Wednesday, October 29, 2014

The Antidepressant Black Box Warning - A Better Solution

There were two opinion pieces in the New England Journal of Medicine this week on the antidepressant black box warning.  Richard A. Friedman, MD contends that the warning had an adverse effect on antidepressant prescriptions, a decreased rates of new depression diagnoses, increase in psychotropic drug poisoning (as a proxy measure for suicide attempts)  and that is reflected in an increase in the rate of completed suicides in people from 10-34 years of age between 1999 and 2010.  He argues for removing the warning entirely.  Marc B. Stone, MD points out that there is contradictory data showing that an increase in suicide rates and no good correlation with an increase in rate and the year of the boxed warning.   He discusses other factors that can result in fluctuating levels of depression diagnosis and treatment, including a change in antidepressant marketing because many antidepressant were becoming generic at the time and how that may have affected the prescription rates.  He cites CDC data on the rate of intentional versus non-intentional overdose as a more appropriate metric and points out that rate was lower both before and after the warning.  He concludes that despite many efforts there is no real correlation between the warning and suicide rates.  Disclosure forms will be available when the article becomes available online but for now Dr. Friedman appears to be affiliated with the Department of Psychiatry, Weill Medical College of Cornell University and Dr. Stone is affiliated with the FDA.

One of the central problems with the debate is the problem of looking at statistical significance in low rates on a longitudinal basis.  In all of the studies I have seen and in these debates, the longitudinal data is almost always interpreted as correlational (we seem to never be able to determine causality) and there appear to be endless number of correlations - and none of them are mathematical.  In these articles alone the authors looked at drug company marketing and sales strategies, the impact of the original warning, the impact of the revised warning,  the impact of the discussion in the media as opposed to the warning, the diagnostic patterns of physician, the impact of managed care and pharmacy benefit managers, and the prescribing patterns of physician (broad versus narrow) as possible correlates.  All of this is analyzed at a qualitative level and apparently not by anyone who is an expert in the analysis of longitudinal data.  The debate becomes a series of true or false statements based on snapshots.  That to me is essentially a political analysis of the data and it seems to lead nowhere.  It can be a question of "my data being better than your data" but it is not the kind a probabilistic analysis that physicians are trained to do.  The central question here is whether the original FDA meta-analysis of clinical trials showing a 4% to 2% ratio of "suicidality" in the treated versus placebo group is valid and what should be done about it, keeping in mind that suicidality did not confer any increased risk of completed suicide.  In this case Dr. Friedman agreed that something should be done based on that meta-analysis so both authors would agree that finding is significant.

They differ on what existing data mean and what should be done.  As a clinical psychiatrist  who deals with side effects at least as much as symptoms of depression and anxiety, I think a lot could be done to improve the awareness of side effects and improve treatment.  The solution is a lot less drastic but more comprehensive than a Black Box Warning.   After all, it is highly likely that most people are going to encounter more common and potentially problematic side effects than intrusive suicidal thoughts  or suicide attempts.   That is probably as true for medications without a black box warning as medications with a black box warning.  Even considering another class of medications with a warning about suicidal ideation - anticonvulsants, says nothing about whether a patient is more likely to experience those thoughts with the anticonvulsant or the antidepressant.  Depression is a common problem in people with epilepsy, what about people needing to take both an anticonvulsant and an antidepressant?

My recommended approach to the problem would resolve a couple of issues.  It would emphasize to the public that a choice to take a medication is not without risk and is not a guarantee of a cure.  That one cannot assume that an FDA approved medication is totally benign and will be completely effective for their problems.  The FDA is unique in terms of the efficacy, side effects, and pharmacosurveillance data that they collect.  They are also not transparent with it.  In that context they expect physicians to make sense out of what is presented to patients in the risk-benefit discussion of whether or not to take a medication.  That leaves the benefit discussion full of unnecessary guesswork about what does and what does not need to be discussed.  In that context a black box warning is just another rare cloud on the horizon.  Using the Back Box warning as a standard, a doubling of suicidality from 2% to 4% with no completed suicides with antidepressants is on par with a 1-6/10,000 chance of Stevens-Johnson's syndrome from carbamazepine.

The solution here is an FDA attachment to the package insert of what needs to be discussed with the patient to give them a better idea of the risks and benefits of a particular medication.  It makes no sense at all to feel forced into a discussion of suicidality from taking a medication when far more patients will experience fatigue, headaches, diarrhea, and discontinuation symptoms.  I have attached a sample of a general outline of what needs to be covered.  I think that Medline plus medication handouts could also be considered.  The FDA can specify what these points are for every medication.  If the psychiatric profession has not set a standard, it is time for the regulators to do more than issue confusing black box warnings and back it up with all of the data in an accessible format on their very confusing web site.  You can bet that the managed care industry does not want their psychiatrists spending an extra few minutes with a patient to have this discussion.  The regulator in this case has a unique opportunity to set a uniform standard for side effect discussions based on the priorities they establish from both clinical trials and pharmacosurveillance.   The solution to the debate of the toxic or non-toxic black box warning is as simple as that.

Most importantly the physicians having the discussion with the patient can document "The FDA recommended risk/benefit discussion for this medication was completed with the patient."

George Dawson, MD, DFAPA    

Friedman RA.  Antidepressants' black box warning 10 years later.  N. Engl J Med 2014;317;18: 1666-1668.

Stone MA.  The FDA warning on antidepressants and suicidality - why the controversy?   N. Engl J Med 2014;317;18: 1666-1668.

Peter Diggle, Patrick Heagerty, Kung-Yee Liang, Scott L. Zeger.  Analysis of Longitudinal Data.  Oxford University Press.  Oxford.  Second Edition 2002.


  1. This would be great if it happened. I've only been counseled once and that on a relatively rare, potentially fatal condition of Stevens–Johnson syndrome.

    I think that pharmacy counseling was supposed to cover most of your talking points but I can't say that is anything like what I used to see years ago.

    1. I think that is a common problem and your experience points out that there is some focus on Black Box warnings. I have seen the blanket statement: "Do you have any questions about the medication?" used by both physicians and pharmacists alike. There has to be a commitment beyond that to discuss adverse effects and what to do if they occur. As an example, I also tell everyone that I do not expect them to tolerate or "get used to" medication side effects and tell them about my rationale for that approach. I also advise people who will be on a medication not to take it for granted if they develop what appears to be a physical illness and consider that it may be a problem with the medication that needs to be checked out sooner rather than later. A focus on Black Box warnings is too low of a standard.

  2. The issue of side effects is extremely germane here, and in even more ways than you mention in your excellent post. The question is not whether antidepressants may increase suicidal ideation, but if they do, WHY is that? Answering this question requires a detailed history not available from the use of treatment outcome measures/symptom checklists, but from other clinical details. It also requires close follow up when these meds are prescribed with an awareness of some common clinical issues - again issues that don't show up on a Hamilton rating scale. See for the issues I think are most important in this debate.