Isotretinoin does not hurt patients’ mental health, study says

While treatment with isotretinoin for acne is said to have a negative impact on mental health, its use appears to instead mitigate the excess psychiatric risk associated with treatment-resistant moderate-to-severe acne, as reported in a large study.

“We observed a consistent association between increasing acne severity, as indicated by antiacne treatment options, and incidence of adverse neuropsychiatric outcomes, but the findings showed that isotretinoin exposure did not add to the risk of neuropsychiatric adverse outcomes over and above what was associated with oral antibiotics,” according to researchers led by Dr Seena Fazel of Oxford University, Oxford, UK.

“Instead, we observed that isotretinoin was associated with reduced incidence of anxiety, depression, sleep problems, nonfatal self-harm, and prescriptions for psychotropic medicines, when compared with patients with acne who were … prescribed oral antibiotics,” Fazel added.

Fazel and colleagues used data from the TriNetX Analytics Network (n=12,371,366) and found that acne diagnosis was associated with higher 12-month incidence of adverse neuropsychiatric outcomes (incidence rate, 57 vs 40 cases per 1,000 person-years; odds ratio [OR], 1.46, 95 percent confidence interval [CI], 1.43–1.50). [Br J Dermatol 2022;doi:10.1111/bjd.21049]

Then, the researchers identified 30,866 patients prescribed isotretinoin for their acne, 44,748 prescribed oral antibiotics, 108,367 prescribed topical antiacne agents, and 78,666 acne patients without an antiacne prescription (control). These patients were matched based on propensity score for baseline confounders.

The 12-month incidence of neuropsychiatric conditions overall was much greater among patients who used any topical antiacne agents (OR, 1.16, 95 percent CI, 1.09–1.22) and those who used oral antibiotics (OR, 1.19, 95 percent CI, 1.11–1.27) as compared with control patients who did not have dispensed prescriptions for any of the selected acne medications.

On the other hand, the incidence was significantly reduced among patients who used isotretinoin vs those on oral antibiotics (OR, 0,80, 95 percent CI, 0.74–0.87), with the incidence especially lower for mood disorders, anxiety disorders, behavioural disorders, and incident prescriptions for psychotropic medicines.

When compared with patients who used topical antiacne medications, patients on isotretinoin had a nonsignificantly lower neuropsychiatric risks (OR, 0.94, 95 percent CI, 0.87–1.02) and were more likely to be prescribed antidepressants (OR, 1.16, 95 percent CI, 1.05–1.28) and develop symptoms involving emotional state (OR, 1.21, 95 percent CI, 1.10–1.45).

Finally, tretinoin exposure only barely preserved the overall excess neuropsychiatric risks as compared with no dispensed prescriptions for any of the selected acne medications (OR, 1.06, 95 percent CI, 0.97–1.16), although patients on tretinoin were more likely to be diagnosed with mood, anxiety, and sleep disorders.

One interesting finding in the current study, Fazel noted, was that patients exposed to isotretinoin developed significantly more physical symptoms than patients in any of the three comparison cohorts, with an increased graded association by the severity of acne.

“Acne-related psychosocial stress in general or pre-existing subclinical mental health problems together with an initial acne flare-up or other isotretinoin-induced physical side-effects may trigger clinically relevant mental health symptoms in patients already vulnerable because of their severe acne, particularly among patients with limited coping and emotional resilience,” Fazel pointed out. [J Youth Adolesc 2017;46:261-276]

“Therefore, it can be suggested that psychosocial vulnerability in general, pre-existing subclinical mental health problems, physical comorbidity, subjective and objective burden of acne symptoms, age at onset and duration of acne symptoms, and the frequency and intensity of isotretinoin-induced physical and neurological side-effects, all contribute to the risk of adverse mental health outcomes during isotretinoin treatment,” he added.

Evidence reassuring

In an accompanying editorial, Drs Jane Ravencroft of Nottingham University Hospitals NHS Trust, Nottingham, UK, and Lawrence Eichenfield of University of California San Diego, La Jolla, California, US, acknowledged that the current large population study helps dispel fears that oral isotretinoin may increase overall risks of psychiatric problems. [Br J Dermatol 2022;doi:10.1111/bjd.21596]

“Isotretinoin is an extremely effective drug for acne, and in our practice, we see improved affect, energy, and self-confidence in many patients after effective acne treatment,” they wrote.

Nevertheless, Ravencroft and Eichenfield noted that individual cases of clinically significant depression and other neuropsychiatric events linked to isotretinoin still persist in the literature, with continuing rare reports of completed suicide during and after treatment. [J Am Acad Dermatol 2021;85:878-884; J Am Acad Dermatol 2017; 76:1068-1076; JAMA Dermatol 2019; 155:1162-1166; J Eur Acad Dermatol Venereol 2020; 34:1293-1301]

“Isotretinoin crosses the blood–brain barrier, and neurobiologists have identified plausible mechanisms to account for brain effects, particularly in young people. Physical side-effects from isotretinoin may contribute to low mood, and it is also possible there are higher rates of awareness of psychiatric adverse events in patients on isotretinoin (ascertainment bias) due to regulatory requirements,” they pointed out. [J Affect Disord 2021;6:100230]

“It is essential that patients are screened at baseline for psychiatric history, which may be associated with increased risk of low mood and suicide during isotretinoin treatment. Ongoing risk management should be practiced consistently and referral pathways put in place to support patients with mood concerns,” according to Ravencroft and Eichenfield. [J Eur Acad Dermatol Venereol 2020; 34:1293-1301]