(Cold water thrown on Prozac Nation)

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Over the past few weeks and months, there has been shock after shock as ordinary people scramble to make sense of how the world's most popular anti-depressants are suddenly being described by regulators as ineffective and perhaps even dangerous.

Twenty years after the first selective serotonin reuptake inhibitor or SSRI was approved for adult use, we're being told that there has long been evidence indicating that these anti-depressants may be no more effective than sugar pills.

We've learned that, especially among young people, the risks of taking the drugs may outweigh the benefits. The British regulatory authority is now concerned enough about the adult risks that it launched a study this week to determine whether the drugs are safe.

What we may be seeing is the beginning of the end for the Prozac Nation -- even if Prozac isn't the specific target.

When Prozac and its SSRI cousins came to market 20 years ago, depression was rarely diagnosed. Now, everybody seems to be depressed and the treatment of choice is drugs not psychotherapy.

Nearly 31 million prescriptions for anti-depressants were written in Canada in 2002. And SSRIs are usually the drug of choice. Billions of dollars worth are sold worldwide -- nearly 14 million SSRI prescriptions were written in Canada alone last year at a cost of $869 million.

The bad news started in Britain. Last spring, regulators warned of the increased suicide risks for children taking paroxetine -- sold as Seroxat in Britain and Paxil in North America. Canadian and American regulators followed with warnings about Paxil and its cousin, Effexor or venlafaxine.

Last month, Britain went further. After analyzing previously unpublished clinical trial data, it banned doctors from writing any new prescriptions of any SSRIs -- except Prozac -- for anyone 18 or younger.

There was no immediate response from either Health Canada or the U.S. Food and Drug Administration. Both are still studying new information drug companies provided them last fall.

Neither has responded to Britain's new study into the risks SSRIs pose to adults. Over the coming months, British researchers will look at a group of patients of all ages -- the oldest is 90 -- who were diagnosed with depression between 1995 and 2001. The aim is to estimate the risk of suicide, suicidal thoughts, non-fatal overdoses and self-laceration in patients treated with both SSRIs and tricyclic antidepressants.

Tricyclic anti-depressants are a large class of older medications including amitriptyline (Elavil), imipramine (Tofranil), clomipramine (Anafranil), nortriptyline (Norventyl) and desipramine (Norpramine) that are now available in generic versions. Because their patents have expired, they are much, much cheaper than SSRIs.

Dr. Jane Garland, head of the mood disorders clinic at B.C. Children's Hospital, says the tricyclics are the "gold standard" anti-depressants, and may be more effective than SSRIs for severe depression.

Despite that, she says, SSRIs have replaced them as first-line medication, with tricyclics being used in more treatment-resistant cases. Garland goes on to say that because the older drugs have much more serious and unpleasant side effects than SSRIs, "they were used more conservatively than the SSRIs."

While British regulators were making their announcement last week, the Wall Street Journal reported on Canadian research that offers an explanation for why nearly 80 per cent of people treated for depression with drugs relapse, compared with just 25 per cent of those who completed a full course of psychotherapy.

Led by neuroscientist Helen Mayberg of the Rotman Research Institute and the University of Toronto, the researchers determined that psychotherapy -- the so-called talk therapy popularized by comedian Woody Allen -- and anti-depressants work in completely different ways and on different parts of the brain.

The drugs reduce activity in the brain's emotion centres or limbic system, while cognitive-behavior therapy quiets overactivity in the cortex.

The Toronto study -- partially funded by the federally supported Canadian Institute for Health Research -- should lead doctors, health administrators and politicians to question why so much more money is being spent on drug therapies for depression than on the more effective psychotherapy.

It should also lead them to ask why more primary-care doctors -- who write the majority of prescriptions for antidepressants -- aren't trained in psychotherapy.

Although with health being split over so many jurisdictions, there's not a great deal of room for optimism that anything will change quickly.

But back to SSRIs and Health Canada. When Health Canada completes its review of the pediatric trial data that it received last fall, the government plans to appoint an expert advisory panel that will begin closed door meetings sometime in February.

There the experts will take a look at the Health Canada review, look at the conclusions of the British regulators regarding pediatric SSRI prescriptions and any information from the new British investigation.

The experts will also analyze what is said at the U.S. Food and Drug administration's Feb. 2 meeting. There in an open forum, experts, drug company officials and others will talk about both pediatric and adult use of SSRIs.

But even after the Canadian panel completes its review, it can only make recommendations to Health Canada. It could, for example, follow the British regulators and ask for labelling that says some or all of the SSRIs are not to be prescribed for patients 18 and younger.

Before any labelling changes are made, Health Canada must meet with the drug companies to reach a consensus on what that labelling should say.

While for most people, the regulators' recent interest in the multi-billion-dollar, anti-depressant business seems sudden, many experts can't believe it's taken so long.

One of those experts -- Dr. Irving Kirsch of the University of Connecticut -- asked nearly two years ago why the American regulators had approved the drugs in the first place.

Irving and four colleagues re-analyzed the SSRI's efficacy data presented by the companies to the FDA between 1987 and 1999 for approval of the six most widely prescribed antidepressants -- Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline), Effexor (venlafaxine), Serzone (nefazodone) and Celexa (citalopram).

They found that nearly 80 per cent of the response to the anti-depressants was duplicated in the patients receiving sugar pills, not drugs (i.e., the SSRIs were no more effective than placebos).

They also found that the rate of improvement in patients receiving the highest doses was not any different than the improvement rates among those receiving lower doses. And they found errors in the way the data were reported and analyzed. Kirsch et al concluded: "To the extent that these data are flawed, the medications should not have been approved."

If it didn't set off regulatory alarm bells for the regulators, it should have for prescribing doctors -- all of whom had easy access to the analysis that was published in the American Psychological Association's July 2002 edition of Prevention & Treatment.

Apparently, doctors weren't alarmed either.

The number of Canadian prescriptions for SSRIs increased in 2002 (up nearly 14 per cent) and is keeping about the same pace for the first 10 months of 2003.

While it is heartening that governments are finally recognizing the need to revisit their approvals of SSRIs, Canadians need to join the chorus of experts asking why a full review has taken so long and why now that Canada is doing that review, it's being held in secret.

dbramham@png.canwest.com