Black-Box Warnings

Last week we wrote about penicillin and the possibility that if it had first appeared in our time, media-fueled hysteria about its rare serious side effects might have prevented its approval by regulatory authorities. Now we are in the early stages of preparing an article on Drugs for Epilepsy for an early 2013 issue of Treatment Guidelines from The Medical Letter, and I am reminded how many central-nervous-system drugs carry black-box warnings in their labeling about the risk of suicidality associated with their use.

The story behind these warnings begins, if I am not mistaken, in the summer of 2003 when GlaxoSmithKline submitted the results of 3 clinical trials to the FDA in an effort to gain approval for use of the SSRI antidepressant Paxil to treat children with obsessive-compulsive disorder. The boilerplate list of side effects that must be documented in such trials includes “emotional lability,” which is defined as crying, mood fluctuations, thoughts of suicide and attempted suicide. In these studies, among a total of 1,134 children aged 7-18 years, emotional lability was observed in 3.2% of those who took the drug and 1.5% of those who received a placebo. There were no suicides.

The FDA took no notice of those rather unremarkable numbers, but as a matter of routine, forwarded the trial results to the UK’s Committee on Safety of Medicines. The Chairman of the Committee issued a press release and sent a letter to British physicians, saying that new data had shown “an increase in the risk of harmful outcomes including episodes of self-harm and potentially suicidal behavior [with paroxetine]” and that the risk was 1.5 and 3.2 times greater (sic) with the drug than with placebo. Those erroneous multipliers were repeated endlessly in the press reports that followed.

Subsequently the UK Committee said it had analyzed numerous published and unpublished studies, and found that SSRIs had not, except for fluoxetine (Prozac), been shown to be effective in children and that the risk of suicide (not emotional lability anymore) made their use unwise. In all of these studies, there were no completed suicides.

Could SSRIs cause suicide? Possibly. They have side effects like agitation and insomnia, and can cause aggressive behavior, especially when they are first started. But worldwide use of these drugs in children and adolescents has been associated with declines in suicide rates, not increases. The solution to the problem of suicidality in depressed patients is to monitor the patients, not deny them use of a drug that can help them.

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  1. The commentary, though insightful, fails to consider several critical questions about nearly all of the numerous drugs rushed into the marketplace over the past 2+ decades.
    How robust is the potential link between the pathophysiologic understanding of the indication and the mechanism of action of the drug? In the case of adolescent affective dysfunction, sometimes leading to the crisis of suicidality, it would seem reasonable to conclude that not much / enough is known about either the cause or the purported treatment (either whether it is efficacious or adverse).
    How robust is the degree of effectiveness shown for the drug in industry-sponsored clinical trials, i.e., how much better is the average patient for having taken the drug? In many cases, certainly with many CNS drugs, though movement in a scale has been statistically favorable in pre-marketing trials, that “benefit” amounts to a potentially imperceptible difference in the life of many people.
    Think about the above when considering the “epidemic” of depression that has brought on a corresponding degree of anti-depressant use in the global populace. Could all this money be spent on measures that might have greater effect? Pharmaceutical companies have not been shown to improve socioeconomic status, but such improvement has been shown to substantively decrease many of the parameters of “depression”. Maybe society should consider using all the moneys for antidepressant prescriptions to this end instead.
    The last critical question is at the heart of this “Black-Box Warnings” commentary, how robust are the safety data for drugs at the time of their marketing? The track record of the entire spectrum of new drugs, part of which is addressed by Dr. Abramowicz, clearly indicates this part of the dossier is woefully insufficient. Specifically when addressing antidepressant use in pediatrics think about what are the long-term effects of giving such substances to brains that are still developing? It is well understood that even through adolescence there are marked changes in the structure and function of this organ, much as in the rest of the pubescent body.
    I am not a mental health professional, but I have cared for a large number of individuals with mental illness. This experience will not put me in the camp of extremists who oppose pharmacologic treatment of disruptive and painful chronic disorders simply because their etiology is based in the brain’s intangible functions. I am convinced, though, that the DSM has been swollen by creation of artifactual disorders needed in order to find a marketplace for otherwise useless substances. And, I am in favor of any measures that put a drag on the insatiable needs of pharmaceutical companies precipitating to actions the consequences of which we do not sufficiently understand. Pharmaceutical executives measure the intended profit for each new drug in billions of dollars. First, this has great potential for leaving in the dust a highly effective drug that promises little return. Second, should we be spending such huge sums for so little potential benefit and an unknown risk when improving access to essentials such as a better diet or housing can have immense, positive impact on an individual, particularly a child?

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