Acne trials explore variety of treatment safety, efficacy issues

Reviewing recent reports, Dr. Leyden, emeritus professor of dermatology, University of Pennsylvania, Philadelphia, finds studies on isotretinoin (Accutane, Roche) and depression, antibiotic resistance and topical retinoid treatment especially noteworthy.

ISOTRETINOIN Many case reports have described the development of depression and suicide in isotretinoin-treated patients, and most clinicians who prescribe isotretinoin have probably encountered patients who develop central nervous system and psychiatric adverse events, including mood changes.

Due to the controversy about the role of isotretinoin in causing depression and suicide and the importance of that issue, various researchers have been prompted to conduct studies investigating the risk and potential pharmacologic mechanisms. A recent small study involving evaluation of acne patients with functional imaging technology found that brain metabolism in the orbitofrontal cortex was decreased in persons treated with isotretinoin relative to controls treated systemically only with antibiotic. Decreased brain metabolism in that same region has also been identified in persons diagnosed with depression, Dr. Leyden tells Dermatology Times.

"There is evidence that retinoids can effect brain neurochemical pathways, and these clinical findings suggest some biologic plausibility for a relationship between isotretinoin and the development of depression. However, it will be important to see whether the results can be reproduced in other series," Dr. Leyden says.

On the other side of the coin, however, a study undertaken by Lee Zane, M.D., and colleagues at the University of California, San Francisco, provides some reassuring data about the purported risk of depression in isotretinoin-treated patients. Using the Kaiser Permanente database to compare a cohort of over 16,000 isotretinoin-treated patients with various age-matched control groups, the investigators found no evidence that isotretinoin was associated with increased rates of suicide, attempted suicide, depression or need for antidepressive treatment.

ANTIBIOTIC RESISTANCE Since antibiotic levels in the follicle cannot be assayed to determine whether administered doses achieve target site concentrations exceeding propionibacterium acnes minimum inhibitory concentration (mic) values, questions about the clinical relevance of in vitro antimicrobial resistance have been investigated by analyzing correlations between clinical outcomes and p. acnes sensitivity.

Findings of a Lancet study in which patients were randomized to one of five oral or topical antibacterial regimens, as well as of various other studies suggest outcomes are worse in patients colonized with less sensitive P. acnes strains.

However, the efficacy of subantimicrobial dose doxycycline monohydrate (Oracea, CollaGenex) in the treatment of rosacea indicates that tetracycline has clinically relevant anti-inflammatory activity and suggests antibiotics exerting anti-inflammatory properties may still be effective treatment for acne regardless of bacterial susceptibility.

TOPICAL RETINOIDS In the area of topical retinoid therapy, a 0.3 percent gel formulation of adapalene (Differin, Galderma) has been shown to be well tolerated and more effective than the currently available 0.1 percent gel preparation.

The new drug application (NDA) for the higher concentration product is currently under review at the Food and Drug Administration (FDA) as are the NDAs for two new fixed combination products containing tretinoin and clindamycin.

Two recent studies also have highlighted the role of retinoid mono-therapy as a maintenance regimen for acne patients. In those respective trials, patients were initiated on a combination regimen consisting of either oral doxycycline 100 mg and adapalene 0.1 percent gel each once daily, or oral minocycline 100 mg twice daily and tazarotene 0.1 percent gel (Tazorac, Allergan) in the evening.

In the adapalene trial, the topical retinoid was significantly superior to vehicle control for maintaining disease improvement. At the conclusion of the maintenance phase in the tazarotene trial, there were no significant differences between any of the three treatment groups when efficacy outcomes were analyzed using multiple endpoints.