Isotretinoin: Risks Beyond Depression, Suicidality Evaluated

A recent analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) data found that beyond the reported associated risks for depression and suicidality, patients taking isotretinoin also can experience significant mood disturbances, self-injury, and psychoses. The authors therefore advised closely monitoring for such events in patients, especially during early treatment for acne.

However, an acne expert predicted that the study, recently published in the Journal of the American Academy of Dermatology, will have little clinical impact because of methodological issues.

With conflicting evidence and controversy surrounding the association of isotretinoin with psychiatric adverse events (AEs), wrote the authors led by Wenjia Nie, MD, of the Dermatology Hospital of Jiangxi Province in Jiangxi, China, it remains unclear which psychiatric AEs beyond the “commonly discussed risks” of depression and suicide require closer monitoring. To address this question, they compared odds ratios of psychiatric with nonpsychiatric AEs among isotretinoin users vs the corresponding ratios among users of other drugs in the FAERS database between 2srcsrc4 and 2src24.

After excluding duplicates, investigators examined 19,412 psychiatric AEs reported by 12,312 patients on isotretinoin. The most frequently reported psychiatric AEs overall included depression (47.5%), suicidal ideation (17.7%), anxiety (15.src%), and altered mood (11.7%). With a reporting odds ratio (ROR) of 3.3src, significantly more psychiatric AEs were reported by isotretinoin drug users than non-isotretinoin drug users.

Influence of Indication

Indication had the greatest impact on overall study findings.

Acne reports showed both a higher relative psychiatric AE frequency and more significant signals than non-acne reports.

Of 96 psychiatric AEs with positive signals among isotretinoin users, investigators assigned 25 — which they categorized into groups such as depressive disorder, bipolar disorder, affective disorder, and others — moderate clinical priority. Additionally, investigators assigned top clinical priority to suicidal ideation (lower limit of the 95% CI/ROR_src25=11.16), major depression (ROR_src25=5.src7), and completed suicide (ROR_src25 =1.39).

“The results indicate that, beyond depression and suicide, other mood disturbance (eg, anxiety disorder, mood change, bipolar disorder, and affective disorder), self-injury, and psychosis also warrant prioritized monitoring during the early stages of treatment, particularly among acne patients,” wrote Nie and colleagues.

However, Emmy Graber, MD, MBA, said that while analyzing FAERS data proved interesting, results should be interpreted skeptically. She is president of The Dermatology Institute of Boston and an affiliate clinical instructor in the Bouvé College of Health Sciences at Northeastern University in Boston. Graber was not involved with the study but was asked to comment.

Unvalidated Data

The problem with trying to extract data from the FAERS, she said, is that anyone — doctor, nurse, or patient — can report any side effect. But the system cannot validate whether the reported AE was truly associated with acne or another diagnosis, or even if the diagnosis is accurate, Graber said.

Isotretinoin often carries a reporting bias, she added, because its potential side effects have garnered so much attention. “The power of suggestion is very strong,” Graber explained. “If patients have in their mind that they may become depressed from a medicine, the moment they feel a little down, they may jump to the conclusion, whether it’s true or not, that it’s due to the isotretinoin.”

Additionally, the study showed a median symptom onset time of 8src days regardless of indication. However, she said, this is also about the midpoint of a typical isotretinoin treatment course.

Authors acknowledged limitations including self-reporting bias and the inability to infer causality from statistical associations. Nevertheless, Graber said, the study will not change clinical practice.

“We as physicians have the advantage that we’re seeing teenagers and adults monthly while they’re on isotretinoin,” she said. “We’re not mental health professionals. But our responsibility lies in asking each month how patients are doing. And sometimes we know these patients better than their primary care physician.”

Accordingly, said Graber, dermatologists’ responsibility to patients on isotretinoin lies not necessarily in diagnosing or treating new psychiatric events but in referring affected patients to clinicians who can do so.

The study was supported by grants from the National Natural Science Foundation of China and the Jiangxi Provincial Clinical Research Center Projects. Graber reported no relevant financial relationships.

John Jesitus is a Denver-based freelance medical writer and editor.