Real-World Evidence of Neuropsychiatric Adverse Reactions to Isotretinoin: Insights from EudraVigilance (2005-2025).

Isotretinoin is a highly effective therapy for severe acne, but its potential neuropsychiatric adverse reactions (NPsRs) have been controversial. This study evaluated EudraVigilance data from 2005 to 2025 to better understand the frequency, typology, and predictors of such events. We conducted a retrospective analysis of 33,381 individual case safety reports (ICSRs) related to isotretinoin. Using descriptive statistics, chi-square tests, and logistic regression, we assessed associations between NPsRs and variables such as age, sex, geographic region, and reporter type. A total of 9793 cases (29.3%) involved at least one NPsR. Depression (31%) and suicidal ideation (8.6%) were the most frequently reported symptoms. Adolescents (12-17 years) had the highest proportion of NPsR cases, while male patients and reports submitted by non-healthcare professionals were significantly overrepresented. Reports from non-European Economic Area countries also had slightly increased odds of including NPsRs. All predictors were statistically significant in the logistic regression model, though the explained variance was modest (Nagelkerke R = 0.065). Neuropsychiatric reactions remain a prominent and persistent signal in isotretinoin pharmacovigilance, particularly among younger patients and non-professional reporters. Although causality cannot be inferred from spontaneous reporting data and confounding factors like acne-related depression cannot be excluded, these findings highlight the clinical value of pre-treatment psychiatric screening, patient-centered education, and proactive mental health monitoring throughout isotretinoin therapy.