Abstract
There is currently considerable controversy regarding a proposed causal relationship between the use of isotretinoin and depression and suicide. A search was made of the MEDLINE, EMBASE and PsychINFO databases using the search terms ‘isotretinoin’, ‘depression’ and ‘suicide’. Despite numerous case reports linking isotretinoin to depression, suicidal ideation and suicide, there is, as yet, no clear proof of an association. While isotretinoin, used to treat acne vulgaris, has not been demonstrated to be associated with depression or suicide, the possibility of a relatively rare idiosyncratic adverse effect remains. GPs have a role in the clinical application of these findings.
INTRODUCTION
Isotretinoin is an efficacious and widely-used therapy for severe acne.1,2 Its introduction has been hailed as ‘an incredible triumph … in the treatment of acne vulgaris’.3 But it is recognised as having a wide range of adverse effects. The most notable of these is teratogenicity,3 but mucocutaneous, ophthalmic, and musculoskeletal effects and effects on plasma lipids and liver function tests are also acknowledged side effects.1,2,4 The relationship of isotretinoin to depression and suicide is more controversial and will be discussed in this article.
METHOD
Searches were made of the MEDLINE, EMBASE and PsychINFO databases. Search terms used were isotretinoin, depression and suicide. The search was confined to English language articles. Reference lists of identified articles were examined for further relevant studies. There were no pre-specified quality criteria for study inclusion. Given the relative paucity of methodologically rigorous studies in this area, and the considerable influence on current practice of case reports, no evidence was excluded on methodological grounds.
RESULTS
Warnings regarding isotretinoin, depression and suicide
In 1998 the US Food and Drug Administration (FDA) issued a warning to physicians regarding a possible association with depression, psychosis, suicidal ideation and suicide.5,6 The FDA recommends the use of signed informed consent forms and a printed patient medication guide for patients prescribed isotretinoin.7,8 The FDA's 1998 warning was noted in the Lancet as being in response to a ‘possible connection … although there is no evidence’.9
What is the evidence for an association?
Case reports
A number of case reports and case series linking isotretinoin to depression or suicide have appeared in the medical and psychological literature since 1982.10-19 Between 1982 and 2000 the FDA has received reports of 394 cases of depression, and 37 suicides occurring in patients exposed to isotretinoin.7,20 It is the fifth most common drug reported to the US Adverse Event Reporting System (AERS) in association with depression, and the tenth most common (and the only non-psychotropic drug) in suicide reports.7 In Canada, psychiatric adverse effects in patients taking isotretinoin have been reported to Health Canada21 — 56 events between 1983 and 2003.22 Forty-two psychiatric reactions were reported to the British Medicines Control Agency between 1982 and 1998,23 including a small number of suicides.24 In Australia from 1995 to 1998 the Adverse Drug Reactions Advisory Committee received 12 reports of depression in patients taking isotretinoin.25 Two cases were described as severe, in four there were psychotic features, in three there was suicidal ideation and there were three suicide attempts (with one completed suicide).
In a number of these case reports, including 25 documented by the FDA,7,20 cessation of the drug has been associated with resolution of the mood disturbance and reinstitution of treatment has been followed by recurrence of depression.
But pitfalls inherent in making inferences of causality from case reports or case series are illustrated by the case reported by Kovacs and Mallory.26 They describe a 17-year-old Korean boy who developed mood and behaviour changes while taking isotretinoin. Symptoms resolved with isotretinoin withdrawal, but re-emerged with rechallenge, and the boy's psychological morbidity was attributed to isotretinoin. It later emerged that the boy's symptoms also coincided with periods of recreational LSD and cannabis use.
Secondary analyses of large data sets
Jick et al27 analysed data from the Canadian Health Database and the UK General Practice Research Database and found no increase in relative risk of incident depression, psychosis, suicide or attempted suicide in users of isotretinoin over users of antibiotics for acne. Similarly, there was no increase in relative risk of these outcomes for prior treatment with isotretinoin versus post-treatment. This was an industry-sponsored study and its methodology has been criticised.28 Specifically, possible underascertainment of psychiatric disorder and suicide, the lack of a non-acne control group, a lack of power for detecting differences in suicide rates, and lack of consideration of acne severity or of isotretinoin dose and duration were claimed to be methodological shortcomings.28
Hersom et al29 performed a retrospective prescription sequence symmetry analysis of isotretinoin and antidepressant pharmacotherapy using a large US database (examining which drug was prescribed first in patients prescribed both isotretinoin and an antidepressant) and demonstrated no support for an association between the use of isotretinoin and the onset of depression.
Wyskowski et al observed that a statistical data mining analysis of all adverse events and drug combinations in the AERS database had calculated that six reports of suicide were expected for isotretinoin compared with the 36 suicides actually reported7 (Table 1).
Assessments of depression as an adverse event in clinical trials and follow-up of treatment with isotretinoin
Prospective Canadian30 and US31 studies found an incidence of depression in patients during a course of isotretinoin therapy of 4% and 11%, respectively. However, these trials were uncontrolled and depression was self-reported in response to a questionnaire item. There was no objective measure of depression. The study of Scheinman et al12 has been quoted as finding an 1% incidence of depression in isotretinoin therapy,26 but did not specifically examine for depression or other psychiatric morbidity. It describes seven patients who spontaneously reported depressive symptoms during clinical trials of isotretinoin, and is best considered a case series (and is cited as such above). A British study32 elicited no long-term side effects of isotretinoin in 88 patients up to 10 years post-therapy, but the authors do not seem to have specifically enquired about depression or other psychiatric effects. Similarly, Goulden et al33 reported on 720 patients who had received one or more courses of isotretinoin and were followed up every 4–6 months for 2–12 years. They found only three cases of depression occurring in this population (all occurring in patients with dysmorphophobia and mild acne). But this was an uncontrolled study and, while adverse effects of the medication were enquired about generally, depression and suicidal ideation were not among the side effects specifically asked about. A further study of adverse effects in 466 isotretinoin recipients in the US34 recorded no instances of depression or other psychiatric effects, but this was a study of data abstracted from clinical notes for self-reported side effects rather than an examination of psychiatric morbidity.
McLane35 reports incidence of ‘psychiatric disorders’ as adverse events of isotretinoin therapy as being 0% and 0.3% in industry-sponsored trials with 69 and 300 subjects, respectively. But these trials were uncontrolled, and the means of ascertainment of psychiatric disorder is not specified (Table 1).
Improvement in depression in clinical trials with isotretinoin
A number of studies have demonstrated an improvement in depression scores in patients with acne during and/or after treatment with isotretinoin.36-38 Interpretation of these treatment studies with regard to the direction of causality in the association between acne and depression is limited by them being uncontrolled and/or not correlating changes in depression with changes in acne severity.
DISCUSSION
Further considerations
A plausible biological mechanism underlying the proposed causative relationship — the effect of retinoids on brain dopamine systems39,40 — has been suggested, although this remains speculative. Etretinate, another retinoid used as therapy in cutaneous disease, has been linked in case reports with depression.41 Additionally, it has been suggested that hypervitaminosis A is associated with psychiatric symptoms including depression, and hypervitaminosis A syndrome has been proposed as a paradigm of retinoid side effects.17,42 Other ‘neuropsychological’ adverse effects — irritability, emotional lability, amnesia, abnormal thinking, headache, fatigue, lethargy, pseudotumour cerebri, incoordination and sustained dreaming — have been reported with use of isotretinoin.1,2,21,30,31,34,35,43
How this fits in
There is currently a controversy regarding the risk of depression and suicide in treatment with isotretinoin. The controversy, thus far, has largely by-passed the general practice audience, but has significant implications for general practice approaches to the management of acne vulgaris.
It is likely that the surveillance systems cited above underestimate the true incidence of adverse effects. However, the background incidence of depression, suicide attempts and completed suicide in adolescents, and the number of patients who have used the drug must also be considered when interpreting the significance of case reports and adverse event monitoring in isotretinoin therapy. Over 8 million patients had used isotretinoin worldwide by 1998.5 The 12-month prevalence of major depression in the US has been found to be 10.3% and of dysthymia to be 2.5% in a major study,44 although prevalence has been somewhat lower in some studies.45 Thirty–day prevalence among adolescents and young adults of major depression was 5.8% and minor depression was 2.1%.46 Depression is more common in the age group affected by acne than in the general population.44,45,47 In 1994, the US suicide rate was 12 per 100 000 population.48 Reported lifetime suicidal ideation in the US is 13.5% and lifetime prevalence of suicide attempt is 4.6%.49 In prospective studies of US50 and Norwegian51 high school students, the 12-month incidence of suicide attempt was 1.7% and 1.3 %, respectively.
It has also been suggested that many of the reported depressive adverse effects in isotretinoin therapy represent depressive or mood symptoms rather than major depression or other clinical depression syndromes.52 In this context it should be noted that an Australian population-based study of high school students has shown 19% of students without clinical depression to have depressed mood.53 Significantly, while in some of the case reports and study findings of depression cited in this review the diagnosis was confirmed by psychiatric opinion,13,14,17,18 others seemed not to be,10,11,19,30,31 while in one case series some diagnoses were psychiatrist-confirmed and some were not.12
Prospective, controlled trials to examine the relationship might seem to be apposite. But recruitment of adequate numbers of subjects into studies powered to detect an increase in suicide would be a daunting prospect. Controlled trials of depression and suicidal ideation may also be problematic — it has been suggested that, given the superior efficacy of isotretinoin and the propensity for severe acne to cause permanent scarring, a randomised trial of isotretinoin compared with a less efficacious control in severe acne would be unethical.32 In this situation, large case-control studies would be welcome.
The context of the debate
While acne may have been, in some quarters, considered a trivial complaint, there is convincing evidence that this is not so. Case reports have suggested depression as a sequela of acne.54 Studies have suggested acne is associated with greater mental health impairment than asthma, epilepsy, diabetes, back pain or arthritis.55 Acne has been associated with depression,56-59 suicidal ideation56 and (in a case series) with suicide,60 along with a number of other psychological problems — anxiety, self-consciousness, emotional difficulties and embarrassment.38,61-66 Studies of treatment with isotretinoin show improvements in depression scores following treatment (as above). The balance of evidence suggests that acne is associated with considerable psychological morbidity, possibly including depression, and that acne is more likely to cause psychological morbidity than to be caused by it.
In fact, the presence of psychological distress in a patient with acne has been proposed as an indication for a more aggressive approach to acne treatment, including the use of isotretinoin.67
Interpretation of the available evidence and the clinical context
The evidence in this area is incomplete. The incidence of depression and suicide during isotretinoin therapy may be no greater than the background incidence. A causal relationship between isotretinioin and psychiatric morbidity, including depression and suicide, has not been demonstrated. In fact, there is evidence that acne itself is associated with psychiatric morbidity and that isotretinoin may attenuate the effect of acne on this psychiatric morbidity. Nevertheless, major depression and suicidal ideation occurring as an idiosyncratic reaction to isotretinoin, as suggested by case reports, remains a possibility — although, if so, this would seem to be a relatively rare occurrence.
Relevance to general practice
In Australia and the UK isotretinoin is not prescribed by GPs.32,68 In the US, many family physicians choose not to prescribe it.69 Referral of patients with acne who would benefit from isotretinoin is the responsibility of the GP, and, therefore, the debate about isotretinoin and depression and suicide in the media,70,71 is of vital interest. GPs are in a position not only to make suggestions or recommendations to patients regarding referral for consideration of isotretinoin treatment, but also to ensure patient decisions are based on a realistic understanding of the benefits and risks of therapy.
It would seem prudent to carefully monitor patients undergoing treatment with isotretinoin for evidence of depression or suicidal ideation. GPs are likely to be better equipped than dermatologists to do so,72-74 and to further manage, or refer for specialist psychiatric care, any emergent psychiatric symptoms or psychological morbidity. A close partnership between dermatologist and GP on a ‘shared-care’ basis is likely to be optimal in this situation.
Conclusions
Consideration of the limited data available would suggest that the incidence of depression and suicide during isotretinoin therapy may be no greater than the background incidence. A causal relationship has not been demonstrated. The occurrence of an idiosyncratic reaction to isotretinoin producing major depression and suicidal ideation, as suggested by case studies, remains a possibility — although, if so, this would seem to be a relatively rare occurrence. Given the evidence suggesting that isotretinoin treatment may attenuate psychiatric associations of acne, and given the evidence that acne is often not a trivial complaint, withholding therapy because of concerns regarding depression or potential for suicide is not justified. Nevertheless, there are grounds for carefully monitoring patients undergoing treatment with isotretinoin for the emergence of depressive and suicidal ideation. Ideally, the patient's GP, as well as their dermatologist, should be involved in this surveillance.
Supplementary Material
Notes
Funding body and reference number
This article was written with support from a NHMRC post-graduate medical scholarship and a NSW Primary Health Care Research Bursary
Competing interests
None
- Received March 18, 2004.
- Revision received May 28, 2004.
- Accepted July 1, 2004.
- © British Journal of General Practice, 2005.