Neuroplasticity Alterations Induced by Isotretinoin use in RARA Gene Polymorphism is Associated with Increased Risk of Depression and Suicidal Ideation in Patients with Vitamin D Deficiency: A Systematic Review and Meta-Analysis
Authors:   Professor of Medicine, Endocrinology and Clinical Nutrition Specialist, Research Physician and Clinical Investigator, Brazil, Julian YV Borges 
Published: October 2024

Rationale: Isotretinoin is widely used for severe acne treatment, but concerns have emerged regarding its potential association with depression and suicidal ideation. Previous studies have produced mixed findings, necessitating a comprehensive evaluation of the evidence. This systematic review and meta-analysis aim to clarify the association between isotretinoin use and the onset of depression or suicidal ideation, focusing on genetic predispositions, particularly in patients with vitamin D deficiency. Objectives: This review assesses the risk of depression and suicidal ideation in patients treated with isotretinoin for severe acne compared to those not using isotretinoin. A secondary focus is placed on identifying specific genetic factors, such as polymorphisms in the RARA and LEP genes, that may predispose patients to these psychiatric side effects. Eligibility Criteria: Randomized controlled trials (RCTs), cohort studies, and case-control studies comparing isotretinoin users to non-users were included. Exclusion criteria included studies that lacked a comparator group or did not report psychiatric outcomes (depression or suicidal ideation). Outcomes: The primary outcome was the incidence of depression or suicidal ideation among isotretinoin users compared to non-users. Secondary outcomes examined the influence of genetic polymorphisms, specifically in the RARA and LEP genes, on the risk of developing psychiatric side effects. Risk of Bias: Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. The overall quality of the included studies was moderate to high. Synthesis Methods: A random-effects meta-analysis was performed to pool odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the I² statistic, and sensitivity analyses were conducted to ensure the robustness of the findings. Included Studies: Fifteen studies were included, comprising 3 randomized controlled trials, 7 cohort studies, and 5 case-control studies, with a total of 8,000 isotretinoin users and 10,000 non-users. The studies were conducted in diverse clinical settings with a follow-up range of 6 months to 5 years. Synthesis of Results: The pooled analysis demonstrated a significant association between isotretinoin use and an increased risk of depression (OR: 1.3, 95% CI: 1.1–1.5, p < 0.05). Specific genetic polymorphisms, particularly in the RARA and LEP genes, were identified as potential risk factors for developing depression among isotretinoin users, particularly in patients with concurrent vitamin D deficiency. Conclusions: Isotretinoin use is associated with an increased risk of depression, particularly in individuals with specific genetic polymorphisms such as RARA and LEP. Clinicians should consider conduct precision medicine genetic testing testing for these polymorphisms before initiating isotretinoin treatment and closely monitor patients for psychiatric alterations, mood changes, especially those with with vitamin D deficiency or genetic predisposition to depression