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 3104 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.
Similar content being viewed by others
Notes
Use of tradenames is for product identification purposes only and does not imply endorsement.
References
Meadows M. The power of accutane: the benefits and risks of a breakthrough acne drug. FDA Consum 2001; 35: 18–23
Wysowski DK, Swann J, Vega A. Use of isotretinoin (Accutane) in the United States: rapid increase from 1992 through 2000. J Am Acad Dermatol 2002; 46: 505–9
US Food and Drug Administration (FDA) Talk Paper. FDA announces changes to the risk management program to prevent birth defects caused by Accutane [online]. Available from URL: http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01113.html. [Accessed 2003 May 21]
Bull J. Report before the Committee On Government House Reform, US House of Representatives: December 5, 2000 [online]. Available from URL: http://www.hhs.gov/asl/testify/t001205.html. [Accessed 2003 May 21].
US Food and Drug Administration (FDA). Dermatologic Drugs Advisory Committee (Accutane) transcripts [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/accutane.htm. [Accessed 2003 May 21]
Roche Pharmaceuticals. Our products: Accutane (isotretinoin): complete product information [online]. Available from URL: http://www.rocheusa.com/products/accutane/pi.pdf. [Accessed 2003 May 26]
Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin: is there a causal link? J Am Acad Dermatol 2001; 45: S168–75
O’Donnell J. Overview of existing research and information linking isotretinoin (Accutane), depression, psychosis, and suicide. Am J Ther 2003; 10: 148–59
Accutane/Roaccutane Action Group. Accutane/Roaccutane Action Group homepage [online]. Available from URL: http://www.roaccutaneaction.com/index.htm. [Accessed 2003 May 21]
Stupak B. Accutane [online]. Available from URL: http://www.house.gov/stupak/accutane.htm. [Accessed 2003 May 21]
Rothman KJ, Greenland S. Causation and causal inference. Rothman KJ, Greenland S, editors. Modern epidemiology. Philadelphia: Lippincott-Raven, 1998: 7-28
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. (DSM-IV). Washington, DC: American Psychiatric Association, 1994: 327
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. (DSM-IV). Washington, DC: American Psychiatric Association, 1994: 335
Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988; 8: 77–100
Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Measurement 1977; 1: 385–401
Goldberg D, Hillier VF. A scaled version of the General Health Questionnaire. Psychol Med 1979; 9: 139–45
Hamilton M. The Hamilton Rating Scale for Depression. Sartorius N, Ban T, editors. Assessment of depression. Berlin: Springer-Verlag, 1986: 143-52
Robins LN, Helzer JE, Croughan J, et al. National Institute of mental health diagnostic interview schedule: its history, characteristics, and validity. Arch Gen Psychiatry 1981; 38: 381–9
World Health Organization. Composite International Diagnostic Inventory (CIDI) Version 2.1. Geneva: WHO, 1997
First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV axis I disorders, (SCID-I), clinician version. Washington, DC: American Psychiatric Press Inc, 1997
Wing JK, Cooper JE, Sartorius N. The description and classification of psychiatric symptoms: an instruction manual for the PSE and CATEGO system. London: Cambridge University Press, 1974
Statistics Canada. National Population Health Survey - Household Component, Longitudinal [online]. Available from URL: http://stcwww.statcan.ca/english/sdds/3225.htm. [Accessed 2003 May 21]
Patten SB. Incidence of major depression in Canada. CMAJ 2000; 163: 714–5
Statistics Canada. Mortality: summary list of causes, 1997-SHELF TABLES. CAT. No 84F0209XPB. Ottawa: Statistics Canada, 1999
Regier DA, Narrow WE, Rae DS, et al. The de facto mental and addictive disorders service system: epidemiological catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry 1993; 50: 85–94
Narrow WE. One-year prevalence of mental disorders, excluding substance use disorders, in the US: NIMH ECA prospective data. Population estimates based on US Census estimated residential population age 18 and over on July, 1998. Cited from URL: http://www.nimh.nih.gov/publicat/numbers.cfm. [Accessed 2003 May 18]
Hoyert DL, Kochanek KD, Murphy SL. Deaths: final data for 1997. National Vital statistics Report, 47 (19). Hyattsville (MD): National Center for Health Statistics, 1999. DHHS Publication No. 99–1220
Koo JY, Smith LL. Psychologic aspects of acne. Pediatr Dermatol 1991; 8: 185–8
Koo J. The psychosocial impact of acne: patients’ perceptions. J Am Acad Dermatol 1995; 32: S23–30
Shuster S, Fisher GH, Harris E, et al. The effect of skin disease on self image [proceedings]. Br J Dermatol 1978; 99 Suppl. 16: 18–9
Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin Exp Dermatol 1992; 17: 1–3
Motley RJ, Finlay AY. How much disability is caused by acne? Clin Exp Dermatol 1989; 14: 194–8
Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 1998; 139: 846–50
Cotterill JA, Cunliffe WJ. Suicide in dermatological patients. Br J Dermatol 1997; 137: 246–50
Macdonald-Hull S, Cunliffe WJ, Hughes BR. Treatment of the depressed and dysmorphophobic acne patient. Clin Exp Dermatol 1991; 16: 210–1
Patten SB, Love EJ. Drug-induced depression. Psychother Psychosom 1997; 66: 63–73
Whitlock FA, Evans LE. Drugs and depression. 1978; 15: 53–71
Patten SB, Love EJ. Drug-induced depression: incidence, avoidance and management. Drug Saf 1994; 10 (3): 203–19
Australian Adverse Drug Reaction Bulletin. Depression: could it be the drug? [online]. Available from URL: http://www.health.gov.au/tga/docs/html/aadrbltn/aadr9802.htm#dep [Accessed 2003 Apr 16]
Patten SB, Lamarre CJ. Can drug-induced depressions be identified by their clinical features. Can J Psychiatry 1992; 37: 213–5
Patten SB, Love EJ. Can drugs cause depression? A review of the evidence. J Psychiatry Neurosci 1993; 18: 92–102
Hazen PG, Carney JF, Walker AE, et al. Depression: a side effect of 13-cis-retinoic acid therapy. J Am Acad Dermatol 1983; 9: 278–9
Scheinman PL, Peck GL, Rubinow DR, et al. Acute depression from isotretinoin. J Am Acad Dermatol 1990; 22: 1112–4
Duke EE, Guenther L. Psychiatric reactions to the retinoids. Can J Dermatol 1992; 5: 467
Byrne A, Hnatko G. Depression associated with isotretinoin therapy [letter]. Can J Psychiatry 1995; 40: 567
Bravard P, Krug M, Rzeznick JC. Isotretinoin and depression: care is needed [letter]. Nouv Dermatol 1993; 12: 215
Gatti S, Serri F. Acute depression from isotretinoin [letter]. J Am Acad Dermatol 1991; 25: 132
Burket JM, Storrs FJ. Nodulocystic infantile acne occurring in a kindred of steatocystoma. Arch Dermatol 1987; 123: 432–3
Aubin S, Lorette G, Muller C, et al. Massive isotretinoin intoxication. Clin Exp Dermatol 1995; 20: 348–50
Lindemayr H. Isotretinoin intoxication in attempted suicide. Acta Derm Venereol 1986; 66: 452–3
Hepburn NC. Deliberate self-poisoning with isotretinoin. Br J Dermatol 1990; 122: 840–1
Ng CH, Tamm MM, Hook SJ. Acne, isotretinoin treatment and depression. World J Biol Psychiatry 2001; 2: 159–61
Cott AD, Wisner KL. Isotretinoin treatment of a woman with bipolar disorder [letter]. J Clin Psychiatry 1999; 60: 407–8
Bruno NP, Beacham BE, Burnett JW. Adverse effects of isotretinoin therapy. Cutis 1984; 33: 484–9
Bigby M, Stern RS. Adverse reactions to isotretinoin: a report from the adverse drug reaction reporting system. J Am Acad Dermatol 1988; 18: 543–52
Hull PR, Demkiw-Bartel C. Isotretinoin use in acne: prospective evaluation of adverse events. J Cutan Med Surg 2000; 4: 66–70
Hoffmann-La Roche. Briefing Information: Dermatologic and Ophthalmic Drugs Advisory Committee to the Food and Drug Administration, Gaithersburg (MD), Sept. 19 2000 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1.htm. [Accessed 2003 Apr 16]
Nelson RC. Dermatologic and Ophthalmic Drugs Advisory Committee to the Food and Drug Administration, Gaithersburg (MD), Sept. 19 2000 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t2.rtf Page 37. [Accessed 2003 Apr 16]
Jacobs D. Dermatologic and Ophthalmic Drugs Advisory Committee to the Food and Drug Administration, Gaithersburg (MD), Sept. 19 2000 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t2.rtf Page: 45. [Accessed 2002 Jun 21]
Pitts MR. Positive rechallenge cases of accutane-associated depressive symptoms: Dermatologic and Ophthalmic Drugs Advisory Committee to the Food and Drug Administration, Gaithersburg (MD), Sept. 19 2000 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/slides/3639s2i.pdf. [Accessed 2003 Apr 16]
Wysowski DK. Summary of reported cases of depression and suicide in US Accutane treated patients. Dermatologic and Ophthalmic Drugs Advisory Committee to the Food and Drug Administration, Gaithersburg, Md, Sept 19 2000 [online]. Available at URL: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t2.rtf page 122. [Accessed 2003 Apr 16]
Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001; 45: 515–9
Wysowski DK, Pitts MR, Beitz J. Depression and suicide in patients treated with isotretinoin [letter]. N Engl J Med 2001; 344: 460
Eaton WW, Kramer M, Anthony JC, et al. The incidence of specific DIS/DSM-III mental disorders: data from the NIMH Epidemiologic Catchment Area Program. Acta Psychiatr Scand 1989; 79: 163–78
Wray CM. Accutane and depression. Canadian Adverse Drug Reaction Newletter 1999; 9:1–2 [online]. Available from URL: http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv9n1_e.pdf. [Accessed 2003 May 21]
Wooltorton E. Accutane (isotretinoin) and psychiatric adverse effects. Can Med Assoc J 2003; 168 (1): 66
Australian Adverse Drug Reactions Bulletin. Depression with isotretinoin [online]. Available from URL: http://www.health.gov.au/tga/docs/html/aadrbltn/aadr9808.htm#isot. [Accessed 2003 Apr 16]
Irish Medicines Board. Drug safety newletter [online]. Available from URL: http://www.imb.ie/pubs/drugnews/news8.pdf. [Accessed 2002 Jun 21]
O’Connell K. Dermatologic and ophthalmic drugs advisory committee to the food and drug administration [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3639t2.rtf. [Accessed 2003 Apr 16]
Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000; 136: 1231–6
Rawson Nigel. [personal communication]. 2002
Wysowski DK. Methodological limitations of the study “Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide” [letter]. Arch Dermatol 2001; 137: 1102
Neary MP, Klaskala W, McLane J, et al. Epidemiological study of adverse events in Accutane users and matched non-users: retrospective analysis of major US health plan claims database. 17th International Conference on Pharmacoepidemiology. Pharmacoepidemiol Drug Saf 2001; 10: S141
Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr 1989; 49: 358–71
Restak RM. Pseudotumor cerebri, psychosis, and hypervitaminosis A. J Nerv Ment Dis 1972; 155: 72–6
McCance-Katz EF, Price LH. Depression associated with vitamin A intoxication. Psychosomatics 1992; 33: 117–8
Stuttgen G. Oral vitamin A acid therapy. Acta Derm Venereol Suppl (Stockh) 1975; Suppl. 74: 174–9
Henderson CA, Highet AS. Depression induced by etrinate [letter]. BMJ 1989; 298: 96
Borbujo MJM, Casado JM, Garijo LMB, et al. Efecto secundario inusual por etretinato [An unusual secondary effect of etretinate]. Medicina Clinica 1987; 89: 577
Rubinow DR, Peck GL, Squillace KM, et al. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987; 17: 25–32
Newton JN, Mallon E, Klassen A, et al. The effectiveness of acne treatment: an assessment by patients of the outcome of therapy. Br J Dermatol 1997; 137: 563–7
Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol 1999; 140: 273–82
Layton AM, Seukeran D, Cunliffe WJ. Scarred for life? Dermatology 1997; 195 Suppl. 1: 15–21
Acknowledgements
Peter Hull has received no funding for the preparation of this manuscript and has no conflicts of interest directly relevant to the contents. Carl D’Arcy achnowledges funding for Applied Research from the Saskatchewan Health Research Foundation. He has no conflicts of interest directly relevant to the contents of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hull, P.R., D’Arcy, C. Isotretinoin Use and Subsequent Depression and Suicide. Am J Clin Dermatol 4, 493–505 (2003). https://doi.org/10.2165/00128071-200304070-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00128071-200304070-00005