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.
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.
