Physiological and Psychological Effects of Isotretinoin in the Treatment of Patients with Acne: A Narrative Review

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TL;DR

This narrative review summarizes the physiological and psychological side effects of isotretinoin (ISO) for acne, finding that teratogenicity, skin/ocular reactions, and blood changes are well-established, while the link to psychological issues remains controversial and may be confounded by acne itself. The review highlights that combination therapies and dose adjustments can mitigate side effects, and that the risk of depression should not preclude ISO use in moderate-to-severe acne. Clinically, careful patient screening and monitoring are essential to optimize treatment outcomes.

Full summary

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**Background:** Acne vulgaris is a common chronic inflammatory skin disorder, and isotretinoin (ISO), a vitamin A derivative, is the only treatment capable of inducing permanent remission by targeting all major pathogenic factors. Despite its efficacy, ISO is associated with several adverse effects, including psychological issues, inflammatory bowel disease (IBD), and teratogenicity, which often cause patient hesitation. This narrative review aims to comprehensively examine both physiological and psychological side effects of ISO to better identify suitable candidates for therapy.

**Methods:** A literature search was conducted in PubMed using the query "(Acne [Title/Abstract]) AND ((Isotretinoin[Title/Abstract]) or (ISO[Title/Abstract]))" with a time limit of after 2018. Initially, 474 articles were identified; after screening titles, abstracts, and relevant references, 160 articles remained. After removing duplicates, 127 articles were ultimately included in this narrative review.

**Key Results:** - **Physical Effects:** The incidence of adverse reactions after 3 months of ISO treatment was 40% in a Nepal study. A review of 11 trials (760 patients) found adverse events twice as high in the ISO group versus controls. In a 2022 study of 90 adolescents, 11 different adverse effects were noted. - **IBD:** A retrospective cohort analysis showed 6-month IBD incidence among ISO-treated acne patients was very low (0.08% vs 0.04% in non-ISO users). Most studies found no significant association between ISO and ulcerative colitis, and a Brazilian consensus concluded no causal relationship. - **Pregnancy and Teratogenicity:** ISO is considered the most teratogenic drug after thalidomide. In exposed pregnancies, spontaneous abortion risk was approximately 20%, and embryopathy risk was 18%–28%. A report of 151 births found 47% had congenital malformations; among 94 prospectively ascertained pregnancies ending in births, 28% had malformations. - **Acne Fulminans (AF):** ISO can induce AF, primarily in adolescent males. A case report described a patient who worsened after 6 weeks on 0.4 mg/kg/day ISO, requiring prednisone and eventual apremilast. The number of AF cases starting at ≤0.2 mg/kg/day was smaller than at 0.5 mg/kg/day (P < 0.05). - **Skin Reaction:** Dry lips occurred in 100% of adolescents in one study. Cheilitis was the most common mucocutaneous side effect and was dose-dependent. Evening primrose oil and omega-3 supplements can improve skin hydration and reduce dryness. - **Ocular Reaction:** Systemic ISO affects ocular surface parameters, meibomian glands, and tear film, causing dry eye, conjunctivitis, and meibomian gland dysfunction. Artificial tears with 0.2% galacto-xyloglucan and 0.4% hyaluronic acid improved symptoms. - **Other Reactions:** Hair loss occurred more frequently with ISO ≥0.5 mg/kg/day (5.7% vs 3.2%). Hepatic dysfunction occurred in up to 15% of patients. ISO increased LDL cholesterol, triglycerides, and AST/ALT. No significant changes were seen in lymphocyte, monocyte, or platelet counts after 3 months. - **Psychological Effects:** Evidence is mixed. Some studies show ISO can lead to depressive behaviors via retinoic acid effects on serotonin and brain metabolism. However, many large studies found no increased risk of depression or suicide; some even reported lower rates of psychiatric outcomes compared to oral antibiotics. A Swedish cohort found attempted suicide risk increased 6 months after treatment, but the risk was already rising before treatment. Experts in Brazil and Spain agreed there is no causal relationship between ISO and psychological effects. - **Dose-Related Effects:** Conventional doses (0.5–1.0 mg/kg/day) improve relapse prevention over low doses (0.1–0.3 mg/kg/day). However, some studies found no difference in recurrence rates with cumulative doses >120 mg/kg versus lower doses. Low-dose ISO (0.25–0.4 mg/kg/day) appears safer for ovarian reserve.

**Clinical Implications:** The review emphasizes that teratogenicity, skin/ocular reactions, and blood changes are well-established and require proactive management, such as combination therapies (e.g., with salicylic acid, pulsed dye laser, or zinc) and dose adjustments to minimize side effects. The most controversial issue—psychological effects—may be confounded by the psychological burden of acne itself. Clinicians should not withhold ISO due to fear of depression but should monitor patients and communicate potential mood changes. Early effective treatment is crucial to reduce scarring. The review also highlights the need for better access to ISO and exploration of alternative therapies like vitamin D or dietary supplements.