Isotretinoin under the spotlight again
Published in Health News and Evidence
Date published: About this date
Practice points | Suicide claims in the UK | The isotretinoin–suicide theory | What is the evidence? | What does it all mean? | What are the implications for clinical practice? | Isotretinoin at a glance | Other resources
There have been renewed claims in the UK that the acne medicine isotretinoin may be linked to suicide.
The UK Commission on Human Medicines will conduct a review of isotretinoin in response to these claims. Australian authorities will wait for these results before making any judgements on its safety.
Existing Australian guidelines for the safe use of isotretinoin already include assessment and monitoring of patients for signs of depression and potential suicide risk.
- Assess patients for signs of depression or suicidal thoughts before starting treatment with isotretinoin.1,2
- Do not automatically exclude patients from treatment with isotretinoin because of a pre-existing psychiatric diagnosis or depression symptoms.1,3
- Counsel patients starting isotretinoin treatment — and, if appropriate, their family — to be mindful that depression and suicidal thoughts,1 though uncommon, may occur.2,4,5
- Monitor patients for signs of depression and suicidal thoughts throughout the course of treatment with isotretinoin.2,4
- Be aware that treatment with isotretinoin may not necessarily need to be permanently discontinued if a patient develops signs of depression, suicidal thoughts or other psychiatric symptoms.3,5
- Refer patients with signs of serious depression, suicidal thoughts or other psychiatric signs promptly for appropriate psychiatric follow up.5
The UK Commission on Human Medicines will perform a review of the acne drug isotretinoin following new claims linking its use to teenage suicide.6
The isotretinoin brand Roaccutane (Roche) has been named as a suspected cause of 14 deaths by suicide in the UK over the last five years.6
The Product Information (PI) for Roaccutane alerts health professionals to possible psychiatric symptoms that may occur while using the drug, and emphasises that there has been extensive worldwide use and that for most people these adverse effects have not occurred.6,7
A spokesperson for the Medicines and Healthcare Products Regulatory Agency (MHRA), the administering body for the Commission on Human Medicines, said:
"No medicine is without risk and isotretinoin is no exception. Since it was licensed in the UK in 1983, the MHRA has kept the safety of isotretinoin under close review. Although isotretinoin is an effective treatment for severe acne, it has important side effects.
"Before starting treatment patients should inform their doctor if they have, or have ever had, depression. During treatment, family and friends may be able to help the patient monitor their mood, and the doctor will ask about any changes in mood during follow up appointments. If a patient receiving isotretinoin develops symptoms of depression or mood changes it may be necessary for isotretinoin treatment to stop.
"An expert advisory group of the Commission on Human Medicines will start a review on isotretinoin at the end of July to evaluate psychiatric adverse reactions associated with isotretinoin. It is considered timely to review the available data regarding the risk of psychiatric adverse reactions associated with isotretinoin, to evaluate their impact on the risk benefit balance, to consider whether further action is required to minimise these risks and to ensure that the product information effectively communicates the risks to healthcare professionals and patients." (email correspondence from MHRA, 24 July 2014)
The Therapeutic Goods Administration (TGA) in Australia is aware of the proposed European review and will wait for the results of the UK Commission before deciding on whether further review is necessary.6
Systemic isotretinoin is fat-soluble and easily crosses the blood–brain barrier, acting at retinoid receptors in brain tissue and interfering with neurotransmitter systems that regulate mood and emotions.10,11
An association between isotretinoin treatment and depression and suicidal behaviour has been suggested, but no definite link has been demonstrated.13
A recent observational study3 reported a rise in the risk of attempted suicide in patients both on treatment and after treatment with isotretinoin (incidence ratio 1.57, 95% confidence interval 0.86 to 2.63).3 However, the risk of attempted suicide was increasing before the treatment was started, so it could not be established whether the increased risk during and after treatment was because of isotretinoin.3,5 A relationship has also been suggested by numerous case reports,5,14-16 but an evidence-based causality has not been demonstrated.2,10,17-20
A large systematic review from 2007 (nine studies, n = 33,588) did not show a statistically significant increase in depression symptoms in patients treated with isotretinoin for acne. No correlation between use of the medicine and suicidal behaviour was identified, but the authors acknowledged that the data are limited, with only one retrospective study available.18. Other studies have reported that isotretinoin may, in fact, have a protective effect against depression.9,18,19
Acne, depression, and suicide
It is well established that individuals with acne vulgaris are more likely to suffer from psychiatric disorders (such as depression, anxiety and social phobia) than people without a diagnosis of acne.1,9,20-22 Suicidal thoughts and attempts are also around twice as common in people with acne than those without acne.1 Existing research into treatment with isotretinoin and depression and suicide risk has not succeeded in clearly distinguishing between mood change due to the drug and due to the acne itself.10,22
Improvement in mood with treatment
A number of studies have demonstrated improvements in mood, and even the resolution of depression symptoms, during the course of isotretinoin treatment.10,19 Although this cause and effect relationship is not proven, it may reflect that successful treatment of acne and subjectively improved facial appearance results in decreased levels of anxiety and depression.1
Pre-existing psychiatric diagnosis
It is not possible to predict which patients treated with isotretinoin will develop symptoms of mental illness.1 Evidence of whether a pre-existing diagnosis of depression, or past suicide attempts are related in any way to psychiatric symptoms during treatment with isotretinoin is meagre and conflicting.4
A case series of 300 patients with bipolar disorder found that patients with a pre-treatment psychiatric diagnosis or a family history of psychiatric disorder are at greater risk of developing symptoms of depression during isotretinoin therapy.5 The study also found that, nine out of ten patients with a pre-treatment diagnosis of bipolar disorder who had been treated with isotretinoin experienced worsening of symptoms of depression during treatment. Eight of the nine patients had improvement in mood on discontinuing the medicine.5
By contrast, a retrospective cohort study found that patients with a history of suicide attempts made relatively fewer new attempts than patients whose suicidal behaviour started in connection with isotretinoin treatment.3 Several reports of severe, idiosyncratic psychiatric symptoms in patients with no pre-treatment psychiatric diagnosis may possibly also challenge the assertion of a relationship between isotretinoin therapy, depression and suicide, and pre-existing psychiatric diagnosis.5,8,10,19
Overall, the conflicting results of a very heterogeneous collection of studies are not adequate to draw final conclusions about a relationship between isotretinoin, depression and suicide.10
Patients treated with isotretinoin will not necessarily experience worsening depression symptoms regardless of whether they have a history of depression.20 Without a way to determine which patients may be at risk of developing psychiatric symptoms during treatment, ongoing communication with all patients undergoing treatment is necessary.1,4
If clinically significant symptoms of depression or suicidal thoughts are identified in a patient who is taking isotretinoin, consult the prescribing dermatologist and refer the patient for psychiatric assessment and support if necessary.1,9,19 Consider stopping treatment based on individual circumstances,1 but in patients on continuing treatment maintain monitoring for psychiatric symptoms.3
Despite the lack of clear evidence on whether there is a causative relationship between the isotretinoin and these symptoms Australian and international guidelines, and published literature, support the use of isotretinoin to treat severe cystic acne unresponsive to other therapy when accompanied by an appropriate level of assessment and monitoring for signs of depression and suicidal thoughts.2,4,5,13,17
Studies of mood change have found that while on isotretinoin overall mood and wellbeing usually improve as acne improves.4
Assess patients starting isotretinoin therapy for signs of depression and suicidal thoughts.1,2,5 Routine clinical assessment and/or a validated instrument, such as the Kessler Psychological Distress Scale (K10), will provide a baseline of symptoms for comparison once isotretinoin treatment has started.1
Young people are particularly affected by depression and the condition is more common in young people with acne. Many acne patients, particularly adolescents, will be depressed before starting isotretinoin treatment.10,13 But psychiatric symptoms, or even a previous diagnosis of depression or a suicide attempt, do not necessarily preclude isotretinoin therapy.1,3
When to stop treatment
If clinically significant mood changes are identified, isotretinoin treatment should be stopped.23 However, some individuals may want to continue with treatment and may be able to do so with the agreement of their dermatologist and under the supervision of a psychiatrist.5,10
Do not assume that symptoms of depression and suicidal thoughts will resolve simply by stopping treatment with isotretinoin as there may be no causal relationship.13 Assess patients who stop isotretinoin treatment due to depressive symptoms; monitor these patients for depression and risk of suicide and refer for formal psychiatric management if necessary.13
Oral isotretinoin is a systemic retinoid and vitamin A analogue.13 It has been demonstrated to be an effective treatment for severe acne,9,17 having been used by around 17 million people globally6 with a relapse rate of 10–20%.4 It works by modulating cell proliferation and differentiation. It also reduces skin inflammation, formation of cysts, sebum excretion, and the number of Propionibacterium acnes bacteria.4
PBS listing and indications
Isotretinoin is PBS listed as Authority Required (Streamlined) for the treatment of severe cystic acne unresponsive to other therapy,24 it can only be prescribed by a specialist physician or dermatologist25 for the treatment of adults or children >12 years.4
- Rowe C, Spelman L, Oziemski M, et al. Isotretinoin and mental health in adolescents: Australian consensus. Australas J Dermatol 2014;55:162–7. [Pubmed].
- European Dermatology Forum. Guideline on the treatment of acne (ICD L70.0). 2011. [Fulltext].
- Sundstrom A, Alfredsson L, Sjolin-Forsberg G, et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 2010;341:c5812. [Pubmed].
- Australian medicines handbook. Adelaide, SA: Australian Medicines Handbook Limited, 2014. [Online] (accessed 3 July 2014).
- Goodfield MJ, Cox NH, Bowser A, et al. Advice on the safe introduction and continued use of isotretinoin in acne in the UK. 2010. Br J Dermatol 2010;162:1172–9. [Pubmed].
- Dunn E. Acne drug under scrutiny after suicide claims. Medical Observer. Chatswood, NSW: Cirrus Media Pty Limited, 2014. [Online] (accessed 3 July 2014).
- Roche Products Pty Ltd. Roaccutane - consumer medicine information. 23 April 2013. [Online].
- Costa CS, Bagatin E, da Silva EMK, Lucio MM, Magin P, Riera R. Oral isoretinoin for acne (Protocol). Cochrane Collaboration 2011. [Fulltext].
- Wolverton SE and Harper JC. Important controversies associated with isotretinoin therapy for acne. Am J Clin Dermatol 2013;14:71–6. [Pubmed].
- Borovaya A, Olisova O, Ruzicka T, et al. Does isotretinoin therapy of acne cure or cause depression? Int J Dermatol 2013;52:1040–52. [Pubmed].
- Jentsch JD, Roth RH and Taylor JR. Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drug action. Prog Brain Res 2000;126:433–53. [Pubmed].
- Thiboutot D, Zaenglein A. Isotretinoin and affective disorders: thirty years later. J Am Acad Dermatol 2013;68:675–6. [Pubmed].
- Therapeutic Guidelines. Dermatology eTG42, 2014. eTG. Melbourne, Victoria: Therapeutic Guidelines Ltd, 2014. [Online] (accessed 3 July 2014).
- Segmiller FM, Ruther T, Linhardt A, et al. Psychosis during treatment with isotretinoin. Ther Adv Psychopharmacol 2013;3:244–5. [Pubmed].
- 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. [Pubmed].
- Gatti S, Serri F. Acute depression from isotretinoin. J Am Acad Dermatol 1991;25:132. [Pubmed].
- American Academy of Dermatology and AAD Association. Position statement on isotretinoin. 2010. [Pubmed].
- Marqueling AL and Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2007;26:210–20. [Pubmed].
- Nevoralova Z, Dvorakova D. Mood changes, depression and suicide risk during isotretinoin treatment: a prospective study. Int J Dermatol 2013;52:163–8. [Pubmed].
- Sullivan JR. Oral isotretinoin. Aust Prescriber 2005;28:59–61. [Online].
- Cook D, Krassas G and Huang T. Acne - best practice management. Aust Fam Physician 2010;39:656–60. [Pubmed].
- Halvorsen JA, Stern RS, Dalgard F, et al. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol 2011;131:363–70. [Pubmed].
- See J. Drug treatment of acne. Australian Prescriber 2012;35:180–2. [Online].
- Pharmaceutical Benefits Scheme (PBS). Anti-acne preparations for systemic use. Canberra, ACT: Commonwealth of Australia, 2014. [Online] (accessed 3 July 2014).
- eMIMS Cloud. Roaccutane (Isotretinoin). St Leonards, NSW: MIMS Australia, 2014. [Online] (accessed 3 July 2014).