What are the mental health risks associated with Accutane (isotretinoin) treatment, particularly in adolescents and young adults with a history of severe acne?

Mental Health Risks of Accutane (Isotretinoin)

Population-based studies show no increased risk of neuropsychiatric conditions with isotretinoin treatment, with an overall relative risk of 0.88 (95% CI 0.77-1.00), and multiple studies demonstrate that isotretinoin actually improves quality of life and decreases symptoms of anxiety and depression in patients with moderate to severe acne. 1

Evidence on Psychiatric Risk

Population-Level Safety Data

• Large population-based studies have not identified an increased risk of neuropsychiatric conditions in patients with acne undergoing isotretinoin treatment 1
• The overall relative risk of neuropsychiatric adverse effects between isotretinoin-exposed and unexposed groups is 0.88 (95% CI 0.77-1.00), suggesting a possible protective effect rather than harm 1
• Studies comparing depression before and after treatment show no statistically significant increase in depression diagnoses or depressive symptoms, with some demonstrating a trend toward fewer or less severe symptoms after isotretinoin therapy 2
• Rates of completed suicide in patients taking isotretinoin (5.6-8.4 per 100,000 enrolled in iPLEDGE) may actually be lower than the general US population 3

Improvement in Mental Health

• Multiple studies indicate that isotretinoin improves quality of life and decreases symptoms of anxiety and depression in patients with moderate to severe acne, which could reduce overall risks of neuropsychiatric adverse events at a population level 1
• Most studies show isotretinoin improves or has no negative effects on mood, memory, attention, or executive functions 4
• Successful treatment of acne with isotretinoin appears to improve both depressive and anxiety symptoms more than topical treatments 5

Isolated Case Reports and FDA Warnings

Sporadic Reports

• Neuropsychiatric adverse effects, including changes in mood, depression, anxiety, suicidal ideation, and completed suicide have been sporadically reported in patients receiving isotretinoin, including with positive challenge/rechallenge, suggesting a potential causal association in susceptible individuals 1
• The FDA warns that isotretinoin may cause depression, psychosis, and rarely suicidal ideation, suicide attempts, suicide, and aggressive/violent behaviors, though no mechanism of action has been established 6
• Between 1997 and 2017,17,829 psychiatric adverse events with isotretinoin use were reported to the FDA, with depressive disorders, emotional lability, and anxiety disorders most frequently reported 3

Important Context

• These reports must be considered in the context of elevated rates of depression and suicide among patients with acne at large—up to 5.6% of patients with moderate acne may have pre-existing suicidal ideations 7, 2
• Available low certainty evidence from 4 observational studies with substantial heterogeneity do not support a significant association between isotretinoin use and neuropsychiatric adverse effect incidence 1
• Rates of depression among isotretinoin users ranged from 1% to 11% across studies, with similar rates in oral antibiotic control groups 2

Mandatory Monitoring Protocol

Pre-Treatment Assessment

• Prior to initiation of isotretinoin treatment, patients and family members must be asked about any history of psychiatric disorder 1, 6
• The physician should consider whether isotretinoin therapy is appropriate for patients with significant psychiatric history; for some patients the risks may outweigh the benefits 6

During Treatment Monitoring

• At each visit during treatment, patients must be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary 1, 6
• Regular screening using validated tools such as the Patient Health Questionnaire-2 (PHQ-2) or PHQ-9 is recommended 8, 4
• Signs and symptoms to monitor include: sad mood, hopelessness, feelings of guilt/worthlessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment 6

Action Steps for Psychiatric Symptoms

• Patients should stop isotretinoin and promptly contact their prescriber if they develop depression, mood disturbance, psychosis, or aggression, without waiting until the next visit 6
• Discontinuation of isotretinoin treatment may be insufficient; further evaluation and referral to a mental health professional may be necessary 6
• For patients with mild to moderate anxiety symptoms, isotretinoin treatment can be continued with close monitoring and more frequent follow-up visits 8

Special Population Considerations

Adolescents and Young Adults

• Given the high prevalence of depression, anxiety, and suicidal ideation/suicide in the general population, especially the adolescent population who may be candidates for isotretinoin therapy, clinicians should individualize therapeutic decisions based on individual differences in response 1
• The US Preventive Services Task Force recommends screening for depression in adults and in adolescents aged 12-18 years, and recommends screening for anxiety in adolescents, regardless of isotretinoin exposure 1
• More than half (52.5%) of all psychiatric adverse events reported to the FDA occurred in 10- to 19-year-old individuals 3

Risk Factors

• Either a personal history of obsessive-compulsive disorder, neurological insult, or family history of major psychiatric illness were present in all cases of manic psychosis reported in one case series 7
• Patients with pre-existing psychiatric conditions or family history require particularly careful consideration and closer monitoring 7

Common Pitfalls to Avoid

• Do not assume all psychiatric symptoms are drug-related—acne itself is strongly associated with depression and anxiety, and isotretinoin often improves these symptoms rather than causing them 1, 5
• Do not ignore the protective effect of treating severe acne—improvement of acne often reduces associated depression, and this benefit may outweigh theoretical psychiatric risks in most patients 2
• Do not fail to utilize mandatory monthly iPLEDGE visits—these provide an opportunity to screen patients for psychiatric conditions and improve outcomes 3
• Do not overlook family history—patients and family members should be asked about psychiatric history, and these reports should be discussed with the patient and/or family 6