From ex-accutane user Stefan Alexander Lay, see all of his youtube videos here.

When Accutane came out on the American market, after being rushed through the FDA approval process, it was listed as a category C drug for risk of birth defects, meaning that it was only of moderate risk. The PDR said that women “should not” get pregnant while on Accutane. Moderate risk means that there are some studies in animals showing birth defects, but it isn’t clear that it is really relevant to humans. There was no requirement that doctors test for pregnancy, or that women take birth control.

Accutane hit the media and was hailed as a wonder drug. Sales soared far being the wildest expectations of Roche executives. Soon every girl with pimples was demanding that pill that her school-mate got that had made her blemishes vanish away.

But not everyone was so sanguine. The Europeans weren’t impressed by Accutane. It was banned in Sweden and Italy and sharply curtailed in other countries, probably related to the results of those trials, which might have included birth defects associated with the use of Accutane.

If there were any birth defects in the European trials, were they reported to the FDA?

Nobody seems to remember. Hmm…

In a series of articles over a decade ago in a newspaper called the Columbus (Ohio) Dispatch, Mark Somerson reported on this story in a series of investigative journalism articles. Remarkably this story about a drug that was equally dangerous as thalidomide never made it beyond the shores of the Wabash River.

Thanks New York Times!

Here’s a scoop for you guys, Mike and Juliet, to add to your ongoing Accutane “investigations”!

It wasn’t only the Europeans that were wary of Accutane, some American dermatologists were as well. In fact, Frank W Yoder, MD, who with Gary L. Peck MD was the first to report on the use of isotretinoin for the treatment of acne in 1977, long before Roche picked it up, warned against the dangers of the drug in the January 1983 edition of the Journal of the American Medical Association, saying that “the potential toxicity of this drug has been seriously underemphasized”. Both American doctors and scientists working for Roche later testified that is was known before it came out on the market that Accutane potentially had a very dangerous risk of birth defects, based on the fact that it was derived from Vitamin A related compounds, well known for many years to cause birth defects in women. Yoder and another doctor involved in the US trials remembered discussing birth defects that occurred during the European trials, although exact names of individuals involved were never produced.

In fact, Roche had known about Accutane for years before the American dermatologists had written about it, but did nothing with the drug. Somerson reported that Dr Werner Bollage, a scientist with the company, wrote in 1971 that it was “inconceivable to develop an agent” that caused birth defects for such a “common complaint as acne.”

For their US clinical trial in the early 1980s, Roche required that all women get tested for pregnancy, and one woman who got pregnant was advised to get an abortion. However, once the drug went on the market, this was no longer required, according to reporting by Somerson.

Henry H. Roenigk MD, another dermatologist who had been involved in the US Accutane trial, was quoted as saying that he published a letter in the May 1982 edition of the journal Dermatology warning of the risk of birth defects, and stating that there had already been birth defects with Accutane (presumably in Europe). Following this Roche wrote a letter to all doctors who had been involved in the US trial and told them not to “divulge trade secrets.”

Nine months after Accutane went on the market in May 1982, babies with birth defects started to appear.

In Sept 8 1983, after the first US birth defect cases were reported, Health Research Group wrote to the FDA urging them to require pregnancy tests and not to bury the warnings about birth defects in the “fine print” at the end of the product labeling.

By 1988 the FDA estimated there could be as many as 1,300 babies born with birth defects because of Accutane. Some of the babies were so deformed that they died in pain after only a few years of life in an institution. Probably many times more babies had mild cognitive defects. And what is worse, despite all efforts, rates of birth defects never went down until iPLEDGE.

Noone deserves that, for any reason.

Originally posted September 28, 2008

My book The Goose That Laid the Golden Egg: Accutane, the truth that had to be told, has been released with 39/42 five star reviews on Amazon and available in paperback or $0.99 on Kindle here. See here for all outlets where it can be obtained.

Goodbye to you too, Yaz

Following this they got admonished by the FDA which led to the unusual settlement of being an ad campaign out to UNDO the effects of the advertising. You see, it wasn’t approved to treat PMDD and acne, and in any case not all women have PMDD or untreated acne, even though the makers of Yaz certainly wish that that was the case. They were promoting it as a lifestyle drug, like look good, get laid, and feel good about yourself. What more could women want? Anyhoo in the new ads an actress looks into the camera and says:

You may have seen some Yaz commercials recently that were not clear. The F.D.A. wants us to correct a few points in those ads.

Indeed. Well first of all I really hate it when they take a perfectly good song and associate with some cheesy product. They should make musicians sign a contract that they will never sell out their tunes which run around in our heads. Second, that $20 million is “chump change” as one commenter pointed out, after they have already made their billions promoting a product for something that it wasn’t approved for, something that can be thought of as the cost of doing business, kind of like the billion that Eli Lilly paying as punishment for off label promotion of Zyprexa not being a big deal when they made 20 billion out of the deal. Finally, noone pointed out the fact that Yaz (and is sister pill Yasmin) (as I have written about before in “Is Your Birth Control Pill Driving You Bananas“) is the mosted posted about medication on medications.com, with most of the women complaining about how it makes them MORE depressed and anxious. Yaz also has drospirenone, a type of progesterone that can lead to elevations of potassium and potential heart failure.

How can it be that your birth control pill makes you depressed? Birth control pills (or oral contraceptive pills, or OCPs) are combinations of sex hormones related to estrogen and progesterone. Normally these sex hormones cycle throughout the month. In addition to controlling reproduction they also have effects on the brain, which is why they can cause anxiety and depression.

Taking the pill effectively blunts the normal variation in hormones; it also eliminates ovulation, which also affects sexuality. In fact, one study showed that strippers who were ovulating made $15 more per hour than strippers who were not ovulating,
and that strippers on the pill made significantly less than other strippers.

You can read more about the relative risks of heart disease and cancer in women of different ages and smoking status in my last post on this topic. However, I recommend using an IUD as the safest form of birth control, or a progesterone only pill.

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.

Their conclusion? No relationship, of course.

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 MD and 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, Hoffman-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].

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 Jan 5 2008

EDT: My book The Goose that Laid the Golden Egg: Accutane, the truth that had to be told is now out and available on Amazon in the US and UK.