behavior, if it is tied to the drugs, occurs within

the first weeks after the drug treatment is started.

Dr. Graae and others say they start children on very low doses of

the medications and that in some cases a low dose is all that is

needed.

Most American experts do not rule out the possibility that in some

young people, the antidepressants may somehow increase the risk of

suicidal thinking or self-harm, though they believe a link remains

unproved.

But even if an association were shown, some say, they would favor

stronger warning labels rather than a recommendation that the drugs

not be used.

Some researchers said they believed that the Food and Drug

Administration, which is conducting its own intensive review of the

drugs and will hold public hearings on Feb. 2, has taken a more

careful and comprehensive approach to investigating the medications'

safety.

Dr. March and other experts said the committee that reviewed the

studies for the British Medicines and Healthcare Products Regulatory

Agency, the British equivalent of the F.D.A., failed to adequately

take into account the complexity of the data and the difficulty of

comparing studies done with varying methodologies and with subjects

who suffered from different degrees of illness. The British agency

has posted summaries on its Web site (www.mhra.gov.uk) of all the

studies reviewed.

The British regulators, some experts said, also did not give proper

weight to the high frequency of suicidal thoughts and attempts among

depressed adolescents in general. A study in 2000 by Norwegian

researchers of close to 10,000 children ages 12 to 20, for example,

found that 30 percent of those who met criteria for a diagnosis of

depression at the beginning of the study had made a suicide attempt

two years later.

Some researchers also questioned the logic of singling out one drug

as better or safer than the others.

Dr. Graham Emslie, a professor of psychiatry at the University of

Texas Southwestern Medical Center and the lead investigator on the

studies of Prozac that the British regulators found convincing, said

that because the studies of different drugs use different measures

and are based on significantly varying numbers of subjects, the

discrepancies in their findings may mean little.

" Any relative difference in effectiveness between S.S.R.I.'s is

probably best explained by methodological differences and not by

specific differences in the medications, " Dr. Emslie said.

The F.D.A., psychiatrists familiar with the agency's investigation

said, is requesting more information from drug companies than was

given to the British drug agency, and has asked outside researchers

to trace back and recode by hand the raw data used in some studies.

The experts said the agency hoped to determine how many of the

reports of suicidal thinking or behavior were real. The F.D.A. also

hopes to tell if the greater incidence of suicidal tendencies found

in some studies among children taking the drugs is meaningful or is

simply an artifact of how the children were assigned to the drug or

placebo groups, the experts said. No suicides were reported in any

of the studies.

If a link is found between some of the drugs and suicidal

tendencies, scientists will then have to figure out how many

children and adolescents may be affected — most experts believe the

number would be very small — and how the drugs produce such behavior.

While emphasizing that any attempt to explain what might be going on

was pure speculation, some experts have offered hypotheses. One is

that some children may have a " paradoxical " reaction to the drugs

that causes them to become extremely restless, agitated or

impulsive. Dr. Graae said that he had treated more than 2,000

children with S.S.R.I.'s and had not seen a case where he thought

the drugs produced suicidal thoughts or behavior. But he said that

he had seen cases of children who had shown " a level of recklessness

or risk taking, not necessarily aimed at injuring oneself. "

Another is that the drugs may produce an unstable emotional state in

some children who actually suffer from manic depression that has

gone undiagnosed.

A third idea is that some incidents may occur in children who are

taking their medication irregularly or who have just stopped the

drug. Some S.S.R.I.'s are metabolized by the body very quickly. When

they are stopped abruptly they can produce a variety of reactions,

including shifts in mood, lightheadedness, flulike symptoms and what

some patients have described as " electrical zapping sensations. "

Children, experts said, metabolize drugs more quickly than adults,

and may be more susceptible to such reactions. In three studies of

Paxil examined by the British regulators, 20 of 34 events " possibly

related to suicidality " occurred during the 30 days after the

children stopped taking the drug, compared with 8 out of 17 in the

placebo group in the same period.

The British action appears to have already made some American

parents more cautious about starting their children on

antidepressants. Dr. Graae said that one couple he saw decided to

postpone their child's treatment with an S.S.R.I. until they could

discuss the issue further.

But for many parents, the pronouncements of government officials has

less impact than their own personal experiences with the drugs.

A woman in Westchester County whose 12-year-old son has taken Zoloft

for several months, for example, said that she resorted to

medication only because she feared her son was on the edge of a

serious breakdown.

" I knew my child was in deep trouble, " the mother said. She added

that on the drug her son had improved greatly.

" It's been night and day, " she said.

But Sara Bostock, who says she believes that Paxil caused her 25-

year-old daughter to commit suicide a few weeks after starting the

drug, sees the British action as the first step toward recognizing

what she calls the dangers of S.S.R.I.'s. Ms. Bostock has campaigned

for the pharmaceutical companies to open privately held data to the

public.

" I admit to anger and outrage over what I believe was a serious

wrong done to my beloved daughter, " Ms. Bostock said in an e-mail

message, " and this ban does represent some vindication for me. "

In fact, the British regulators stopped short of an outright ban,

saying that for some children, including those who were already

doing well on an S.S.R.I. and those who could not tolerate Prozac,

their use might still be warranted.

What everyone agrees on is that only more research and more detailed

analysis of the studies that exist will be able to provide answers

to parents and clinicians.

" We should let the data tell the story, " Dr. March said.

Copyright 2003 The New York Times Company