Accutane and Depression: What the Evidence Shows

What the label actually says

The Absorica label carries a Warnings and Precautions section headed Psychiatric Disorders: 'ABSORICA/ABSORICA LD may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors' [1]. It tells prescribers to ask patients and family members about any history of psychiatric disorder before starting, and to assess for symptoms of depression, mood disturbance, psychosis or aggression at each visit during treatment [1].

The older-format Accutane label states: 'No mechanism of action has been established for these events' [4].

The adverse reactions section lists suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations among psychiatric reactions reported in trials and after marketing, and notes that because some were reported voluntarily the frequency cannot be reliably estimated [1]. One clinical pattern is recorded: 'Of the patients reporting depression, some reported that the depression subsided with discontinuation of treatment and recurred with reinstitution of treatment' [1].

Do controlled studies show more depression on isotretinoin?

A 2017 systematic review and meta-analysis by Huang and Cheng in the Journal of the American Academy of Dermatology included 31 studies [3]. In the controlled studies, the change in depression scores from baseline did not differ significantly between patients taking isotretinoin and patients on another acne treatment (standardized mean difference -0.334, 95% CI -0.680 to 0.011) [3]. Across treated patients, the prevalence of depression after treatment fell (relative risk 0.588, 95% CI 0.382 to 0.904) and mean depression scores dropped from baseline (standardized mean difference -0.335, 95% CI -0.498 to -0.172) [3]. The review included no randomized trials and found large variation between studies [3].

Several individual cohorts point the same way. In a study of 132 adolescents aged 12 to 19 with moderate to severe acne, 101 of whom completed follow-up, CES-D scores suggesting clinically significant depression were no more common on isotretinoin than on conservative acne therapy, and new-onset scores did not differ significantly; depressive symptoms decreased with either treatment [2]. A prospective study of 215 patients (mean age 20) found no difference between isotretinoin and antibiotic or topical treatment in the change in mean depression scores (P = 0.62) [7]. Five isotretinoin patients in that study were withdrawn because of worsening mood; the authors said no definite causal relationship was established, and that the study did not support a direct link apart from a 'rare unpredictable idiosyncratic side-effect' [7]. In a smaller cohort of 38 patients followed for 8 weeks, depression severity decreased after two weeks of treatment, and the improvement was correlated with acne-related quality of life rather than acne grade [8].

Not every study agrees. A Quebec case-crossover study compared isotretinoin exposure in a 5-month window before a first depression diagnosis with an earlier 5-month control window. It included 126 cases drawn from 30,496 subjects, and found a crude relative risk of 2.00 (95% CI 1.03 to 3.89) and an adjusted relative risk of 2.68 (95% CI 1.10 to 6.48) [12]. The authors called it the first controlled study to find a statistically significant association between isotretinoin and depression [12].

Suicide attempts in a French national cohort

A French cohort using national health insurance data from 2009 to 2016 followed 443,814 people aged 10 to 50 who were exposed to oral isotretinoin, a total of 244,154 person-years [5]. Hospitalized suicide attempts during treatment occurred at a lower rate than in the French general population (standardized incidence ratio 0.6, 95% CI 0.53 to 0.67) [5]. Comparing isotretinoin starts in the two months before a suicide attempt with starts in the preceding two-month control period, the case-time-control odds ratio was 0.89 (95% CI 0.68 to 1.16), and results held when completed suicides were added to the outcome [5]. The authors concluded there was no evidence that starting isotretinoin triggers a suicide attempt [5].

Acne itself and mood

Acne is itself linked to mood problems. In a population study of 3,775 adolescents aged 18 to 19, suicidal ideation was reported about twice as often by girls reporting very much acne as by girls reporting no or little acne (25.5% versus 11.9%), and about three times as often by boys (22.6% versus 6.3%), with an adjusted odds ratio of 1.80 (95% CI 1.30 to 2.50) for substantial acne [9]. The authors noted that psychiatric adverse events associated with acne therapies may instead reflect the burden of substantial acne [9].

The picture is not uniform. Among 165 Finnish male conscripts with acne compared with 150 with mild knee symptoms, at least moderate depressive symptoms were reported by 9.7% versus 13.3% and suicidal ideation by 14.5% versus 10.7%, neither difference statistically significant, and acne severity was not associated with depression scores [10].

Does isotretinoin act on the brain? What one mouse study shows

A study in mice given a dose matching the clinical 1 mg/kg/day of 13-cis-retinoic acid found reduced cell proliferation in the hippocampus and subventricular zone, suppressed hippocampal neurogenesis, and severely disrupted performance on a spatial radial maze task [11]. That is a laboratory finding about brain regions that continue to generate new cells in adulthood. The abstract reports learning outcomes, not mood, and the Accutane label states that no mechanism of action has been established for the psychiatric events reported in patients [4].

What the label says to do if mood changes

The Absorica label says that if a patient develops depression, mood disturbance, psychosis or aggression, patients or caregivers are to stop the drug immediately and promptly contact their health care provider. It adds that discontinuation may be insufficient and that further evaluation, such as referral to a mental health professional, may be necessary [1]. The Accutane label adds that reports of mental health problems or a family history of psychiatric disorders should be discussed with the patient and family, that referral to a mental health professional may be necessary, and that the physician should consider whether therapy is appropriate, since for some patients the risks may outweigh the benefits [4].

The Absorica label's contraindications are pregnancy and hypersensitivity to isotretinoin, vitamin A or any component; psychiatric illness is not listed there [1].

The iPLEDGE REMS exists because of embryo-fetal toxicity, and its stated goal is mitigating that risk [6].

Limits of the evidence

The meta-analysis included no randomized trials and had large variation between studies [3]. The authors of the 215-patient study said a larger study was needed to confirm their findings [7]. The label states that the frequency of the psychiatric reactions it lists cannot be reliably estimated [1]. The studies above reach different conclusions on whether isotretinoin exposure is associated with a depression diagnosis [3][12].