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Accutane may counter, not cause, depressive symptoms

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St. Louis  A recent study shows that isotretinoin has the potential to improve depressed mood among adolescent users much more often than to cause it, as the package insert warns.

According to a study conducted by a team of doctors at St. Louis University Health Sciences Center and later published in the May issue of Archives of Dermatology, the use of isotretinoin, particularly Accutane (Hoffman La-Roche), in the treatment of moderate to severe acne in adolescents was not associated with an increase in depressive symptoms.

"On the contrary," write the study's authors, "our study shows that treatment of acne improves depressive symptoms."

FDA labeling decision

Accutane is a synthetic molecule derived from vitamin A, which is involved in growth and maintenance of skin. The drug prevents pimples by correcting abnormal follicular keratinization and shrinking the enlarged sebaceous glands that contribute to the primary pathogenesis of acne. Accutane has proved to be a highly effective drug in the treatment of severe acne, but data has emerged in recent years that suggest the drug may cause severe depression and even suicide in some patients.

In 1986, the Food and Drug Administration (FDA) mandated a change in the package insert to include the risk of depression. In 2000, the FDA mandated that this risk be placed on the package label with the words "Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide and aggressive behavior."

Not convinced

Elaine Siegfried, M.D., associate clinical professor of pediatrics and dermatology, St. Louis University, and private practitioner at Kids Dermatology in St. Louis, is the study's corresponding author. Prior to initiating the study, Dr. Siegfried says she wasn't convinced that Accutane caused symptoms of depression, let alone suicidal ideation.

"I think it's important to note that suicide, sadly, is the No. 2 (and) 3 cause of death among teenagers in this country," she says. "I've treated hundreds of teenage patients with Accutane, and have had no patients with suicidal ideation or attempts and, thankfully, none who have committed suicide. Accutane is a drug that gets negative press because it can cause birth defects, so it already had a strike against it in terms of public perception. When statistics and case reports were released linking the drug to depression and even suicide in some teenage patients, we wondered whether there wasn't an overreaction  whether the depression issue could be colored by the angst over side effects that can lead to birth defects.

"To quote a fellow dermatologist, Dr. Richard Fried, 'Scientific data pales in comparison to well-orchestrated media sensationalism.'"

New research study

Dr. Siegfried and her colleagues at St. Louis University decided to conduct their own study among their moderate-to-severe acne patients. The study began in 1997 and was completed in 2002.

"Our study was not funded or supported in any way by any pharmaceutical company," Dr. Siegfried says. "In fact, we got no funding from any source. The lack of a budget was the reason for the study's shortcomings: the relatively small size and lack of randomization. It was a study designed to include patients we saw in our practice over a five-year period."

Study objective

The objective of the study was to determine whether patients with moderate to severe acne who were treated with Accutane showed an increase in depressive symptoms compared with a control group of similar patients treated with conservative therapy.

The researchers assessed 132 patients aged 12 to 19 for depression, using a simple, 20-question psychiatric instrument that had been validated in adolescents: the Center for Epidemiological Studies Depression Scale (CES-D). Scores of 17 and above were suggestive of depression. Of the 132 patients, 59 were treated with Accutane; the rest were treated with topical antibiotics, topical retinoids and oral antibiotics. Depression was assessed at baseline and reassessed about four months post-treatment.

Study results

The study showed that at baseline, 14.3 percent of the Accutane group had CES-D scores of 17 or higher, while 19.2 percent in the conservative-therapy group scored 17 or higher. At follow-up, 8.2 percent of the Accutane patients scored 17 or higher, while 15.4 percent in the conservative-therapy group scored 17 or more.

"What we saw in our study is the opposite of what spontaneous reporting and uncontrolled case reports have suggested, and which led to the FDA mandating warnings on the Accutane packaging," Dr. Siegfried says. "Our study suggests that far from causing depression, Accutane may have helped improve the mood of our patients as their acne cleared."

Study limitations

Dr. Siegfried emphasizes that her study was small and not randomized, and that larger, randomized studies would be required to address any doubts about a rare risk of depression, suicide or impulsivity associated with Accutane therapy.

"We asked the question because we thought the mandated warnings regarding serious depressive side effects that could lead to suicidal thoughts and action might have been overstated," she says. "Isotretinoin is now available in a generic formulation, so there is very little incentive for doing a larger study. Whether the FDA will take any further steps remains to be seen. The FDA's workings are often mysterious to me, and I seriously doubt that our findings will affect the package insert warnings regarding the risks of depressive side effects of Accutane."

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The relationship between isotretinoin treatment and depression and suicide, however, remains controversial. Although the manufacturer, on the basis of FDA guidelines, lists depression as a possible side effect, there is no consensus on a causal role for isotretinoin in the development of depression and suicide. The high incidence of depression in the general population makes it difficult to identify small increases specifically related to an additional factor, such as isotretinoin administration. One large epidemiological study did not demonstrate a significantly increased risk for suicide in patients treated with isotretinoin (3). Some authors have argued that cases of depression associated with isotretinoin administration are merely coincidental (20) or that isotretinoin actually leads to an improvement in anxiety and depression because of the clearing of disfiguring acne (21). Studies have shown an improvement in feelings of general well-being or self-image (22, 23) or in feelings of anxiety (20, 24–28) among patients with cystic acne following isotretinoin administration, although the findings were more directly related to improvement in measures of patient satisfaction, rather than clinical symptoms of depression.

To establish a causal role of isotretinoin in the development of depression and suicide, it is critical to establish a plausible biological pathway. This requires that isotretinoin must enter the central nervous system (CNS) and have an effect on the functioning of brain areas and neurochemical systems that mediate depression. Retinoids have important effects on the developing brain in animal studies (29, 30), and use of isotretinoin during pregnancy has long been known to result in CNS defects in newborns (31). Multiple positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have shown low metabolism and/or blood flow at baseline in depressed subjects in the left (32–35) and bilateral (36–43) dorsolateral prefrontal cortex and medial prefrontal cortex/anterior cingulate (34, 38, 41–48) or blunted activation with cognitive tasks in the anterior cingulate (49, 50). Other PET and SPECT studies of patients with unipolar depression showed low metabolism and/or blood flow in the caudate (36–41, 51, 52), thalamus (37), temporal cortex (37, 38, 51, 53, 54), parietal cortex (34, 40, 51), and left putamen (37). Experimental induction of depression resulted in a specific decrease in metabolism in the orbitofrontal cortex (part of the prefrontal cortex) (55, 56). The purpose of the current study was to assess the effects of isotretinoin treatment on brain functioning. We hypothesized that treatment with isotretinoin, but not antibiotic, would be associated with a decrease in orbitofrontal cortical brain metabolism as measured with [18F]fluorodeoxyglucose (FDG) PET. (Bremner et. al., 2005) --http://ajp.psychiatryonline.org/cgi/content/full/162/5/983

Also, see my post in the following thread: http://www.acne.org/messageboard/index.php...p=1378571


-Roaccutane Science: http://max001.proboards42.com

-FDA Advisory Committee on Accutane (2000)

-Accutane package label (2005)

-Tretinoin (systemic) package label (2004) (peripheral neuropathy is unlisted)

-Tretinoin (CCO Formulary, Rev. 2004/2005)

-Package label history

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