Evaluation of isotretinoin effects on depression, sleep apnea and sleep quality

Abstract Background Isotretinoin is used to treat severe acne, treatment-resistant moderate acne, and acne that leads to scarring or psychological distress. It has many side effects and is also associated with depression, sleep apnea, and sleep disturbances. Objectives In this study, we aimed to evaluate the effects of isotretinoin on depression, sleep apnea, and sleep quality. Methods A total of 42 patients diagnosed with acne and started isotretinoin treatment were included in the study. In order to compare the effects of isotretinoin, patients were asked to fill out a questionnaire containing the Beck Depression Inventory (BDI), the Berlin Questionnaire (BQ), and the Pittsburg Sleep Quality Index (PSQI) at baseline and third months of treatment. Results There was no statistically significant difference in BDI, BQ, and PSQI scores between the 1st and 3rd months of treatment (p = .53, p = .5, p = .35). Conclusion This study showed that isotretinoin had no significant effects on depression and sleep quality.


Introduction
Acne vulgaris (AV) is a chronic and inflammatory disease that affects the pilosebaceous unit.It is a common skin condition affecting up to 85% of adolescents [1].It can lead to various psychiatric problems such as anxiety, depression, social isolation, low self-esteem, and even suicidal thoughts [2].
Since 1982, isotretinoin has been effectively used to treat severe acne, moderate acne that is resistant to treatment, and acne that causes psychological distress or scarring [3].Isotretinoin has many reported side effects, including dryness of mucocutaneous membranes, headache, hyperlipidaemia, and musculoskeletal pain [4].
Vitamin A is involved in cellular growth and differentiation and has significant functions in the central nervous system [5,6].Aggression, depression, loss of concentration, and psychotic symptoms have been reported in cases of vitamin A toxicity [7,8].Isotretinoin, a derivative of vitamin A, may have an impact on the central nervous system, potentially leading to psychiatric side effects such as depression, behavioural disturbances, and suicidality.However, studies have reported conflicting results regarding the association between isotretinoin and depression.Some studies have reported positive impacts on depression due to acne recovery, while others have found no association between isotretinoin and depression [9][10][11][12].
Sleep apnea has a significant impact on sleep quality and can cause excessive daytime sleepiness.A few individual safety reports have been published in the literature revealing that isotretinoin may cause sleep apnea [13].Delta oscillations in the electroencephalogram (EEG) assess sleep depth and the homeostatic need for sleep [14].Maret et al. reported that the retinoic acid receptor affects delta oscillation in the sleep EEG of mice, suggesting that retinoic acids may affect sleep functions [15].There are also a few cases revealing that isotretinoin may cause sleep disturbances [16][17][18].This study aimed to assess the true correlation between isotretinoin usage and depression.It was also aimed to investigate whether the drug has any effects on sleep apnea and sleep quality.

Materials and methods
A total of 42 acne vulgaris patients who were admitted to the Department of Dermatology of Ankara Training and Research Hospital and started isotretinoin were included in the study.The local ethics committee approved the study (E-20-214).All participants were informed about the study and a written consent form was obtained.The study was performed in accordance with the latest version of the 'Helsinki Declaration' and 'Guidelines for Good Clinical Practice' .
Patients who had any systemic disease, depression or other psychiatric disorders, sleeping disorders, and sleep apnea were not included in the study.The ones who had a BMI ≥30 were also not included.The demographic characteristics of the patient group such as age, sex, BMI, and place of residence were recorded.A daily dose of 0.5-1 mg/kg isotretinoin was initiated.The total cumulative dose of isotretinoin was also calculated and recorded.The severity of acne in the patients was assessed using the global acne scoring system and classified as mild (1-18 points), moderate (19-30 points), or severe (≥31 points) [19].
All of the patients were asked to fill out the questionnaires at baseline and 12th weeks of treatment including the Beck Depression Inventory (BDI), the Berlin Questionnaire (BQ), and the Pittsburgh Sleep Quality Index (PSQI).The scores of BDI, BQ, and PSQI were calculated and compared at baseline and 12th weeks of isotretinoin.
BDI is a self-report questionnaire consisting of 21 items designed to measure depressive symptoms.Each question is scored on a scale of 0-3, and the total score is calculated by summing up all of the results.The total score is categorized as 'no or minimal depression' (less than 10 points), 'mild depression' (10-18 points), 'moderate depression' (19-29 points) and 'severe depression' (30 points or more) [20].
Berlin Questionnaire (BQ) is designed to search for obstructive sleep apnea (OSA).It contains three sections: the first section evaluates snoring, the second section evaluates daytime sleepiness, and the third section investigates the history of hypertension and obesity.At the end of the questionnaire, each section is evaluated separately.Tests that show two or more positive sections are considered to have a high risk for OSA [21].
PSQI is designed to assess sleep quality and contains 19 self-reported items divided into seven subcategories.These subcategories evaluate sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction.Additionally, there is a section for the roommate or bed partner of the filler to answer, which is not included in the total score.A total score of 5 or higher indicates poor sleep quality [22].

Statistical analysis
Descriptive statistics were analysed in the IBM SPSS 22.0 program.Shapiro-Wilk test was applied to reveal whether the data were suitable for normal distribution.The t-test was used to compare the means of two independent groups in a normal distribution.Pearson correlation analysis was used to determine whether there is a linear relationship between two numerical measurements, and if so, what is the direction and severity of this relationship.The statistical significance was accepted as p < .05for this study.

Results
A total of 42 patients were included in this study.Of the 42 patients, 14 (33.3%) were male and 28 (66.7%) were female.The mean age was 20.47 ± 4.01 years.The mean BMI of the patients was 22.08.All patients were living at home with their families except for one patient who was living in the dormitory.Two (4.8%) of the patients had mild acne, 21 (50%) had moderate acne and 19 (45.2%) had severe acne.The mean total cumulative dose of isotretinoin was 2911 milligrams (mg) at the end of the 12th week of treatment.The mean time of sleep of the patients was 8 h 4 min per day (Table 1).
The scores of BDI, BQ and PSQI questionnaires of all patients were evaluated at the first and third month of treatment.18 (42.9%) of the patients had no-minimal depression, 13 (31%) had mild, 3 (7.1%)had moderate, and 8 (19%) had severe depression.At the end of 3rd month of treatment; 20 (47.6%) of the patients had no-minimal depression, 11 (26.2%) had mild depression, 8 (19%) had moderate depression and 3 (7.1%)had severe depression.It was found that the overall BDI scores decreased compared to the baseline, but there was no statistically significant difference (p = .53).
There was no statistically significant difference between the first and 3rd months of treatment in terms of total and three subgroup scores of BQ (p = .5,p = .52,p = .62,p = 1).
There was no statistically significant difference between the first and third months of treatment in terms of PSQI scores (p = .035)and also between PSQI subgroups (p = .55,p = .42,p = .89,p = .4,p = .4,p = 1, p = .3).At baseline, 23 patients had a total PSQI score of ≥5.After 12 weeks of treatment, this number increased to 29.However, there was no statistically significant difference between the first and 3 rd months of treatment (p = 0.17) (Table 2).
There was a positive correlation between the BDI scores and the PSQI scores within 3 months (Table 3).

Discussion
Isotretinoin is used to treat severe acne, treatment-resistant acne, and acne that causes scarring or psychological distress [3].There are many side effects reported due to isotretinoin.However, some side effects are not fully understood and are not fully associated with isotretinoin and need to be further evaluated in future studies.There is no sufficient data in the literature determining the exact effects of isotretinoin on depression and sleep quality.
Sleep disturbances are commonly reported in adolescents.According to the American Academy of Sleep Medicine expert panel, a sleep duration of 8-10 h is sufficient for adolescents.The research reported that most of the adolescents sleep fewer hours [23].Many factors affect sleep quality such as lifestyle behaviours (smoking, eating habits, alcohol consumption), mental health state (depression, anxiety), social factors, and physical factors [24].The main reason for evaluating depression in this study was the strong association between sleep disorders and depression.Patients with chronic sleep disorders are more likely to have mental disorders such as depression.A meta-analysis of prospective studies showed that both short and long sleep duration increases the risk of depression [25].On the other hand, sleeping disorders can be seen in depression, especially insomnia [23][24][25][26].Additionally, The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) includes insomnia or hypersomnia as a diagnostic criterion for depression diagnosis [27].These findings reveal a bi-directional strong relationship between sleep disorders and depression.
In this study, baseline BDI scores were higher than third month scores, with no statistical difference.Moreover, the number of patients with poor sleep quality increased after 12 weeks, with no statistical difference.Therefore, due to decreased depression scores, increased PSQI scores cannot be attributed to the depression of patients.These findings support the theory that isotretinoin may affect sleep quality in these patients regardless of depression.
Besides the bi-directional link between sleep disturbances and depression, having AV and isotretinoin treatment is also linked to depression.Numerous studies have shown that individuals who have acne are more likely to experience depression than those without acne [28,29].However, the relationship between isotretinoin usage and depression is controversial.Oliveira et al. 's meta-analytic research found that the association between isotretinoin and depression was primarily reported in case reports and retrospective studies [30].Prospective studies did not show any association between isotretinoin usage and depression [9,10,[31][32][33][34].This result can be explained by the differences between the designs of the studies.For example, prospective studies, usually exclude patients who have a personal or family history of psychiatric disease from the study.This may have led to lower depression rates associated with isotretinoin.Some studies reported improvement of depressive symptoms in acne patients after isotretinoin treatment [9][10][11][12][35][36][37].This result may be related to the improvement of self-image provided by the regression of acne lesions.Some of the studies using BDI to evaluate the effects of isotretinoin on depression have reported statistically significant positive effects [9,32,36].In this study, depression scores were found to be decreased after treatment with no statistically significant difference.This result could be due to the small number of patients included in the study.
Sleep apnea is characterized by airway obstruction that leads to nocturnal hypoxaemia.Sleep apnea has significant effects on sleep quality.Also, excessive daytime sleepiness is one of the main sleep apnea symptoms.According to Individual safety reports, 106 patients reported sleep apnea among the 168.235 side effects due to isotretinoin treatment.This rate was found to be higher than other drugs.Similarly, isotretinoin-induced sleep apnea (100 among 150.424side effects) was found to be higher than other acne treatments (1 among 210.104side effects) [13].In the present study, none of the patients had a high risk for sleep apnea before and after 3rd months of isotretinoin.To our knowledge, this is the first prospective study that evaluates the association between isotretinoin and sleep apnea.Future studies including larger amount of patients are needed in order to come to an exact conclusion on this topic.
The effects of isotretinoin on sleep quality is a topic that is not fully understood.There are only a few cases of sleep disturbances reported in patients receiving isotretinoin [16][17][18]38].Isotretinoin has effects on the dopaminergic, cholinergic, and serotonergic neurotransmission which is considered the mechanism of isotretinoin on sleep [15,39].However, in the literature, conflicting cases of sleep disorders (both hypersomnia and insomnia) that have different mechanisms have been reported with isotretinoin usage.Therefore, it is difficult to detect the exact efficacy of isotretinoin on sleep disorders.
Gupta et al. reported sustained dreaming in two patients receiving isotretinoin which subsided spontaneously after some time.It is known that dreaming is related to rapid eye movement (REM) sleep.In these cases, isotretinoin may have lengthened the duration of REM sleep which may have led to persistent dreaming [16].
Hypersomnolence has been reported as one of the symptoms in cases of vitamin A toxicity.Similarly, two different cases of hypersomnia were reported after receiving isotretinoin [17,18].In a study, after a four-week vitamin A deficiency diet, mice EEG showed a decreased delta wave in the non-rapid eye movement (NREM) state (deep sleep state), .000total 40 compared to the control group [40].These findings suggest that isotretinoin may affect delta waves in the NREM state and lead to hypersomnia.Contrary to the aforementioned mechanism, there are some reported cases of insomnia induced by isotretinoin.The uS Food and Drug Administration (FDA) adverse event reporting system has extracted 1095 cases of insomnia related to isotretinoin out of 218 594 adverse effects.The correlation between isotretinoin and insomnia was significant when compared to other acne treatments [41].Assiri et al. reported a patient who had severe insomnia after six months of isotretinoin treatment.The patient's symptoms were subsided after dose reduction [38].Ismailogulları et al. performed polysomnography (PSG) on patients before and first month of isotretinoin.They reported increased sleep efficiency without effects on sleep stage and daytime sleepiness.Delta wave in slow wave sleep (a state of NREM sleep) decreased insignificantly.These results were inconsistent with the hypothesis that isotretinoin increases delta waves in slow-wave sleep.Moreover, the increase in sleep efficiency was interpreted as a 'first-night effect' , in which the patients slept well the second time because of familiarity with the procedure [42].
In this study, the PSQI scores were found to be increased by 0.55 points after 3 months of treatment, with no statistically significant difference.While evaluating PSQI subgroups; from the questions that access sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, and daytime dysfunction; higher scores were obtained.Still, there was no statistically significant difference in any subgroups.Overall, we could not reveal any effect of isotretinoin on sleep.Interestingly, one of the patients stated that he could not fall into deep sleep starting from the second month of treatment.The statement of this patient was evaluated as an idiosyncratic reaction.
This study has some limitations.As revealed before, it included a small number of patients.The study did not include a control group in order to compare the subjects.The patients were only assessed by questionnaires and no further examinations (psychiatric examination, PSG) were performed.

Conclusion
This study showed no association between isotretinoin and depression, sleep apnea, or sleep quality.The literature contains only a few case reports of sleep disturbances due to isotretinoin treatment and only one study in a small group of patients.Further studies with larger sample groups and more objective examinations are needed to reveal the exact effects of isotretinoin on sleep quality and depression.

Table 1 .
Characteristics of patients.

Table 2 .
Comparison of scoring systems between week 0 and week 12.

Table 3 .
Correlation analysis between Bdi and PsQi score at week 0 and week 12.