The common skin condition of acne has been associated with considerable morbidity, particularly psychiatric and psychological, but one of the most efficacious treatments, isotretinoin, has raised concerns about whether it’s related to psychiatric morbidity, including suicidality.
Australian experts Parker Magin, PhD1, and Shaun Prentice, PhD2, in an editorial in JAMA, refer to a meta-analysis led by the University of Singapore, published in JAMA Dermatology, about the drug, and conclude, like the researchers, that discussing the (rare) risks with patients, and psychiatric monitoring during treatment, are recommended.
In their study, the authors had said that while there are many treatments for acne, isotretinoin, particularly, is unique. It is efficacious and can result in a durable improvement in the condition.
But it can also be associated with various side effects, including mucocutaneous dryness, photosensitivity, and musculoskeletal symptoms, among others.
In particular, there have been concerns and controversy regarding whether isotretinoin is associated with psychiatric morbidity, including suicidality.
Magin and Prentice write:
In this issue of JAMA Dermatology, Tan et al report further evidence relevant to this contentious area of study.
In a systematic review of observational studies (mainly cohort studies) of patients treated for acne, they investigated the incidence and relative risk of suicide and psychiatric disorders (for one-, five-, and 10-year periods post treatment).
Meta-analyses were performed for the one-year incidence of the outcomes and for relative risk at a range of times post-treatment for a suite of psychiatric outcomes, including completed suicide, suicide attempt, suicide ideation, self-harm, all psychiatric disorders, anxiety, psychotic disorders, sleep disorders, depression, mood disorders, and bipolar disorder.
The authors also performed meta-regression for one-year incidence of depression and for one-year incidence of completed suicide.
Tan et al used a rigorous and comprehensive search strategy while also hand-checking the reference lists of included articles.
Although there is some uncertainty regarding the effectiveness of their strategies to optimise consistency in record screening and data extraction, the authors thoroughly assessed the reporting quality of included articles and took a balanced approach to consider the implications of methodological limitations for both included studies and their own review.
Furthermore, the statistical approach taken was justified, with the use of meta-regression to assist with understanding the role of participant- and study-level factors in contributing to the heterogeneity in the outcomes.
Regarding the findings of incidence of the various psychiatric outcomes, the authors report results for attempted suicide and depression incidence comparable with previous studies in the general populations of adolescents and young adults.
In the two meta-regressions performed, older age was associated with a lower one-year incidence of depression, and male sex was associated with a higher one-year incidence of completed suicide.
The review also cited two individual studies of isotretinoin users which found that a psychiatric history was associated with incident psychiatric disease and suicide attempt and that a cumulative dose of isotretinoin was associated with a lower risk of suicide attempt.
The findings of most clinical relevance are those of relative risk for suicide and psychiatric disorders.
There was no significant increased risk of any of the suicide or psychiatric outcomes in patients taking isotretinoin.
Patients taking isotretinoin were significantly less likely than non-users to attempt suicide at three, four, and five years after isotretinoin treatment, with there being no difference during treatment, at six months, and at one, two, and 10 years after treatment.
The question, then, is, what are the implications for clinicians managing acne?
The big-picture implication can be framed fairly clearly. Tan et al state that their meta-analysis showed no increased epidemiologic risk of suicide or depression among isotretinoin users.
This conclusion is reasonable, but, as the authors caution, there are some caveats to the statement in terms of translation to practice. They have been careful to stress that the effect sizes of a number of the estimates have wide CIs and that a level of uncertainty remains for these particular associations.
There is also, as the authors note, considerable potential for bias operating in these observational studies. It is not possible, however, to know how much individual study biases influence the findings, or even in which direction.
Overall, the totality of the findings, with previous evidence around a lack of association of isotretinoin use with depression (for which there is some evidence of improvement with isotretinoin treatment) or anxiety, is broadly reassuring.
It seems clear that patients with severe or markedly problematic acne (as defined in current guidelines) can be offered isotretinoin as a treatment option for this often distressing condition.
The confidence of the recommendation, in terms of psychiatric safety, is based on, as Tan et al remark, epidemiologic risk. There remains, though, concern about granularity in the data that these epidemiologic analyses may not detect.
The basis of this concern is that psychiatric sequelae of isotretinoin use are biologically plausible and that there have been numerous rechallenge case studies to suggest a causal relationship.
These considerations should be taken with the epidemiologic evidence of treatment with isotretinoin not having an overall (treatment population level) adverse effect on psychiatric outcomes and possibly improving some psychiatric outcomes, both of which are not unexpected for an efficacious treatment of a condition associated with considerable psychiatric morbidity.
One could conclude that it is plausible that isotretinoin has markedly adverse, idiosyncratic psychiatric effects in a small minority of individual patients. It is also plausible that these presumably rare occurrences are not detectable in studies where the majority of patients experience no adverse psychiatric outcomes or even positive outcomes.
The challenge, then, for clinicians is determining which patients with acne may be at risk of such reactions.
In their meta-regressions, Tan et al found younger age at isotretinoin initiation to be associated with a higher risk of depression and male sex to be associated with a higher risk of completed suicide.
In a French population-based comprehensive case series and nested case-control study, psychiatric history, especially anxiety, was a risk factor for suicide attempt.
But restricting isotretinoin use on the basis of age or sex is not practicable. The psychiatric impacts of acne (including anxiety) are considered an indication for isotretinoin therapy in patients whose acne severity in and of itself may not have warranted isotretinoin treatment.
Furthermore, these risk factors for psychiatric morbidity during isotretinoin therapy are so common as not to be useful markers of the need for targeted psychiatric surveillance.
As the authors suggest, discussing with patients the possible, albeit apparently rare, psychiatric adverse effects of the drug and having a degree of psychiatric monitoring (and prompt review in the event of emerging symptoms) for all patients seems a reasonable approach.
Just how this surveillance may be best achieved is open to debate, and there is a strong argument that the prescribing dermatologist may not be the clinician best placed to do this.
Dermatologists generally have limited psychiatric expertise.
General practitioners have the requisite experience in detecting and managing psychiatric morbidity and may be able to treat the patient’s acne within a broader context (including the necessary contraception for female patients taking isotretinoin).
A shared care model of dermatologist and GP would be ideal. Whether or not a more formal shared care model is considered appropriate, there is sound rationale for dermatologists screening for psychiatric morbidity in patients prescribed isotretinoin, using patient-reported outcome measures, such as the Patient Health Questionnaire-2 and the Patient-Reported Outcomes Measurement Information System Depression Bank.
Patients with positive screening results would be referred for appropriate care as per, for example, the management algorithm suggested by McDonald et al.
Thus, Tan et al have added usefully to the literature in this area, but their findings are far from the final word. The psychiatric conditions associated with acne and, in turn, proposed to be precipitated by isotretinoin, are many and complex.
Randomised controlled trial findings are of limited utility. Observational studies of this question are subject to multiple potential biases.
Clinicians, though, can take some degree of further reassurance from this extension of the literature around the psychiatric sequelae of isotretinoin.
Study details
Risk of Suicide and Psychiatric Disorders Among Isotretinoin UsersA Meta-Analysis
Nicole Kye Wen Tan; Adelina Tang; Neil Chen Yi Lun MacAlevey, et al.
Published in JAMA Dermatology on 29 November 2023
Key Points
Question
Is isotretinoin use associated with the risk of suicide and psychiatric disorders?
Findings
In this meta-analysis of 25 studies including 1 625 891 participants, the 1-year absolute risk of completed suicide, suicide attempt, suicide ideation, and self-harm among isotretinoin users was less than 0.5% each, while that of depression was 3.83%. Isotretinoin was not associated with the relative risk of all psychiatric disorders, and isotretinoin users were less likely than nonusers to attempt suicide at two to four years after treatment.
Meaning
These findings indicate that there is no epidemiological evidence to suggest an increased relative risk of suicide or psychiatric conditions among isotretinoin users at a population level.
Abstract
Importance
Isotretinoin is hypothesised to contribute to the development of psychiatric disorders, but the epidemiological association and risk factors associated with psychiatric disorders among isotretinoin users remain unclear.
Objective
To clarify the absolute and relative risk and risk factors associated with suicide and psychiatric disorders among isotretinoin users.
Data Sources
PubMed, Embase, Web of Science, and Scopus were searched from inception until January 24, 2023.
Study Selection
Randomised trials and observational studies were selected if they reported the absolute risk, relative risk, and risk factors for suicide and psychiatric disorders among isotretinoin users.
Data Extraction and Synthesis
Relevant data were extracted and risk of bias was evaluated at the study level using the Newcastle-Ottawa Scale. Data were pooled using inverse variance-weighted meta-analyses. Heterogeneity was measured using the I2 statistic, and meta-regression analyses were performed.
Main Outcomes and Measures
Absolute risk (percentage), relative risks (risk ratios [RR]), and risk factors (RR) of suicide and psychiatric disorders among isotretinoin users.
Results
A total of 25 studies including 1 625 891 participants were included in the review and 24 in the meta-analysis. Among the included studies, participants’ average age ranged from 16 to 38 years, and distribution by sex ranged from 0% to 100% male. The 1-year pooled absolute risk from between 2 and 8 studies of completed suicide, suicide attempt, suicide ideation, and self-harm were each less than 0.5%, while that of depression was 3.83% (95% CI, 2.45-5.93; I2 = 77%) in 11 studies. Isotretinoin users were less likely than nonusers to attempt suicide at 2 years (RR, 0.92; 95% CI, 0.84-1.00; I2 = 0%), 3 years (RR, 0.86; 95% CI, 0.77-0.95; I2 = 0%), and 4 years (RR, 0.85; 95% CI, 0.72-1.00; I2 = 23%) following treatment. Isotretinoin was not associated with the risk of all psychiatric disorders (RR, 1.08; 95% CI, 0.99-1.19; I2 = 0%). Study-level meta-regression found that studies with participants of older age reported lower 1-year absolute risk of depression, while those with a higher percentage of male participants reported a higher 1-year absolute risk of completed suicide.
Conclusions and Relevance
The findings suggest that at a population level, isotretinoin users do not have increased risk of suicide or psychiatric conditions but may instead have a lower risk of suicide attempts at two to four years following treatment. While these findings are reassuring, clinicians should continue to practice holistic psychodermatologic care and monitor patients for signs of mental distress during isotretinoin treatment.
JAMA Dermatology article – Isotretinoin and adverse psychiatric effects (Open access)
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