Article

Isotretinoin Use and Subsequent Depression and Suicide

Department of Medicine, Division of Dermatology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
American Journal of Clinical Dermatology (Impact Factor: 2.52). 02/2003; 4(7):493-505. DOI: 10.2165/00128071-200304070-00005
Source: PubMed

ABSTRACT The growing number of reported cases of depression and suicide associated with isotretinoin (a retinoid receptor agonist) use in patients with acne has prompted concern among dermatologists, patients, and their relatives and has triggered new warnings from regulators including depression-related, patient-informed consent forms. In establishing a cause-effect relationship, it is useful to judiciously consider whether there is an association, what is the nature of that association, if there is a plausible biological mechanism of action, the validity and reliability of measures used and the strength of study designs. Hoffmann-La Roche estimates that by April 2001 approximately 12 million patients worldwide have used isotretinoin, with 5 million patients in the US.A MEDLINE search between January 1966 and May 14 2003 of the published medical literature found 24 documented cases of isotretinoin-associated depression, with 3 suicides. One additional patient committed suicide during the fourth month of isotretinoin treatment and 3 further patients attempted suicide by taking an overdose of isotretinoin. The US FDA's Adverse Event Reporting System (AERS) contains almost 23,000 reports for isotretinoin from its approval in 1982 to December 2002. As of November 30, 2002, AERS contained 3,104 reports (US and foreign) with at least one reported psychiatric event. The FDA is aware of 173 reports of suicide (both US and foreign) in association with isotretinoin. Reports of positive dechallenge and rechallenge present a strong signal pointing to an association between isotretinoin and depression. A Hoffmann-La Roche sponsored epidemiological study failed to find any evidence of an association between isotretinoin and depression or suicide. However, the design of the study was flawed and the evidence was deemed inconclusive. Further studies using strong study designs, reliable and valid measures, and adequate sample sizes may bring us closer to the answer. The evidence suggesting a relationship between isotretinoin and depression needs to be weighed against the increasing prevalence of depression among adolescents and young adults and the psychological impact of acne. The literature contains credible evidence that isotretinoin treatment may reduce the psychosocial impact of acne in some patients. At the present time, there is no known pharmacological mechanism that would account for psychiatric symptomatology as a result of isotretinoin treatment; however, retinoid receptors are widely distributed in the brain and more research is needed to ascertain whether they have a role in depression. In the meantime, for the practitioner, the obvious benefit of isotretinoin in treating acne should encourage continued use. However, patients and their relatives must be informed and depressive symptoms should be actively assessed at each visit and, if necessary, referral to a psychiatrist, antidepressant therapy or discontinuation of isotretinoin should be considered.

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    • "Reports have also suggested an association between the use of 13-cis-RA (or isotretinoin), a medication for acne, and the onset of depression, as well as psychosis and suicide in a subgroup of vulnerable individuals [33,34]. This evidence includes case reports, studies showing a temporal association between depression onset and exposure to the drug, challenge and re-challenge cases, evidence of a drug class effect, dose response, and the existence of biologically plausible mechanisms for the association [35–37]. "
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    • "However, isotretinoin therapy is associated with significant adverse effects including hypertriglyceridemia, xerostomia, intracranial hypertension, and severe teratogenicity (Brelsford and Beute, 2008). The association with depression and suicidal ideation remains controversial, with a recent study suggesting that the association could be with acne rather than isotretinoin (Hull and D'Arcy, 2003; Sundstrom et al., 2010). "
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    • "In conclusion, cases reported add to a few previous similar reports of isotretinoin-induced psychiatric manifestations in individuals with a positive To the Editors, Isotretinoin, a synthetic retinoid that is used against severe, recalcitrant nodulocystic acne, has been associated in several case-series and some retrospective and uncontrolled studies with various psychiatric side-effects (depression, violent behaviour, suicidality and psychotic symptoms) (Ng et al. 2001; Hull and d'Arcy 2003; Kontaxakis et al. 2009). Depressive symptoms are most often reported at 1 month after isotretinoin initiation at an estimated incidence of 1–11% (Bremner and McCaffery 2008). "
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