The Antidepressant Warning Affair: What Really Happened?

This tale unfolds in three chapters:

Chapter One. Critics of the pharmaceutical industry amass evidence that trials showing an excess risk of suicidal behavior among children and adolescents taking many serotonin-type (SSRI) antidepressants had been suppressed for many years. Responding, regulatory agencies in the US and Europe issue label warnings on SSRI drugs (except for fluoxetine or Prozac) for pediatric use.

Chapter Two. The prescriptions of SSRI's for children decline. Studies are then published by child psychiatrists claiming to show that the immediate result has been a worrying upsurge in suicides among young people. The authors claim that what has happened is typical of regulatory excess, and that while a few cases of suicidal behavior may have been caused by these drugs, their widespread use in kids clearly prevented a far greater number of suicides from occurring--prevention that has now ceased as physicians are scared off by label warnings from using these drugs even where they could save lives. The industry critics then note, first, that many of these rise-in-suicide studies are poorly designed (for instance, assuming a decline in prescriptions but actually having no data to prove that); and second, that many of the authors of these Chapter Two studies have financial ties to the industry.

Lineberry TW, Bostwick JM, Beebe TJ, Decker PA. Impact of the FDA black box warning on physician antidepressant prescribing and practice patterns: opening Pandora's suicide box. Mayo Clin Proc 82:518-20, 2007.

Gibbons RD, Brown CH, Hur K, Marcus SM, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 164:1356-63, 2007.

Chapter Three. More extensive and better designed studies appear from non-industry-funded sources. Olfson and Shaffer, for instance, note that the data Gibbons et al. relied on was a brief uptick in suicide rates at a single point in time, and that the best available data subsequently showed that this uptick had been a random event and not a sustained trend. In a more detailed study, Wheeler et al. looked at the UK situation, where the dropoff in SSRI pediatric prescriptions following the 2003 warning was much deeper than in the US, presumably creating a situation in which even more suicides would subsequently have occurred. On tracking long-term trends in both suicides and self-harm behavior, they found no effect of the abrupt change in prescribing of SSRIs on either.

Olfson M, Shaffer D. SSRI prescriptions and the rate of suicide. Am J Psychiatry 164:1907-8, 2007.

Wheeler BW, Gunnell D, Metcalfe C, Stephens P, Martin RM. The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological study. BMJ 336:542-5, 2008.

Comment: Anyone who had been following the literature on SSRIs generally knows that one of the major debates about pharmacologic treatment of depression in recent years is whether SSRI antidepressants as a group--quite apart from their risks--are demonstrably better than placebo in their average effectiveness. Given the difficulty in large-scale meta-analyses of demonstrating the effectiveness of this class of drugs, the claim that their widepread use was preventing many suicides, and the dropoff in their use led to a singificant increase in the suicide rate, was implausible on its face. As a family physician who prescribed many of these drugs (probably, in hindsight, far too many) for many years, I can testify to individual cases where the drugs appeared to be extremely effective. But here we are talking about population effects, not individual effects. The results of the more recent studies, showing no significant change in suicide rates, certainly appear overall to be more plausible, all things considered. And that, in turn, seems to suggest that the warnings regarding the increased risk of suicidal behavior among children and adolescents taking these drugs were prudent and evidence-based, and not the hysterical over-reaction that some industry-friendly physicians have alleged.