How to cite this article: Rubio-García L, Pulido-Díaz N, Jíménez-López JL. Isotretinoin and depressive symptoms in patiens with severe and recurrent acne. Rev Med Inst Mex Seguro Soc. 2015;53 Supl 1:S54-9.
Received: October 22nd 2014
Accepted: March 6th 2015
Leticia Rubio-García,a Nancy Pulido-Díaz,a José Luis Jímenez-Lópezb
aDepartamento de Dermatología
bDepartamento de Psiquiatría
Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México
Communication with: Leticia Rubio-García
Telephone: (55) 5724 5900, extensión 24085
Background: Since use of isotretinoin for acne management it has been published controversial results about its association with depression. The objective of this study was to know if use of isotretinoin in patients with severe and recurrent acne (SRA) is associated with depression.
Methods: 22 patients with diagnosis of SRA were included from the National Medical Center La Raza’s Acne Clinic. They completed the Beck Depression inventory (IDB-II) before, during (2 months) and after treatment with isotretinoin (4 months), calculated at 0.5 mg/kg.
Results: The patients reported low depressive symptoms before treatment that reduced at the end (median = 6 and 0, respectively, p < 0.001).
Conclusions: Treatment with isotretinoin in this sample of patients with severe and recurrent acne produced no increase in depressive symptoms, but improvement, due to the best corporal image self-perception.
Keywords: Acne, Isotretinoin, Depressive symptoms.
Acne vulgaris is the most common skin disease worldwide and therefore the dermatologic diagnosis most made by dermatologists and non-dermatologists.1
According to data from various studies, it is estimated that 57.5% of acne cases attending dermatological consultations are moderate inflammatory, followed by mild inflammatory with 25%.2 This condition can cause chronic inflammatory injury to the pilosebaceous unit,3,4 leading to changes in the patient's appearance, and, although at first glance it may seem like a trivial disease that resolves after age 25, the scars and the psychological impact of acne (depression, anxiety, anguish, frustration, social withdrawal, and even suicidal ideation) may be as important as those of chronic diseases such as epilepsy, diabetes, asthma, or arthritis.5,6
The treatment for this entity ranges from topical to systemic, and from that which has been proven effective,7 to that which still lacks sufficient scientific evidence for use.8 Oral isotretinoin (cis retinoic acid13) is the drug officially approved for treatment of recurrent severe cystic or nodular acne that has not responded to other forms of treatment (evidence level IA).9,10
Neurobiological involvement of retinoic acid in affective disorders is still not entirely clear. Research in the field of retinoic acid in SNC has focused on brain development, considering it highly teratogenic; recent studies, mostly in animals, show that it can influence the adult brain by inducing changes in behavior and inhibition of neurogenesis in the hippocampus.11
There are several publications that have associated this drug with psychiatric disorders such as anxiety, depression, psychosis, panic attacks, and suicidal ideation.12,15 The evidence is conflicting, some argue that there is an association between isotretinoin and depression in susceptible patients,17 others say that there is no association,18 or that the difference is not significant, and yet others say it is inconclusive due to methodological shortcomings, and others say that is contradictory, such as Rubinow, who noted that the level of anxiety and depression in patients with cystic acne is reduced after successful treatment with isotretinoin.19
Finally, a similar study by Nevoralová Z which included 100 patients managed with isotretinoin, looked for the association between this and depressive symptoms and suicidal ideation, concluding that there was no association and that, contrary to expectations, there was statistically significant improvement in Beck Scale scores (BDI-II) after use; i.e. reduced depressive symptoms.20 Therefore, establishing a causal relationship between isotretinoin, depression, and acne is critical because the results in various publications are questionable.21 Because of this, some patients considered candidates for management with this drug are distrustful and even refuse to receive such treatment.
Patients were included with clinical diagnosis of severe and/or recurrent acne belonging to the acne clinic, over 16 years old, who had never received treatment with isotretinoin, and who agreed to participate in the study. No patients were included who had contraindications to the use of isotretinoin, or with affective disorders at baseline. The study excluded patients who during treatment with isotretinoin developed affective disorders or presented figures of cholesterol, triglycerides, bilirubin, GOT, and GPT three times higher than normal limits in any of the bimonthly measurements. Surveillance and monitoring of patients was done monthly.
After signing the informed consent, they were given appointments at the the outpatient dermatology clinic and were administered the BDI-II to assess the presence and severity of depressive symptoms at 0, 2, and 4 months of treatment with isotretinoin. Patients with scores higher than 20 in this inventory at any of these times were referred to the psychiatric service for assessment and specialized management. The dose of isotretinoin was estimated at 0.5 mg/kg/day and was to be taken in one dose.
Statistical analysis was performed using Stata version 12. Descriptive data analysis was done using simple frequencies and percentages for variables and measures of central tendency for quantitative variables (mean and standard deviation if the distribution was normal, or median with 25th and 75th percentiles if not normal distribution). To compare differences in scores on the Beck Depression Scale at the three moments of the study, the Kruskal-Wallis test was used while the differences between two moments were compared with the Mann-Whitney test.
The subjects were divided into groups according to the presence of scores above zero. To compare the distribution of frequencies between the three moments of the study, Cochrane’s Q test was used, and the McNemar test was used to compare two moments. Biochemical parameters were compared using ANOVA one-way or Student’s t. A p-value < 0.05 was considered statistically significant.
A total of 23 subjects were included in the study, of whom one was not included because they had a score above 20 on the Beck Depression Scale. The final sample was composed of 22 participants. 72.7% were men, the average age was 20.8 ± 5.6 years. About 85% of the subjects had high school or undergraduate education, and the most frequent occupation was student (Table I).
|Table I Characteristics of study participants|
|Age, years||20.8 ± 5.6|
|Data are presented as number (%) or average ± standard deviation. * includes 5 occupations with a frequency of one each: stylist, home-maker, engineer, physician, and marketer|
Median overall scores of the Beck Depression Scale was 6.5, 3, and 0, at the moments: before treatment, at 2 months, and 4 months; significant difference was found in scores at the beginning and at the end (p < 0.001) (Table II). Differences were found in the three moments in irritability, body image, and hypochondria, which decreased or improved (body image) with the treatment; i.e. they were more satisfied, their thoughts of self-accusation, irritability, and hypochondria decreased, while they had significant improvements in their body image (Table III). Differences were found in dissatisfaction, self-accusation, irritability, body image, and hypochondria, with improvement during treatment (Table IV). No statistically significant differences were found in the biochemical parameters (total bilirubin, total cholesterol, triglycerides, GOT, or GPT) in the three moments of the study.
|Table II Scores of study participants from Beck Depression Scale at different moments of the treatment|
|Beck Depression Scale score
During treatment (2 months)
After treatment (4 months)
|Data are presented as median (25th percentile, 75th percentile)|
|Table III Scores of items on the Beck Depression Scale at different moments of treatment|
|Subscale||Before treatment||At 2 months of
|At 4 months of
|Sadness||0(0-1)||0(0-1)||0 (0-0)||0.327||0.766||0.015 *||0.057|
|Pessimism||0(0-1)||0(0-0)||0 (0-0)||0.285(h)||0.338||0.025 *||0.032 *|
|Past Failure||0(0-0)||0(0-0)||0 (0-0)||0.956||0.317||0.317||ND|
|Loss of Pleasure||0(0-1)||0(0-1)||0 (0-0)||0.146||0.569||0.005 *||0.020 *|
|Guilt||0(0-0)||0(0-0)||0 (0-0)||0,584||0.317||0.157||0.046 *|
|Punishment||0(0-0)||0(0-0)||0 (0-0)||0.668||0.046 *||ND||0.046 *|
|Self-criticalness||0(0-1)||0(0-1)||0 (0-0)||0.250||0.706||0.025 *||0.014 *|
|Suicidal ideation||0(0-0)||0(0-0)||0 (0-0)||0.956||1,000||0.317||0.317|
|Agitation||1(0-1)||0.5(0-1)||0 (0-0)||0.010 *||0.343||0.001 *||0.001 *|
|Loss of Interest||0(0-1)||0(0-0)||0 (0-0)||0.559||0.257||0.083||0.057|
|Indecisiveness||0(0-0)||0(0-1)||0 (0-0)||0.489||0.392||0.025 *||0.317|
|Worthlessness||0(0-1)||0(0-0)||0 (0-0)||0.050 *||0.007 *||0.157||0.002 *|
|Loss of Energy||0(0-1)||0(0-0)||0 (0-0)||0.427||0.414||0.083||0.025 *|
|Sleep disorders||0(0-1)||0(0-1)||0 (0-0)||0.206||0.480||0.014 *||0.046 *|
|Fatigue||0(0-0)||0(0-1)||0 (0-0)||0.285(h)||0.414||0.014 *||0.103|
|Loss of appetite||0(0-0)||0(0-0)||0 (0-0)||0.668||0.166||0.046 *||1,000|
|Weight loss||0(0-0)||0(0-0)||0 (0-0)||0.427||0.212||0.157||0.026 *|
|Hypochondria||0.5(0-1)||0(0-1)||0 (0-0)||0.004 *||0.028 *||0.014 *||0.001 *|
|Loss of Libido||0(0-0)||0(0-0)||0 (0-0)||0.731||0.564||0.083||0.046 *|
|Data are presented as median (25 percentile, 75th percentile)
p-valueusing Kruskal-Wallis test
P1: Mann - Whitney U test between measurements before treatment and at 2 months
P2: Mann - Whitney U test between measurements at 2 and 4 months of treatment
P3: Mann - Whitney U test between measurements before treatment and at 4 months
|Table IV Percentage of subjects with scores greater than 0 in Beck Depression Scale items|
|Subscale||Before treatment||At 2 months of treatment||At 4 months of treatment||P||P1||P2||P3|
|Loss of Pleasure||10(45.5)||9(40.9)||3(13.6)||0.028 *||0.065||0.031 *||1,000|
|Self-criticalness||7(31.8)||6(27.3)||1(4.5)||0.032 *||1,000||0.063||0.031 *|
|Agitation||13(59.1)||11(50)||2(9.1)||0.002 *||0.754||0.004 *||0.003 *|
|Loss of Interest||6(27.3)||5(22.7)||2(9.1)||0.156||1,000||0.250||.219|
|Indecisiveness||3(13.6)||7(31.8)||3(13.6)||0. 041 *||0.125||0.125||1,000|
|Worthlessness||10(45.5)||3(13.6)||1(4.5)||0.001 *||0.039 *||0.500||0.004 *|
|Loss of Energy||7(31.8)||5(22.7)||2(9.1)||0.066||0.688||0.250||0.063|
|Fatigue||5(22.7)||7(31.8)||1(4.5)||0.045 *||0.688||0.031 *||0.219|
|Loss of appetite||1(4.5)||4(18.2)||1(4.5)||0.165||0.375||0.250||1,000|
|Hypochondria||11(50)||6(27.3)||1(4.5)||0.002 *||0180||0.063||0.002 *|
|Loss of Libido||4(18.2)||3(13.6)||1(4.5)||0.097||1,000||0.500||0.250|
|Data are presented as number (%)
p-value by Cochrane Q test
P1: McNemar test between measurements before treatment and at 2 months
P2: McNemar test between measurements at 2 and 4 months of treatment
P3: McNemar test between measurements before treatment and at 4 months
The improvement in scores on the BDI-II was significant, which shows that there is no association between isotretinoin and the occurrence of depressive symptoms and, conversely, it has a beneficial effect related to the improvement obtained, as indicated by Rubinow19 and Nevoralová.20 These findings seem to confirm what is reported on the development of depression in predisposed patients,17 because we included only those who had Beck Scale scores that did not qualify as having depression. However, although none had depression during the study, family or personal history of depression that could bring risk were not investigated.
While the absence of a control group could be considered a weakness of our study, we note that the ideal control group would be designed to receive no treatment or only with topical or oral antibiotic therapy; however, we must remember that the characteristic of our selected sample is that they had not responded to treatment with first-line therapy. So to not receive treatment or to receive what they had not responded for another 4 or 6 months for research purposes when what subject needs is solutions to lessen the severity of their skin disease, was not ethically possible, or even advisable.
Finally, while biochemical monitoring allows us to glimpse the safety in the hepatic and lipid profile of isotretinoin use, the BDI-II is a useful tool to detect patients at risk for depression and to intervene in a timely and specialized manner where necessary.
Isotretinoin, which is constituted as first-line management in patients with severe and/or recurrent acne, proved to be a useful drug to reduce depressive symptoms caused by the impact of the dermatosis on body image in patients without predisposition to depression, as well being safe from a biochemical point of view. We recommend emotional evaluation of patients with acne before starting and during treatment with isotretinoin.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.