Pooled meta-analysis does not support association between isotretinoin treatment for acne and worsening of depression.
Although isotretinoin is often a godsend for patients with severe acne, prescribers have long worried about a possible connection between isotretinoin use and depressive symptoms. However, the first pooled meta-analysis of pertinent data not only fails to support such an association, but it also suggests that isotretinoin may improve acne sufferers' depression.
"The relationship between isotretinoin treatment for acne and depression is controversial," said Yu-Chen Huang, M.D., of the Department of Dermatology at Taipei Medical University. Among 3 of the most comprehensive reviews on the topic, 2 – by Strahan et al.1 and Marqueling et al.2 in 2006 and 2007, respectively – found no support for a causative link between isotretinoin and depression. The third, Bremner et al. in 2012,3 concluded there was a causal link.
"The systematic reviews by Stranahan et al., Marqueling et al. and Bremner et al. did not include a pooling analysis to derive their conclusions. That meant they only provided a qualitative analysis," said Dr. Huang. Conversely, she said, pooled meta-analysis provides a quantitative evaluation that's easier to understand.
Along with showing no positive association between isotretinoin and depression, she said, her and colleagues' meta-analysis showed that "incidence of depression declined after isotretinoin use, and depressive symptoms improved for most patients with acne. Although individual susceptibility to isotretinoin cannot be ruled out, the available evidence suggests that patients with nodulcystic acne can safely be treated with isotretinoin without increasing the risk of depression." The study appeared in the June 2017 edition of the Journal of the American Academy of Dermatology.
Dr. Huang and colleagues screened 172 studies published between the inception of isotretinoin treatment and September 30, 2016, and found 31 studies that provided depression prevalence figures or depression scores. Finding no randomized controlled trials, they included population-based studies, nonrandomized trials and prospective open-label studies that reported such data for at least 15 patients.
Of the 31 studies, 10 controlled studies and 15 open-label studies found no association between isotretinoin use and depression risk; of these 25 studies, 11 (2 controlled and 9 open-label) found significant improvement in depression scores or frequency of depression after isotretinoin therapy. Conversely, 2 studies (one population-based, one open-label) showed that isotretinoin significantly increased the risk of depression or depression scores. Another open-label study found an insignificant increase in depression risk.
For meta-analysis, investigators pooled results of 19 (controlled and open-label) studies that included a total of 1,411 patients who received depression evaluations at baseline and post-treatment. Depression scores decreased significantly from baseline regardless of the correlation value (standardized mean difference -0.335, 95% confidence interval/CI -0.498 to -0.172). Mean depression scores also decreased significantly based on Beck Depression Inventory and Hospital Anxiety Depression Scale-Depression at follow-up periods of 1 to 2 months and beyond 4 months. After isotretinoin treatment, prevalence of depression declined significantly (relative risk/RR 0.588, 95% CI 0.382-0.904).
With a high degree of variability between studies included in this analysis, investigators used the standardized mean difference outcome measure for the meta-analysis of continuous data to get consistent results when combining the non-standardized outcome scales reported across studies. In multivariate regression analysis, studies having a high proportion of male patients and a high study quality score correlated significantly with smaller declines in depression scores.
The meta-analysis included no randomized controlled trials because no such trials exist for isotretinoin and depression, said Dr. Huang. Because investigators reviewed only the isotretinoin dosage used for acne, she added, "We cannot conclude that the high dose of isotretinoin used for cancer treatment (up to 3 mg/kg/day) is not associated with depression." In one such study, 25% of patients exhibited post-treatment depression.4
Ultimately, she said, some patients are more susceptible to depression than others – whether or not they have acne or other conditions. Dr. Huang and colleagues also suggested that because a few studies described newly developed depression occurring during treatment with either isotretinoin or antibiotics, depression may be associated with acne independent of treatment method. Therefore, she said, "Closely monitoring patients with acne for depressive symptoms is essential to identify patients at high risk."
1. Strahan JE, Raimer S. Isotretinoin and the controversy of psychiatric adverse effects. Int J Dermatol. 2006;45:789-799.
2. Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg. 2007;26:210-220.
3. Bremner JD, Shearer KD, McCaffery PJ. Retinoic acid and affective disorders: the evidence for an association. J Clin Psychiatry. 2012;73:37-50.
4. Meyskens FL. Short clinical reports. J Am Acad Dermatol. 1982;6:732.