Published: June 2005

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Acne, Isotretinoin and Depression

Information on this subject has been updated. Read the most recent information.

Prescriber Update 26(1): 10-13
June 2005

This article was originally published in the Drug and Therapeutics Bulletin* 2003;41:76-78, and has been reprinted here with kind permission from Which? Ltd, 2 Marylebone Road, London NW1 4DF, United Kingdom.

At any one time, most 16-18-year-olds and up to half of adults have acne.¹  In 60% of all teenagers, the condition will be sufficiently severe for them to self-treat or seek medical advice.²  Up to half of 12-20-year-olds with acne develop psychological or social problems.³  Oral isotretinoin, which is used for the treatment of severe acne,⁴ might be expected to improve psychological functioning.^5,6  However, there have been suggestions that the drug itself might cause depression and suicide.⁷  Here we consider these concerns, and the implications for the use of isotretinoin when managing patients of all ages.

Background

Most patients with mild acne (i.e. few to several papules or pustules, but no nodules/cysts) or moderate acne (several to many papules and pustules, plus few to several nodules/cysts) manage themselves or are treated in primary care with topical antimicrobials, keratolytics or retinoids and/or oral antibacterials.^8,9  Oral isotretinoin is an option for the 0.6-1.4% of young adults with severe acne (numerous and/or extensive papules and pustules, plus many nodules/cysts, possibly also with pitting or scarring).⁸

What is isotretinoin?

Isotretinoin (13-cis retinoic acid) is a derivative of vitamin A.  Following oral administration, it is converted to all-trans retinoic acid within target cells (sebocytes) and this metabolite suppresses sebaceous gland activity.¹⁰  Isotretinoin was originally licensed for use in the USA as Accutane in 1982, and in the UK it is currently available from Roche (as Roaccutane^®) and from Schering Health (as non-proprietary isotretinoin).  [New Zealand brands of isotretinoin include Isotane^® and Oratane^®]

Clinical efficacy

Isotretinoin, which is recommended as a 12-16-week course,¹¹ can be highly effective in moderate to severe acne when other treatments have failed.  A meta-analysis of three trials, including a total of 426 patients, suggested isotretinoin cured around 85% of patients after an average treatment course of 4 months.¹²  The optimal dose was 1mg/kg/day with a maximum cumulative dose of 120mg/kg.  After stopping the drug, about 1 in 5 patients relapsed.

Established unwanted effects

Isotretinoin has many unwanted effects.  It is teratogenic, causes cheilitis (inflammation of the lips), dry eyes and dry nasal mucosa, and may cause minor nosebleeds, dry skin and photosensitivity, muscle aches and pains and fatigue, visual disturbances, thinning of scalp hair, and a transient rise in liver transaminases and serum triglyceride concentrations.¹¹  Due to its potential toxicity, isotretinoin is only licenced [in the UK] for prescription by, or under the supervision of, consultant dermatologists,¹¹ and it is therefore almost exclusively dispensed by hospital pharmacies.  Some specified community pharmacies [in the UK] may supply it after authorisation by a dermatologist for specific patients.  [In New Zealand, isotretinoin should only be prescribed by physicians who are experienced in the use of systemic retinoids, preferably dermatologists.^A  The Isotane brand is fully funded when prescribed by a dermatologist and dispensed by a hospital or community pharmacy contracted to dispense as a hospital pharmacy.^B]

What about depression?

Scattered case reports of mood change, depression and suicide in patients taking isotretinoin have appeared since the drug was first licensed.¹³  However, establishing whether isotretinoin causes or aggravates depression is complicated by the high background prevalence of psychiatric illness among adolescents in general (estimated at over 25% in one study¹⁴) and among patients with acne (over 50% in a study of dermatology outpatients with a mean age of 24 years¹⁵).  Published studies have been unable to adjust fully for these potentially confounding factors.

Collated evidence from case reports

A review of spontaneous reports to the USA Food and Drug Administration (FDA) between 1982 and 2000 included 431 cases of depression, suicidal ideation, suicide attempts or suicide among patients (aged 13-32 years) treated with isotretinoin (0.5-2.5mg/kg/day).⁷  Some of these case reports fulfilled criteria suggesting a causal association: depression beginning or worsening after starting the drug, improvement in symptoms after withdrawal of the drug, and worsening of symptoms when the drug was reintroduced.  However, it is not obvious how isotretinoin could cause such effects, particularly where depression or suicide occurs months after stopping the drug.  The reports included 37 patients who committed suicide, of whom 24 were still taking the drug (median duration of treatment 3 months) and 13 had stopped (suicide occurred a median of 2.5 months after stopping isotretinoin).  In all, 22% of these patients had a history of psychiatric illness and a further 40% had other factors that could have contributed to the suicide.  Estimates of the numbers of suicides that could be expected in this population in the absence of any predisposing effect of isotretinoin during the same time period varied between 6 (based on comparisons with other drugs monitored by the FDA) and 400 (using national incidence rates), compared with the 37 observed.  The authors therefore suggested that the number of suicides reported did not exceed that predicted, although they acknowledged the possibility of considerable under-reporting of suicide to the FDA.  The type of data collated in this study do not allow adjustment for the potentially confounding effect of acne itself in depression, suicidal ideation and possibly even suicide.^15,16  However, at least some of the patients in this study were depressed in spite of improvements in their acne, raising the possibility that isotretinoin was a contributing factor in patients' mood disturbance.⁷

Epidemiological studies

A retrospective study separately analysed data from two primary care databases, one from Canada and the other from the UK, involving a total of 7,535 isotretinoin-users and 14,376 oral antibacterial-users (mostly aged 10-29 years) who had acne and for whom database information was available for at least 1 year after the first isotretinoin or antibacterial prescription.³  For neither group of patients were details given on the severity of the acne or on the treatment regimen used.  This calls into question whether the two groups were directly comparable with regard to these criteria.  These limitations must be borne in mind when considering the study results, which showed no increased risk of depression or psychosis among current isotretinoin-users compared with antibacterial-users (relative risk in Canada 1.2, 95% CI 0.9-1.76; in the UK 1.3, 95% CI 0.2-5.7).  Also, the study did not have sufficient power to detect small differences in suicide rates.  Additionally, it may not have identified all the patients with psychiatric disorders.  For example, neither diagnostic interviews nor death-certificate data were used, and it is known that depression is under-diagnosed in primary care.^17,18  Also, the number of patients on isotretinoin in the UK database may have been under-reported because the drug was prescribed by dermatologists whereas the database is limited to information from primary care.

A recent retrospective database study examined the records of 2,821 patients (aged 12-49 years) who had received both isotretinoin and antidepressant medication, to see if there was a greater likelihood of receiving the antidepressant after the isotretinoin rather than before (which could indicate a depression-provoking effect of isotretinoin).¹⁹  No significantly increased risk of receiving antidepressant after isotretinoin was found.

Prospective clinical studies of psychiatric events occurring in patients on isotretinoin have all involved small numbers of participants and lacked the power to identify or rule out an association.  One example is a non-randomised study, in which 215 patients (aged 15-50 years), mostly with severe acne, were treated with isotretinoin, or antibacterials plus topical treatments.²⁰  Isotretinoin-users had more severe acne than those treated with antibacterials (p<0.001).  Five out of 174 patients taking isotretinoin (2.9%) complained of worsening mood and the drug was stopped.  In 2 of these people, depression was thought not to be related to isotretinoin use because there were other psychosocial stressors present that could account for the symptoms, and these patients were continued on, or retreated with, isotretinoin without a recurrence of their depressed mood.  Whether the symptoms in the other 3 people were due to isotretinoin or other factors was not clear.  No depression was reported in the antibacterial group.  The Beck Depression Inventory scores for the two groups did not differ significantly during the treatment period.  The small number of people with depression and the difference in acne severity between the groups at the start of the study mean that the results are not robust and cannot be generalised to all patients.

Prospective randomised controlled studies would be needed to resolve whether isotretinoin makes depression more likely.  Since any additional risk, if present, appears small, a trial would probably need several thousand patients in each of the two arms to detect an effect.  Also, such trials would be difficult because withholding a drug of proven efficacy is likely to be ethically unacceptable and it would be difficult to blind participants due to the efficacy and unwanted effects of the drug.

Is isotretinoin overprescribed?

Dermatologists from several countries have recommended that, given isotretinoin's efficacy, the drug should also be prescribed to patients with mild or moderate acne.²¹  In keeping with this, a recent overview of the use of isotretinoin in the USA reported that isotretinoin is being used there for mild to moderate acne, increasing the population exposed to the drug and potentially to its unwanted effects.²²

Published advice on use

The current UK summary of product characteristics (SPC) from Roche (last revised January 2002) contains a warning that "Roaccutane may cause depression, psychotic symptoms and rarely suicide attempts and suicide.  Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary."²³  We have been advised by the company that the wording in the SPC is currently under review.  [In New Zealand, the data sheet for Isotane states that "Depression, psychosis and rarely, suicidal ideation and attempts have been reported in patients treated with isotretinoin.  Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary.  Although no mechanism of action for these events has been established, discontinuation of therapy may be insufficient and further evaluation by a psychiatrist may be necessary."^A]

Current guidelines from the British Association of Dermatologists conclude that whether isotretinoin can produce mood change is unproven.²⁴  However, they also include the following recommendations:

"A direct enquiry about previous psychiatric health should be made of all patients who are being considered for isotretinoin and the facts recorded fully in the notes.  All patients, and their parents in the case of minors and adolescents, should be made aware of the potential for mood change in a realistic, non-judgemental way, and should be advised to ask their family and friends to comment if such change should occur.  Direct enquiry about psychological symptoms should be made at each clinic visit.  If symptoms of depression or mood change do occur, then ideally, isotretinoin treatment should be discontinued. However, some patients, after discussion, may wish to continue with the drug because of the benefit to their skin.  In this case, specialist psychiatric support should be obtained. If serious psychiatric illness is suspected, there should be an immediate referral to the psychiatric services."

Healthcare professionals, and especially prescribers of isotretinoin, should be aware of the potential problems of depression among people with acne, and monitor for such symptoms.  A history of depression is not an absolute contraindication to the use of isotretinoin, but the patient needs to be fully aware that symptoms might worsen on treatment.  Any new episode of depression which occurs also requires close monitoring and treatment.  All those in primary care directly involved in treating the patient (e.g. GP, nurse practitioner) need to be informed of any mood changes to allow a collaborative approach to management.  If severe mood changes do occur while using the drug, specialist psychiatric support is advisable, with referrals being made urgently if there is an immediate concern about suicide.  Less severe symptoms of depression could be managed by the GP or the community mental health team.  Counselling and support may also be available from voluntary agencies (such as the UK Acne Support Group: www.m2w3.com/acne/).  Psychiatric follow-up (by a specialist or in primary care) may need to be continued beyond the duration of isotretinoin therapy.

Conclusion

Oral isotretinoin is an effective treatment for patients with severe acne, but concerns have been raised that it may occasionally cause depression.  However, retrospective studies have failed to demonstrate a clear relationship between isotretinoin and depression, and the few available prospective studies have lacked the power to identify such an association.  Large randomised prospective studies of sufficiently long duration would be required to quantify any risks and weigh these against the benefits of isotretinoin.  These studies would be difficult to carry out as they would inevitably deny some patients an accepted treatment, and blinding of treatment allocation would be difficult to achieve.

Clinicians should be alert to the high prevalence of depression among people with acne, and discuss these issues with patients and their carers before and during treatment.  Because of its many unwanted effects, including a possible but unproven effect on mood, isotretinoin should ideally be reserved for patients with severe acne which has not responded to other therapies (and should only be prescribed by dermatologists).  If depression or other mood change occurs, then, ideally, isotretinoin treatment should be discontinued.  If treatment is continued, psychiatric support should be obtained.  If serious psychiatric problems occur, the patient should be referred to a psychiatrist immediately.

References

1. Cordain L et al. Acne vulgaris. A disease of Western civilization. Arch Dermatol 2002;138:1584-90.
2. Jones H. Acne vulgaris. Med Int 1992;103:4340-3.
3. Jick SS et al. Isotretinoin use and risk of depression, psychotic symptoms, suicide and attempted suicide. Arch Dermatol 2000;136:1231-6 .
4. Leyden JJ. Therapy for acne vulgaris. N Engl J Med 1997;336:1156-62.
5. 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.
6. Rubinow DR et al. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987; 17: 25-32.
7. Wysowski DK et al. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515-9.
8. Pochi PE et al. Report of the consensus conference on acne classification. J Am Acad Dermatol 1991;24:495-500.
9. Joint Formulary Committee. British National Formulary. Edition 46. London:Royal Pharmaceutical Society of Great Britain and British Medical Association, September 2003.
10. Tsukada M et al. 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol 2000;115:321-7.
11. Isotretinoin. Summary of product characteristics, UK. Schering Health Care Limited, July 2002.
12. Wessels F et al. The cost-effectiveness of isotretinoin in the treatment of acne. Part 1. A meta-analysis of effectiveness literature. S Afr Med J 1999;89:780-4.
13. Ng CHN, Schweitzer I. The association between depression and isotretinoin use in acne. Aust N Z J Psychiatry 2003;37:78-84.
14. Lewinsohn PM et al. Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clin Psychol Rev 1998;18:765-94.
15. 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.
16. Cotterill J, Cunliffe WJ. Suicide in dermatological patients. Br J Dermatol 1997;137:246-50.
17. Mild depression in general practice: time for a rethink? DTB 2003;41:60-4.
18. Wysowski DK, Beitz J. Methodological limitations of the study "Isotretinoin use and risk of depression, psychotic symptoms, suicide and attempted suicide". Arch Dermatol 2001;137:1102-3.
19. Hersom K et al. Isotretinoin and antidepressant pharmacotherapy: a prescription sequence symmetry analysis. J Am Acad Dermatol 2003;49:424-32.
20. Ng CH et al. Prospective study of depressive symptoms and quality of life in acne vulgaris patients treated with isotretinoin compared to antibiotic and topical therapy. Aust J Dermatol 2002;43:262-8.
21. Cunliffe WJ et al. Roaccutane treatment guidelines: results of an international survey. Dermatology 1997;194:351-7.
22. O'Donnell J. Overview of existing research and information linking isotretinoin (Accutane), depression, psychosis, and suicide. Am J Ther 2003;10:148-59.
23. Roaccutane. Summary of product characteristics, UK. Roche Products Limited, February 2002.
24. British Association of Dermatologists. Isotretinoin. Advice on the safe introduction and continued use of isotretinoin in acne [online]. Available: www.bad.org.uk/doctors/guidelines/isotretinoin.htm [Accessed 25 September 2003].

References for New Zealand-specific notes

1. Pacific Pharmaceuticals Ltd. Isotane data sheet 23 February 2004. www.medsafe.govt.nz/Profs/Datasheet/I/Isotanecap.htm
2. Pharmaceutical Management Agency (Pharmac). New Zealand Pharmaceutical Schedule December 2004.

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