Article available from: http://www.nejm.org/content/2001/0344/0006/0460a.asp
The New England Journal of Medicine -- February 8, 2001 -- Vol. 344, No. 6
Depression and Suicide in Patients Treated with Isotretinoin
To the Editor:
Between 1982 and May 2000, the Food and Drug Administration (FDA) received reports of 431 cases of depression, suicidal ideation, suicide attempts, or suicide in U.S. patients treated with isotretinoin (Accutane, Hoffmann-LaRoche), which is indicated for the treatment of severe nodular acne.
There were 37 patients who committed suicide, 24 of them while using isotretinoin and 13 after ceasing to use it. Of these patients, 31 (84 percent) were male, and their median age was 17 years (range, 13 to 32). Among those still using the drug at the time of the suicide, the median duration of use was 3 months; for those who had stopped using it, the median interval between stopping the drug and committing suicide was 2.5 months. A history of psychiatric illness was reported for 8 of the 37 patients (22 percent).
The median peak dose was 1.0 mg per kilogram of body weight per day (recommended range, 0.5 to 2.0 mg per kilogram per day). For the same period, the FDA analyzed reports of 110 U.S. patients who were hospitalized for depression, suicidal ideation, or suicide attempts while using isotretinoin (85 patients) or after stopping its use (25 patients). Of the 110, 62 (56 percent) were female and their median age was 17 years (range, 12 to 47).
The median duration of use of the drug before hospitalization was one month; for those who had stopped using it, the median interval between stopping use and hospitalization was three months. A history of psychiatric illness was reported for 48 of these patients (44 percent). The median peak dose was 1.1 mg per kilogram per day. In many patients, there was improvement after discontinuation of the drug and psychiatric treatment, but others had persistent depression after the drug was discontinued. Four patients were rechallenged with isotretinoin; symptoms developed again in one, and the other three were able to continue using the drug at a reduced dose, while abstaining from alcohol, or while continuing to take an antidepressant.
There were an additional 284 reports of patients with depression who were not hospitalized, of whom 149 (52 percent) had accompanying physical side effects. Of these patients, 24 were rechallenged with isotretinoin, with return of depression. Although the number of suicides reported among users of isotretinoin does not exceed the number that would be predicted on the basis of the suicide rate in the United States (1) and the estimated number of patients exposed to the drug, (2) isotretinoin ranks among the top 10 drugs in the FDA's data base in terms of the number of reports of depression and suicide attempts among its users.
Possible explanations for the high number of such reports are better reporting than with other drugs and a relation between severe acne and depression. A warning concerning depression and suicide was added to the labeling of isotretinoin in 1998; however, the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee recently advised that more information be made available concerning these adverse events. Physicians should request that patients and their parents report promptly any changes in behavior that might be symptomatic of depression, so that patients may be evaluated for appropriate treatment.
(The views expressed in this letter are those of the authors and do not necessarily represent the official position of the FDA.)
Diane K. Wysowski, Ph.D. Marilyn Pitts, Pharm.D. Julie Beitz, M.D. Food and Drug Administration Rockville, MD 20857
1. Hoyert DL, Kochanek KD, Murphy SL. Deaths: final data for 1997. Nat Vital Stat Rep 1999;47:1-104.
2. Nelson R. Pharmacoepidemiologic analysis of Accutane-associated psychiatric events. Presentation for Hoffmann-LaRoche at the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee meeting, Gaithersburg, Md., September 19, 2000.