What is the association between isotretinoin (13-cis-retinoic acid) and mood changes?

Association Between Isotretinoin and Mood Changes

The association between isotretinoin and mood changes is indeed highly tenuous—meta-analyses and population-based studies show no causal link between isotretinoin and depression, and most patients actually experience mood improvement as their acne clears. 1

Evidence Against a Causal Relationship

The highest quality guideline evidence from the American Academy of Dermatology establishes that:

• No evidence-based link exists between isotretinoin and depression, anxiety, mood changes, or suicidal ideation/suicide on a population basis 1
• Meta-analyses found no association between isotretinoin and increased risk of depression, with depressive symptoms overall decreasing following treatment 1
• The relative risk of neuropsychiatric adverse events between exposed and non-exposed groups is 0.88 (95% CI: 0.77-1.00), suggesting a possible protective effect rather than harm 2
• Multiple studies demonstrate isotretinoin improves or has no negative effects on mood, memory, attention, or executive functions 1

The Paradox: Individual Case Reports vs. Population Data

Despite the lack of population-level evidence, there exists a critical nuance:

• Isolated case reports document patients who experience mood changes with positive dechallenge and rechallenge responses 1
• The FDA has received 431 reports of depression-related events from 1982-2000, including 37 suicides, though causality remains unestablished 3
• Approximately 10.5% of adolescent patients may experience subtle mood changes including depressive symptoms, anxiety, aggression, or emotional lability, though 88% improve to baseline regardless of management 4

Clinical Implications and Monitoring

While isotretinoin is associated with improved mood for the majority of patients as their acne improves, it remains sensible to educate patients and families about depression and monitor for concerning symptoms during treatment 1

The American Academy of Dermatology recommends:

• Use validated screening tools like the Patient Health Questionnaire-2 (PHQ-2) or PHQ-9 at each visit 5, 2
• Assess for symptoms of depression, mood disturbance, psychosis, or aggression at each visit to determine if further evaluation is needed 5, 6
• Establish baseline psychiatric status before initiating treatment 5

Important Caveats

The prescribing physician should continue to monitor for psychiatric symptoms given the high prevalence of depression and suicidal ideation in the adolescent population who are candidates for isotretinoin therapy, making therapeutic decisions within the context of each individual patient 1

Key warning signs from the FDA label include:

• Sad mood, hopelessness, feelings of guilt or worthlessness 6
• Loss of pleasure or interest in activities, fatigue, difficulty concentrating 6
• Changes in sleep pattern, weight, or appetite 6
• Suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses 6

Patients should stop isotretinoin and promptly contact their prescriber if mood disturbance develops, without waiting until the next visit—discontinuation alone may be insufficient and further psychiatric evaluation may be necessary 6

The Bottom Line on Quality of Life

Isotretinoin may improve quality of life and decrease symptoms of anxiety and depression in patients with moderate to severe acne, potentially reducing overall risks of neuropsychiatric adverse events at a population level 5, 2