Rather than admit that one of their silver bullets, Accutane (isotretinoin), which was a “goose laying the golden egg” for F. Hoffmann-La Roche Pharmaceuticals (and their various “Roche” associates world-wide) to the tune of a billion dollars a year, could make kids kill themselves or cause grotesque birth defects in the kids of over half of women exposed when pregnant, dermatologists have sung themselves a lullaby that their magic pills don’t make kids depressed, they actually make them better, by clearing up those ugly zits that drive them to despair. In what can only be described as a tragic collusion of conflicts of interest (COI) amongst their Key Opinion Leaders (KOLs) and willful denial amongst the lowly rank and file, they have decided to say “What? Me Worry?”

When the heat got turned up on Roche Pharmaceuticals after the son of Congressman Bart Stupak’s (D-Mich) son Bart Jr. died of suicide while on Accutane in 2000, they got busy and called a “Scientific Advisory Board” meeting at the Ritz Carlton in Alexandria, Virginia, to opine on the topic of the relationship between Accutane treatment and depression. This meeting included figures from psychiatry like Kathleen Merikangas, PhD, Stuart Montgomery, PhD, and David Nutt, MD, Chair of Dermatology David Bickers MD, and psychiatrist Douglas Jacobs, MD. Between the lot of them I think they have written about one paper total in the literature on the subject. But they did get paid a nice consulting fee for their efforts, of course.

Accutane and depression

Their conclusion? No relationship, of course.

I wasn’t aware you were an Accutane expert, Kathleen!

I challenge them all to a debate. I’ll fight them with one hand behind my back!

Fact is Accutane’s efficacy for acne was discovered a decade before Roche put a patent on it, in a paper in the New England Journal of Medicine.

I have communicated with two of the authors, both dermatologists, Frank Yoder MDand Gary Peck, MD.

Both of them agreed with my opinion that Accutane can cause depression in some individuals.

What is really sad about this whole sordid tale is how degenerated the so-called dermatology “literature” has become on the topic.

For example, the most commonly cited study to support the statement that acne is associated with depression, a study that has been cited several hundred times by dermatologists writing in the literature, involved only ten patients with acne and no comparison subjects (Gupta et al., 1990). No statistics were performed (obviously since there was no comparison group). Scores on the questionnaires for anxiety and depression were not related to severity of acne.

And the fact is that the rest of the literature isn’t any better. Objective measures of acne do not correlate with severity of anxiety or depression. Acne does not cause major depression. It is simple as that.

Sure, kids worry about their zits and feel better when they go away, but the studies do not support the conclusion that acne causes major depression, and that treatment of acne cures depression.

In spite of this the manufacturer of Accutane, Hoffmann-LaRoche, has consistently downplayed the risks of suicide and depression and has denied a causal association (McCoy, 2004). The dermatology community has joined with the manufacturer in praising the merits of this medication for the treatment of acne which they describe as the “penicillin of dermatology”. It took only 10 months for the FDA to approve Accutane for the treatment of cystic and nodular acne in May of 1982, however controversy has followed it from the time of its initial launch. In January of 1983 one of the authors of the first paper to describe the use of isotretinoin for the treatment of acne in 1977, Dr. Frank Yoder, wrote about the potential dangers of Accutane (Yoder, 1983). In 1990 Dr. David Graham of the FDA highlighted the inability of the Dermatological Medications Advisory Committee to the FDA to be impartial since it was made up entirely of dermatologists (Green & Hutt, 2002). At that time he stated that Accutane should be taken off of the market, mainly because of the risk of birth defects. Indeed its use has always been curtailed or highly restricted in European countries, unlike the US where it is often prescribed for minor blemishes. Strong feelings about the utility of isotretinoin for the treatment of acne in the dermatology community, and forceful marketing by the manufacturer in the US, have caused a delay in awareness of the potential risks in the US. In 1998, the year that the FDA first approached Hoffmann-LaRoche about adding a warning related to suicide with Accutane to its label, the manufacturer ran an ad that stated, “Effective treatment of severe recalcitrant nodular acne minimizes progressive physical scarring, as well as negative psychosocial effects such as depression and poor self image” (Green & Hutt, 2002). This was in spite of the fact that less than half of patients prescribed the medication actually had nodular acne. The FDA required that Hoffman-LaRoche pull the ad.

In 2000 Congressman Bart Stupak’s son, Bart Jr., committed suicide while on Accutane. Congressman Stupak called for congressional hearings on the safety of the drug and in September of that year the FDA called a Dermatologic Advisory Committee meeting on the topic. In November of 2001 an educational grant from Roche funded a supplement of the Journal of the American Academy of Dermatology on isotretinoin which followed the Scientific Advisory Board Meeting in Alexandria VA they held on the topic. The basic science-related articles focused on retinoids and the skin, essentially ignoring the large extant literature on retinoids and the central nervous system. Psychiatric side effects merited literally two sentences, and one article, written by one of Roche’s hired guns, stated that there was no evidence for any association (Jacobs et al., 2001), ignoring the reported challenge-rechallenge cases which have been cited in the pharmacoepidemiology literature as adequate in and of themselves to establish causality (Strom, 2005). This led members of the FDA to write a letter of response, “in the interest of public health,” admonishing the authors of these articles for the short shrift they paid to the issue of Accutane and psychiatric side effects (O’Connell, Wilkin, Pitts, 2002).

The degree to which dermatologists have thrown science and logic out of the window in order to protect their magic bullet is simply remarkable. For instance in a 2004 article entitled “Myths of Isotretinoin Therapy” (Alcalay, 2004) “isotretinoin causes depression and suicide attempts” was listed as a “myth”. The article went on to state that any risk needed to be “weighed against the increasing prevalence of depression among adolescents and young adults and the psychological impact of acne.” [In fact, depression is not increasing amongst teenagers and acne has not been associated with clinical depression, rather only changes in self esteem].

Here are some authentic mythic figures for you, Dr. Alcalay! And they don’t have any pharmaceutical industry COIs!

Mythic figures

Aktan, S., Ozmen, E., Sanli, B. (2000). Anxiety, depression, and nature of acne vulgaris in adolescents. International Journal of Dermatology, 39, 354-357.

Alcalay, J. (2004). Myths of isotretinoin therapy in patients with acne: A personal opinion. Journal of Drugs in Dermatology, 3(2), 179-182.

Green, J., Hutt, P. (2002). Babies, blemishes, and FDA: A history of Accutane regulation in the United States., Leda. Cambridge, MA.

Gupta, M. A., Gupta, A. K., Schork, N. J., Ellis, C. N., Voorhees, J. J. (1990). Psychiatric aspects of the treatment of mild to moderate facial acne: Some preliminary observations. International Journal of Dermatology, 29(10), 719-721.

Jacobs, D. G., Deutsch, N., Brewer, M. (2001). Suicide, depression, and isotretinoin: Is there a causal link? Journal of the American Academy of Dermatology, 45, S168.

Kellett, S. C., Gawkrodger, D. J. (1999). The psychological and emotional impact of acne and the effect of treatment with isotretinoin. British Journal of Dermatology, 273-282.

McCoy, K. (2004, December 7, 2004). Drug Maker rebuffed call to monitor users. USA Today, pp. 1-2.

O’Connell, K. A., Wilkin, J. K., Pitts, M. (2002). Isotretinoin (Accutane) and serious psychiatric adverse events. Journal of the American Academy of Dermatology, 48(2), 306-307.

Shuster, S., Fisher, G. H., Harris, E., Binnel, D. (1978). The effect of skin disease on self-image. British Journal of Dermatology, 99(Suppl 16), 18-19.

Smithard, A., Glazebrook, C., Williams, H. C. (2001). Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. British Journal of Dermatology, 145, 274-279.

Strom, B. L. (Ed.). (2005). Pharmacoepidemiology (4 ed.). New York: Wiley.

Van der Meeren, H. L. M., van der Schaar, W. W., van den Hurk, C. M. A. M. (1985). The psychological impact of severe acne. Cutis, 36(1), 84-86.

Wu, S. F., Kinder, B. N., Trunnell, T. N., Fulton, J. E. (1988). Role of anxiety and anger in acne patients: Relationship with the severity of the disorder. Journal of the American Academy of Dermatology, 18, 325-333.

Yoder, F. W. (1983). Isotretinoin: A word of caution. Journal of the American Medical Association, 249(3), 350-351.

[originally posted on January 5, 2008, on beforeyoutakethatpill.com; Accutane was taken off the market in 2009, the manufacturer citing “business reasons”, but people continue to kill themselves on generic versions of isotretinoin.]

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