Response

Samamé’s editorial ^{Reference Samamé1} offers a timely and comprehensive review of the ongoing debate over isotretinoin and its potential psychiatric side-effects, including mood changes and suicidality. While concerns about these risks have lingered for decades, the author emphasises that current evidence fails to establish a clear causal link between isotretinoin use and mental health issues. We share Samamé’s view that excessive worry over these psychiatric side-effects is disproportionate, and clinical practice should instead focus on carefully weighing the medication’s efficacy against any potential mental health risks when treating individual patients. However, the ongoing debate, shaped by methodological complexities and clinical uncertainties, highlights the need for continued reflection and research in this area.

The editorial highlights a critical paradox: the target population for isotretinoin treatment inherently has a higher risk of mental health issues. Furthermore, the psychosocial repercussions of severe acne, such as social stigma and chronic distress, may exacerbate the emergence of mental health issues. Existing studies often lack adequate control for baseline psychiatric conditions and the severity of acne, which could lead to an overestimation of isotretinoin’s psychiatric side-effects. Samamé’s summary of large cohort studies and meta-analyses suggests that, at the population level, the use of isotretinoin does not correlate with an increased risk of psychiatric disorders when compared to acne patients treated with alternative therapies or the general population. Notably, the editorial mentions that some studies even suggest a protective effect, potentially attributable to the profound psychological benefits of acne clearance. However, the methodological limitations of these studies should not be overlooked. For example, if clinicians avoid prescribing isotretinoin to high-risk psychiatric patients, ‘indication bias’ may artificially lower the risk estimates – a practice hinted at in the editorial. These subtle differences highlight the challenge of isolating the effects of isotretinoin from the inherent complexity of the patient population.

We also feel it is necessary to mention the incident physical symptoms associated with isotretinoin use. A large-scale propensity-matched cohort study involving over 12 million acne patients found that, although isotretinoin users did not exhibit an increased risk of mental health disorders or suicide compared to those receiving alternative treatments or no acne medication, they reported significantly higher rates of incident physical symptoms, including headaches, nausea, vomiting, dry mouth, conjunctivitis, pain, cheilitis and fatigue. ^{Reference Samamé1} These symptoms were more pronounced with increasing acne severity. The psychosocial burden of acne, combined with these incident physical symptoms, may exacerbate the risk of mental disorders in vulnerable individuals. Furthermore, some of these symptoms – such as fatigue, malaise, mood instability and anhedonia – could be misclassified as depressive symptoms because of their non-specific or overlapping nature. ^{Reference Paljarvi, McPherson, Luciano, Herttua and Fazel2} Therefore, more nuanced research is urgently needed to clarify the relationship between incident physical symptoms and mental health outcomes, as well as to improve the accuracy of psychiatric diagnoses. This will enable a more comprehensive and objective assessment of isotretinoin’s mechanisms and its broader impact on patients.

Samamé emphasises that although current research provides initial insights into the relationship between isotretinoin and mental health risks, significant gaps remain. The editorial notes that most studies on isotretinoin are retrospective, making them susceptible to recall and selection biases. ^{Reference Chen, Wang, Chung, Tsao, Chien and Hung3–Reference Wysowski, Pitts and Beitz6} Prospective studies with standardised psychiatric assessments, longitudinal follow-ups and rigorous control for confounders are urgently needed. In addition, the underlying biological mechanisms of isotretinoin remain unclear. Animal studies have shown that 13-cis-retinoic acid (i.e. isotretinoin) can induce depression-related behaviours in rodents, including increased immobility in the forced swim test and tail suspension test, as well as reduced sucrose preference, indicating anhedonia. These behavioural changes are linked to suppressed hippocampal neurogenesis, increased hypothalamic–pituitary–adrenal (HPA) axis activity and alterations in monoamine system function. ^{Reference Hu, Van Dam, Wang, Lucassen and Zhou7} However, these findings are limited by small sample sizes, variability in animal models and inconsistent dosing regimens, highlighting the need for more rigorous and controlled studies. Further investigation into the neurobiological mechanisms of isotretinoin is essential to better understand its potential risks and address the existing gaps in knowledge.

As advocated by the editorial, while existing studies suggest no direct link between isotretinoin and psychiatric disorders or suicide risk at the population level, physicians should still assess a patient’s mental health before treatment, especially for those with a psychiatric history. During treatment, one should focus on monitoring physical side-effects and consider a cautious approach with lower doses or more frequent follow-ups. Physicians should also inform patients of potential risks to support informed decision-making, trust and treatment adherence. Finally, multidisciplinary collaboration between dermatologists and psychiatrists is essential for timely mental health management, joint assessment of treatment effectiveness and ensuring overall patient safety.

Samamé’s editorial provides a much-needed perspective on the isotretinoin debate, emphasising the importance of evidence-based decision-making in clinical practice. While concerns about psychiatric adverse events should not be dismissed, the available evidence does not support a blanket avoidance of isotretinoin in patients with severe acne. Instead, a careful, individualised approach that considers both the dermatological and psychiatric aspects of the patient’s condition is essential. Future research must prioritise high-quality designs to resolve lingering uncertainties, ensuring that isotretinoin continues to benefit those who need it most, without undue fear or stigma.