Much ado about (almost) nothing: Revisiting Paxil in adolescents

adolescent brain Paxil

BMJ recently published a re-analysis of a 2001 study published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), evaluating the use of paroxetine (Paxil) to treat teens with depression. This re-analysis falls under the RIAT (restoring invisible and abandoned trials) initiative that encourages companies and researchers to update findings from past clinical trials.

This news is essentially “much ado about nothing,” because no one was doing anything based upon the 2001 study. But it is worth noting because it was not the best moment for the JAACAP and the authors of the original article.

The 2001 study, and the “black box” warning

The initial study published in the JAACAP compared imipramine, a tricyclic antidepressant, and Paxil, a selective serotonin re-uptake inhibitor (SSRI).

For a psychiatry journal, the JAACAP has a high impact factor. And as well-respected researchers, the authors relied upon methodology and measures that were pretty much state-of-the-art in 2001, finding a mild advantage to Paxil over imipramine and over a placebo.

Two years later, in 2003, an analysis of pooled data from Canadian and British health records concluded that the rates of suicidality, self-harm and suicidal ideation in adolescents who had depression and were treated with SSRIs were twice that of those not treated with SSRIs. This led to all SSRIs being labeled with a “black box” warning—the highest FDA warning—for usage up to the age of 25 for suicidal ideation and suicidal attempts.

Later, when researchers stratified suicidality by antidepressant, Paxil had the highest rate of suicidal behaviors, presumably because it has a short half-life—meaning your body clears it fast.

Those of us in the field felt that yes, there was a statistical difference between the two groups that had led to the black box warning, but that:

  • the data was less than rigorous
  • the rates of suicidality, self-harm and suicidal ideation were much lower than has generally been found when researchers look at a non-clinical teen population.

This is the opposite of what one would logically expect. Nonetheless, since 2003, all SSRIs, including Paxil, have carried a black box.

From a consumer point of view, nothing has changed. Paxil was never FDA-approved for depression in teens and still isn’t. Next to nobody prescribes Paxil today.

The 2015 reanalysis

Even though Paxil has never been FDA-approved for depression in adolescents, there has always been controversy about whether or not the drug is worthwhile. Thus the BMJ—another very prestigious medical journal—went back and reviewed the 2001 study.

Because the field has advanced over the years, the authors of the reanalysis were able to do some new manipulations of the old data. They concluded that, “neither paroxetine nor high-dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.”

No one’s arguing with the BMJ authors that there was some faulty analysis in the 2001 study, but when it comes to clinical practice, this is not new news. Neither drug is a go-to medication for adolescents.

The authors of the original JAACAP article argue that the analysis it published was the state of the art at the time, and that no one currently uses the agents in question. I myself haven’t written a new prescription for Paxil in 15 or 20 years!

Takeaways for prescribers and consumers

In the 33 years I’ve been a psychiatrist, the agents we have prescribed for depression in teens have changed. In the 1980s, we used tricyclics such as imipramine. In the 1990s, we used SSRIs such as Prozac, Zoloft and Paxil. Today, Prozac and Lexapro are our first-line agents for a few reasons:

  • Prozac, often the medication of choice, has been around the longest.
  • Prozac has a very long half-life, which means if the patient goes away for a weekend and doesn’t take the medication, he or she doesn’t experience withdrawal.
  • Weight gain is not a common side effect of Prozac.
  • Lexapro and Prozac are the only SSRIs approved for usage in adolescent depression.

From a consumer point of view, nothing has changed. Paxil was never FDA-approved for depression in teens and still isn’t. Next to nobody prescribes Paxil today. Tricyclics are not FDA-approved either, and because tricyclics in overdose are extremely toxic, nobody prescribes imipramine either. So in this case, state-of-the- art analysis, which of course is critical, has led to news that doesn’t change practice.

Stuart Goldman paxilStuart Goldman, MD, is a senior associate in the Department of Psychiatry at Boston Children’s Hospital, and an assistant professor at Harvard Medical School. He specializes in depressive disorders.