Healthy Skepticism Library item: 1534

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Publication type: news

Bramham D.
Depressed Kids: The Drug Debate: Are the young used as guinea pigs for untested antidepressants?
Sterling News Service 2003 Dec 11

Full text:

FIRST OF TWO PARTS

Every year more and more kids — some still in preschool — are popping pills for anxiety, depression, even shyness.

What they’re mostly taking are selective seratonin reuptake inhibitors, or SSRIs.

Paxil, or paroxetine, is the most commonly prescribed SSRI and experts estimate that five per cent of those prescriptions are written for patients 18 and younger, including some preschoolers. With 3.57 million prescriptions written for Paxil in the 12 months from September 2002 to September 2003 in Canada, that means about 178,500 of those were for kids. That’s a 58 per cent increase over just five years ago.

In B.C., an estimated 20,700 Paxil prescriptions were written for kids between Oct. 1, 2002, and the end of October this year. That’s a 68.8-per-cent increase over five years ago.

Yet with the exception of Prozac, or fluoxetine, Paxil and its SSRI cousins have never been fully tested on kids. They’ve never been approved for pediatric use and because drug companies have never sought pediatric approval, they have never had to show regulators the results of clinical trials.

And, by the way, nobody has ever done a study to determine what effect SSRIs will have on their developing brains and bodies.

Doctors know how little real information there is about the effects of these drugs on little kids and teens. Parents should.

Yet that hasn’t slowed sales at all. Billions of dollars’ worth are sold globally each year. In Canada, nearly 14 million prescriptions for SSRIs were filled in 2002 at a cost of $869 million. In B.C. alone, doctors wrote 1.69 million prescriptions for the drugs at a cost of $116.3 million.

There have always been questions about them — their efficacy and their effects. But again, it hasn’t in any way dissuaded doctors from prescribing them by the millions.

Until this spring. Evidence was presented to the British drug regulatory agency in late May that wasn’t new, it was only new to the regulators.

It was raw data from seven-year-old clinical trials that had never before been available. There was no reason for the drug company GlaxoSmithKline to release it because until 2003, it was not applying for pediatric use of paroxetine.

The data showed that kids on paroxetine (sold as Seroxat in Britain and Paxil in North America) were 1.5 to 3.2 times more likely to be suicidal than kids taking placebos. Ironically, the trials found that kids taking placebos were almost as likely to get well as kids on the real pills.

In June, Britain advised doctors to quit prescribing the most popular of the SSRIs — paroxetine — to anyone under 18.

The British regulatory agency said that paroxetine not only appears to be harmful to kids, it may be no more effective in treating anxiety and depression than sugar pills.

It was stunning news for families and physicians and it pushed other regulatory agencies into action.

Within a few weeks, the U.S. food and drug administration warned physicians about the new evidence, but stopped short of recommending against pediatric use of paroxetine. Instead it urged physicians to watch their patients more carefully for suicide. A few weeks later, it issued an advisory that another SSRI, venlafaxine (which is marketed as Effexor) is “ineffective” in treating childhood depression.

Canada followed the Americans’ lead in both cases.

By October 2003, the clamour of parents, patients and physicians demanding more information grew so loud that the FDA announced it will hold a special meeting Feb. 2 to discuss all of the published data, the new data and, if required, recommend further studies on eight different SSRIs. The list includes paroxetine (Paxil), venlafaxine (Effexor), fluvoxamine (Luvox), citalopram (Celexa), sertraline (Zoloft), nefazadone (Serzone) and mirtazapine (Remeron).

The doctors — mostly family physicians and pediatricians — started calling experts like Dr. Jane Garland, a psychiatrist and clinical head of the mood disorders clinic at B.C.‘s Children’s Hospital, and Dr. Marshall Korenblum, chief psychiatrist at Toronto’s Hincks-Dellcrest Centre for Children and training director in psychiatry at Toronto’s Sick Children’s Hospital.

“We were caught with our pants down,” says Garland.

But after spending the summer digging out everything she could find on SSRIs, Garland says she and her colleagues shouldn’t have been.

“The evidence was before us. We just weren’t paying attention.”

In the fall, Garland circulated a couple of papers to her colleagues here and internationally, summarizing the information that is available.

Here is a sampling of some of the information she has provided to B.C. doctors.

- Prior to 1997, more than a dozen controlled studies demonstrated that SSRIs were no more efficacious than placebos in treating childhood depression.

- In a published paroxetine study, one in 10 (10.5 per cent) of the patients taking Paxil had a “serious” adverse effect compared to just one in 100 of the placebo patients and nearly eight of 100 (7.5 per cent) taking paroxetine required hospitalization.

- Seven of 10 young patients treated with Zoloft (or sertraline) for a major depressive episode would improve, but only one of those improvements could be directly attributed to the medication.

Despite the evidence, Garland said Wednesday, “I don’t think that it was necessarily the right solution to go to a full ban [in Britain]. Their point is that people are not looking at the data objectively, but it leaves people with very few treatment options. … It seems that they [the British committee members] were reacting to the profession not dealing with this issue rationally.”

The reassurance Garland offers physicians is this: Even though there has been a consistently observed doubling of the rate of suicidal thinking in patients treated with several different SSRIs, the incidence is only between two and five per cent and “no completed suicides have been reported.”

Like Garland, Korenblum was caught off guard by the advisories. But he’s not at all sure that regulators did the right thing by putting out the advisories.

In his experience, Korenblum says Paxil is “very, very effective and very, very safe.” He started using it on adolescents more than five years ago and has continued to use it despite the warnings.

Not a single patient of his has become more suicidal on Paxil. But Korenblum admits he is very conservative in prescribing and has never given antidepressants to patients younger than 13 and has only prescribed drugs as part of a treatment program that includes extensive counselling and monitoring.

“I was skeptical and remain skeptical about the warnings,” Korenblum says. “I’m skeptical that the link [to increased suicides] is as strong as the British studies suggested.”

He raises some interesting questions that, so far, have not been answered by any of the regulators.

Why did this research on paroxetine only come to light now, nearly a decade after the first SSRIs came on the market?

Why do the advisories cover only paroxetine in Britain and paroxetine and venlafaxine in North America and not the whole group, since all of them work the same way?

And, why do the advisories only mention children and not adults when there have been similar concerns raised as recently as this spring in the American Journal of Psychiatry about increased suicidal events among adults taking SSRIs in trials compared to those on placebos?

Garland is less skeptical about the warnings.

Although concerned that some of the most severely depressed children may now not be getting what they need to help them, Garland says over the years more and more children are being given SSRIs for milder and milder conditions even though a risk-benefit analysis is on the side of not giving the pills.

She cites published results that found seven out of 10 kids getting an SSRI during clinical trials got better. But what does that mean when six of 10 kids taking placebos also got better during the trials?

It’s something that also troubles Korenblum, who talks about the “medicalizing of the human condition.”

Korenblum asks, but doesn’t answer, the key questions in the broader debate about mood-altering drugs that began before Prozac, the first SSRI, came on the market: Are we pathologizing the normal human condition by turning every sadness, every normal anxiety, every existential doubt into an illness that needs to be treated?

Far from being reassured by what happened this summer with SSRIs and the advisories, what it has done is raise dozens of serious and troubling questions, not just about the drugs but about how they are regulated. It made it clear that regulators are not as powerful, well-informed or as independent as most of us believe or would like.

In a perfect world, there would be obvious heroes and villains in a story of how kids as little as three came to be taking drugs that not only may not work, but might actually hurt them. But at the confluence of drugs, big money and politics, it is far from a perfect world.

To unravel this, let’s start with some stark truths.

- There is not a single study that shows that an abnormality in a person’s ability to metabolize seratonin causes depression, according to Dr. David Healy, who has written three books and more than 1,200 articles about SSRIs. In fact, he says there’s not a single psychiatrist, pharmacologist, pharmacist or pharmaceutical executive who can explain exactly how a selective seratonin reuptake inhibitor work or even how seratonin works.

- Most drugs given to children have never, ever been approved for pediatric or adolescent use, whether they are drugs for liver disease, cancer or depression, because drug companies ask for adult approval, not pediatric approval.

Yet doctors routinely prescribe them as a so-called “off-label use” on the assumption that the drugs are safe for adults, they’ll be safe for kids too.

Off-label prescribing is such an accepted practice that even though SSRIs have never been approved for pediatric use — Prozac being the exception — they are recommended as first-line treatment by the American Academy of Children and Adolescent Psychiatry.

Dosages are determined by extrapolating from the recommended adult dose based on considerations such as weight and height.

One of the reasons drugs aren’t tested on kids is simple economics. Drug companies almost always apply to have a drug licensed for adult use and because of that there is no need for them to prove to the regulators that the drugs are safe for children or teens. But once approved, doctors aren’t limited to adult-only uses. So why would pharmaceutical companies go to the substantial expense of repeating drug trials on kids when doctors will be able to prescribe them off-label anyway?

This is changing, albeit slowly. Two years ago, the United States passed legislation extending patent protection to individual drugs for five years, if pharmaceutical companies agreed to do pediatric trials on the drug.

But getting that legislation passed was difficult. Ethicists and parents raised a troubling question: Should kids be guinea pigs? It was answered with another even more troubling question: Is it ethical to put kids on drugs that have never been tested on kids?

- There have never been any studies of the long-term effects of SSRIs on adults or children.

Again it comes back to economics. Long-term studies cost tens of millions of dollars. Pharmaceutical companies have no reasons to do them once their drugs have regulatory approval and, so far, except in rare cases, countries and research institutions have had little interest or money for doing them.

It’s why nefazadone (Serozone) was sold for nearly a decade before it was pulled off Canadian shelves in November. It took that long to establish the link between its use and severe liver damage. But even with that link, Canada waited nearly a year longer than European countries to ban its sale.

- No major studies involving adults or children have been done comparing the long-term effectiveness of SSRIs versus extensive therapy that includes exercise as well as talk and teaching patients skills to cope with anxiety- and depression-inducing situations.

Yet every year, the number of prescriptions for selective seratonin reuptake inhibitors rises. SSRIs are now among the most commonly prescribed drugs in the world — $12-billion worth were prescribed last year.

In Canada, it can partially be explained by how doctors are paid. Here, a doctor gets a set rate for treating a patient suffering from anxiety or depression. The fee is the same whether the doctor does a 15-minute examination and prescribes a drug or spends an hour doing counselling and teaching coping strategies. Most docs are choosing the quicker route not only for themselves but because Garland says that’s what many patients are asking for.

- Finally, what most people — including many doctors — don’t know is that when regulators approve drugs, they do so on the basis of testing and research done by the company.

Garland noted in a commentary sent to colleagues in September that the majority of completed studies of antidepressants in children and adolescents have never been published. That’s created a dilemma for psychiatrists trying to come up with practice guidelines for the use of these drugs, but the problem is worse for the average general practitioners who are most likely to be faced with the decision of prescribing or not.

And if deciding whether to prescribe or not is hard for professionals, deciding at a time of crisis whether to allow a child to take one of these drugs is excruciating for parents.

In part two, a look at what lessons might be learned from the SSRI debate.