The Corpus Callosum

This is kind of an old story, I know.  Still, every once in a while it is good to revisit these things.  When the topic first came up in 2004, it was the subject of much newspaper space and blog commentary.  But now, it has pretty much faded from the national consciousness.  Has anything more come of it?

In a recent editorial in the American Journal of Psychiatry, Gregory E. Simon, M.D., M.P.H., reviews the largest and most informative studies on the subject:

How Can We Know Whether Antidepressants Increase Suicide Risk?
Am J Psychiatry 163:1861-1863, November 2006
doi: 10.1176/appi.ajp.163.11.1861
© 2006 American Psychiatric Association

In this issue of the Journal, Gibbons and colleagues use pharmacy records and mortality data to examine the association between rates of antidepressant use and rates of suicide death in children and younger adolescents. They find that U.S. counties with higher rates of SSRI antidepressant use had lower rates of suicide death, and that this relationship persisted after accounting for potential confounding factors. This finding is consistent with two other observational studies (1, 2) finding that increasing rates of antidepressant use among adolescents were accompanied by stable or declining suicide rates.

These findings seem to conflict with a meta-analysis of data from randomized placebo-controlled trials (3) and with a recent case/control study (4). Using data from all placebo-controlled antidepressant trials in children and adolescents, Hammad and colleagues at the U.S. Food and Drug Administration (FDA) found that risk of suicidal ideation and suicidal behavior was nearly twice as high during treatment with several newer antidepressants compared with placebo (3). It is important to note that the number of actual suicide attempts in those placebo-controlled trials was too small to compare and that the number of suicide deaths was zero...

There is more, of course, so you really have to read the whole thing (it is short).  Some studies suggest one conclusion, while other sugget the opposite, and none is completely conclusive.  He points out later in the article:

It is unlikely that additional randomized trials will provide a final answer to this question, either for adolescents or adults. A randomized trial to definitively determine whether a specific antidepressant increases or decreases risk of suicide death would need to include several hundred thousand patients. Such a study will never occur. Observational studies using computerized pharmacy data can include such large populations, but those studies are always subject to confounding or other biases.

The fact is, there are limits to what studies can tell us.  It simply is not possible to perform the study that would be required to get a definitive answer.  

So if I cannot give a definitive answer, what is the point of this post?  The point is twofold.  First, I think it is a good idea to follow up on stories such as this, because you cannot rely on the media to do the follow-up.  Second, I think this illustrates how important it is to do a full review of the pertinent literature before trying to formulate a conclusion that will impact your behavior in any significant way.  

As philosophers of science like to point out, the key factor that differentiates science from pseudoscience is not whether a given study is correct or not.  Rather, the cornerstones of science are the way that topics are selected (falsifiable hypotheses), information is processed (publication and peer review), and the way that conclusions are handled (all conclusions are tentative).  

If you are walking around with a preconceived notion about something, and want to find support for it, there is a fair chance that you will find a citation somewhere to support it, possibly even in a peer-reviewed article.  But merely citing that one article does not really support your position.  In order to be valid, it has to be interpreted in the context of all that is known about the subject.  

As an illustrative aside, you may want to look at recent exchange in the online journal, PLOS Medicine, on the topic of antidepressants and suicide.  The original article was Modeling of the Temporal Patterns of Fluoxetine Prescriptions and Suicide Rates in the United States.  It was accompanied by an editorial (Suicide Rates and Antidepressant Prescribing: A Casual or Causal Relationship?), then followed by a somewhat sarcastic rehash of the same data (Fluoxetine and Suicide Rates: Suicide and the Economy), which was then followed by an "author's reply."  The gist of the exchange is this: the authors of the original paper showed that there was an inverse relationship between suicide and the rate of prescribing of fluoxetine.  The editorial examined the omnipresent question of the relationship between correlation and causation, something that the authors of the original paper acknowledged fully.  In their words, "While these types of data cannot lead to conclusions on causality..."  The paper on suicide and the economy showed that the inverse correlation between the (improving) economy and the (declining) rate of suicide was strong that the correlation between fluoxetine prescriptions and the decline in suicide rate.

The whole exchange is kind of amusing, but it is a good illustration of how misleading any one article can be.  The point of the original paper in the exchange was not to prove anything, but to show an instance of the absence of falsification.  That is a perfectly valid thing to do.  It is only a small contribution, but it is meaningful.  The more different perspectives one takes on a hypothesis, the more convincing it is when no falsification is found.  

Of course, in the practice of medicine, we cannot just sit around and pontificate on these things.  Sooner or later, we have to actually use the information, and incorporate it into the clinical decision-making process.  How did Dr. Simon formulate the antidepressant and suicide risk data?  This is what he tells patients:

The Food and Drug Administration requires a warning that antidepressant medications can sometimes cause or increase thoughts of suicide. Studies in children and adolescents have shown that antidepressants can increase suicidal thoughts. However, other studies have shown that the overall risk of attempting suicide goes down after starting antidepressant medication. Even if antidepressants help most people who take them, some people may have very negative reactions. Thus, it is important that we have regular contact over the next few weeks. If you have thoughts about suicide or about harming yourself, please contact me right away.

Well said.