Rarely have we been exposed to a more bewildering array of data and opinions as over the past year on the subject of antidepressants in children. Ever more definitive meta-analyses and databases are published on a weekly basis. Researcher-clinicians of impeccable credentials look at the same data and deliver opposite opinions.
If the experts can’t agree, what’s a poor psychiatrist to do? Let’s look at the data.
Controlled trials of antidepressants in children and adolescents. It all started in 1997, when Congress passed a well-intentioned though poorly-formulated act called the FDA Modernization Act (FDAMA). The goal was to encourage drug makers to test more meds in children. Accordingly, the FDA authorized a 6-month patent extension to drug makers who conducted pediatric clinical trials of existing drugs. This was a strong financial incentive, because companies can rack up a lot more profit in 6 months than it costs to run a couple of clinical trials.
So, most antidepressant makers started testing SSRIs and SNRIs in kids. But the results were not glowing. Of 15 placebo-controlled trials of ADs for depression in children, only three found a statistically significant benefit (see http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-04-Tab02-LaughrenJan5.pdf for a surprisingly interesting and engaging FDA memo reviewing these studies). Two of the three positive studies were Prozac (fluoxetine) studies, leading to its FDA approval for pediatric depression in January 2003. Of note, these studies did not include the recent Treatment for Adolescence with Depression Study (TADS), which again showed a benefit (though modest) of Prozac over placebo (JAMA 2004; 292:807-820).
Before moving on the issue of suicidality, is it fair to conclude that antidepressants don’t work for children, based on these results? No. Reason #1: In other studies, SSRIs clearly beat placebo for the treatment of a range of anxiety disorders in kids, including OCD (Am J Psychiatry 2003; 160:1919- 28). Reason #2: Like Manhattan night clubs, controlled clinical trials let in only very select people. According to the most thorough study of this problem to date, only 12% of the typical patients walking into your office would make it through all the inclusion and exclusion criteria of most trials (Am J Psychiatry 2002; 159:469-473.) So the lukewarm antidepressant data may not apply to the patients that we actually treat. Reason # 3: Recall that these trials were conducted in response to the financial “carrot” of a 6-month patent extension. To gain this prize, drug makers weren’t required to conduct good or careful studies–they were merely required to submit two studies that met the basic criteria of study design. So there was very little incentive to go to the extra labor and expense required to show a difference between drug and placebo.
The suicidality controversy. In February of 2004, Andrew Mosholder, M.D., M.P.H., an epidemiologist with the FDA, submitted his review of all pediatric clinical trials of ADs submitted to the FDA to date. He had access to all published and unpublished data, and he basically counted up the number of “serious” suicide-related events (meaning actual episodes of self harm plus serious suicidal ideation) reported in all these trials in patients on active drug versus patients on placebo. Here are his numbers:
Active drug: 54 serious suicide-related events/2298 patients = 2.3%
Placebo: 24 serious suicide-related events/1952 patients = 1.2%
So, the excess degree of suicidality attributable to drugs (that is, beyond the suicidality related to placebo treatment alone) is 54-24 = 30, divided by the total number of patients (4250), which yields 0.7%, or 1 out of 140 patients. This means that, on the average, you would have to treat 140 patients with an AD to create drug-induced suicidality in one.
There was not a single completed suicide in any of these patients, but nonetheless, these results did not look very good–roughly twice the chance of suicidality on drug versus placebo. Faced with these results, Mosholder recommended that the FDA discourage the use of newer ADs in pediatric depression, with the exception of Prozac, the only drug with enough positive data to make the benefits outweigh the risk. In fact, the Brits had already issued a public announcement to that effect 3 months before this report. The MHRA (the British equivalent of the FDA) announced on December 10, 2003, that Effexor (venlafaxine) and all SSRIs except Prozac were contraindicated in pediatric depression.
Nonetheless, Mosholder’s bosses disagreed with his conclusions and actually forbade him from sharing his ideas at an FDA hearing in February 2004. Not only was he barred from presenting his report, but, incredibly, he was told that if anyone asked him a question he could only respond by using a prepared, officially sanctioned script! (See BMJ 2004; 329: 307.) ideas at an FDA hearing in February 2004. Not only was he barred from presenting his report, but, incredibly, he was told that if anyone asked him a question he could only respond by using a prepared, officially sanctioned script! (See BMJ 2004; 329: 307.)
The reason for this apparent “cover-up” was that the FDA was skeptical that events coded as “suicide-related” were accurately coded. Not being able to resolve the issue themselves, they hired a group from Columbia University to pore over all the adverse events and to reclassify them. They did so, and ended up digging up even more cases of suicidal behavior (95 vs. the original 78), concluding, like Mosholder, that antidepressants were nearly twice as likely to lead to suicidality as placebo.
At this point, the FDA could not delay action anymore, and in September a subcommittee recommended a “black box warning” against AD use in kids, which will be appearing soon in a drug insert near you.
So. What’s the TCR take on all this drama?
1. The newer antidepressants probably lead to an uncomfortable sense of agitation in children, which, in a very small percentage of patients, can lead to either suicidal ideation or non-lethal attempts at self-harm.
2. These ADs are effective for kids with anxiety disorders, but only Prozac has consistent data showing benefit for kids with depression and is the only FDA-approved medication for this indication. Whether this Prozac “superiority” is real or not is a matter of ongoing debate and controversy.
3. When starting ADs in kids, make sure parents take complaints of nervousness or agitation seriously and call you for instructions. You’d be wise to stop the medication at that point.
TCR VERDICT: ADs in kids: Tiny risk, but questionable gain