Report

Psychiatric Kaymak Report et al. symptoms related to isotretinoin

XXX Blackwell Oxford, International IJD 1365-4632 0011-9059 2008 The UK Publishing International Journal Ltd of Dermatology Society of Dermatology

Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents
Yesim Kaymak, MD, Ender Taner, MD, and Yasemen Taner, MD

From the Dermatology Specialist, University of Gazi, Health Center, Gaza, Palestine, Psychiatry Specialist, University of Gazi, Health Center, Gaza, Palestine, and Child and Adolescent Psychiatry Specialist, University of Ufuk, Faculty of Medicine, Department of Child and Adolescent Psychiatry, Ankara, Turkey Correspondence Yeim Kaymak, MD Hodere cad. air Baki Sok. 2/5 Y Ayranci-Ankara 06540, Turkey E-mail: yesimkaymak@yahoo.com

Abstract
Background Since the introduction of isotretinoin to the market, many adverse psychiatric effects, including depression, anxiety and suicide attempts were reported. The aim of this study was to determine whether patients with acne who were treated with isotretinoin experienced signicant increases in psychiatric symptoms over a 4-month period compared with patients who received topical acne therapy. Methods Seventy-eight acne patients were allocated either to isotretinoin treatment (study group) (n = 37) or to topical treatment (control group) (n = 41). Their psychological status was evaluated at the baseline, second and fourth months of the treatment. All patients were required to complete the dermatology life quality index (DLQI), the Hospital anxiety and depression (HAD) scale, and the beck depression inventory (BDI). Results The two groups were not different from each other in terms of DLQI, BDI, HAD-A, HAD-D and total HAD scores at baseline. However, at the end of the second month quality of life was more impaired in the topical treatment group compared to the isotretinoin group (P < 0.05), and there were no difference between two groups in terms of BDI, HAD-A, HAD-D, and total HAD scores (P > 0.05). At the end of fourth month quality of life and all psychological test scores had improved more in the isotretinoin group compared to topical treatment group (P < 0.05). Conclusion Results of the present study indicate that there is no increase in depressive and anxiety symptoms in the isotretinoin treatment group compared to that in the topical group. Instead, successful treatment of acne seems to improve both depressive and anxiety symptoms and improve quality of life.

Introduction Isotretinoin is a synthetic oral retinoid that has great efficacy against severe, recalcitrant, nodulocystic acne. Since its introduction to the market, many adverse psychiatric effects, including depression, psychosis, mood swings, violent behavior, suicide, and suicide attempts were reported.13 Although some case reports and open label studies investigated the association of depression and isotretinoin treatment, results were conflicting.4,5 The overall lack of concrete scientific data limits any conclusion that can be drawn about a causal relationship between isotretinoin and adverse psychiatric events.6 The incidence of depression in isotretinoin users is 0% in studies with a control group and 11.5% in studies without controls. These rates are similar to the incidence of
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depression in the general population, which is known to be about 1%.68 Depression is a multifactorial disorder, and both acne and psychiatric disorders,9,10 often affect people in the 15 24 years age group. Eighty-five to 90% of adolescents and young adults have some degree of acne. The main goal of acne treatment is to prevent physical scarring by limiting the number of lesions and the duration of the disease, thereby minimizing its psychological impact.11,12 The psychological impact of acne is well documented, particularly in adolescents.1214 Studies have shown that adolescents with acne are at higher risk of depression and suicidal ideation and have lower self-esteem than their counterparts without acne.13,15 Effective dermatological treatment of acne has been shown in some studies to decrease symptoms of depression and anxiety
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and to improve significantly other psychological parameters.16 The potential association between isotretinoin use and depression may be compounded by severe acne,1 and it is difficult to distinguish between drug-related and nondrug related depressive symptoms, such as environmentally or physiologically induced symptoms. A substantial proportion of cases had psychiatric histories and other possible contributing factors (e.g. personal relationship problems, stressful life events, alcohol use) besides their skin disorders and isotretinoin use. The final decision of the FDA concerning adverse psychiatric effects of isotretinoin states that epidemiological studies to date have not shown an association between isotretinoin and depression or suicide because acne itself may be a risk factor for depression. They asserted that there are no known absolute or relative psychiatric contraindications to isotretinoin. Finally, they emphasized that there are no published data that address dose dependence. Despite these recommendations, some patients and clinicians continue to believe that isotretinoin causes dangerous psychiatric effects.6 The aim of this study was to determine whether patients with acne who were treated with isotretinoin experienced significant increases in depressive symptoms, anxiety levels and change in life quality over a 4-month period compared with patients who received topical acne therapy.

Figure 1 Study flowchart

Materials and Methods

Participants A total of 78 patients with severe, moderate or mild acne who applied to the outpatient dermatology clinic of a university health center were included in the study. Participants were recruited from September 2006 to May 2007. Study design and outcome measures At the initial visit, demographic variables, duration of the acne and any previous treatment were noted. School success and the presence of psychiatric disorders, both in their families and themselves, which might have affected the psychological status of the patients, were also noted. This study was designed to be a prospective and controlled trial. Patients were not randomized, but instead factors such as previous treatment failure, the severity and duration of the acne, patient preference, and patient concerns about adverse drug effects inuenced the choice of treatment. Acne was graded using the Global Acne Grading Scale.17 Accordingly, patients were allocated either to isotretinoin treatment (study group) (n = 37) or to topical treatment (control group) (n = 41). Thirty-six patients received 0.50.8 mg/kg/d of isotretinoin with food in two divided doses for at least 20 weeks, ensuring that the cumulative dose was 100 mg/kg. Topical treatment consisted of either topical antibiotics or topical retinoids. The study design is outlined in Fig. 1.
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For the patients who were enrolled for isotretinoin treatment, a pregnancy test result was required for women with childbearing potential before initiating the treatment, and they were warned to use contraceptive methods during treatment. Patients were not allowed to use tetracycline derivatives or other vitamin A preparations. At the initial visit and during the monthly follow-up visits, the following tests were requested: hemoglobin, hematocrit, leukocytes, thrombocyte, urea, creatinine, direct and indirect bilirubin, liver enzymes (SGOT, SGPT, GGT, ALP), total cholesterol, lipid prole (VLDL, LDL, HDL, triglycerides) and urinalysis. The patients psychological status was evaluated at the baseline, second and fourth months of the treatment by the second author who was blind to the treatment groups. All patients were required to complete the dermatology life quality index (DLQI),17 the hospital anxiety and depression (HAD) scale, and the beck depression inventory (BDI).18,19 The DLQI consists of 10 questions exploring the aspects of life affected by skin disease. It is analyzed under six headings: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Total scores can range from 0 to 30, with higher scores indicating greater disability.18 HAD is a self-rating scale used to assess the risk and to measure the level of depression and anxiety. It contains 14 questions, 7 related to depression and 7 to anxiety.19 The validity and reliability of the Turkish version was good and cut-off points for the depression subscale and anxiety subscale were 7
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out of 8 and 10 out of 11, respectively.20 The BDI is a self-rating Likert type scale composed of 21 items which evaluates the level of depression. Each question is rated from 0 to 3 points. The sum of the points shows the level of depression.21 Subjects with BDI scores over 13 were considered as depressive.22 Any psychiatric intervention, either medical or psychotherapeutic, was considered to be an exclusion criteria in order not to affect the psychological test scores.

Table 1 Mean values, standard deviations and test results of the

two treatment groups

Isotretinoin group (n = 36) Measures DS0 DS2 DS4 DLQI0 DLQI2 DLQI4 BDI0 BDI2 BDI4 HAD-A0 HAD-A2 HAD-A4 HAD-D0 HAD-D2 HAD-D4 HAD-T0 HAD-T2 HAD-T4 Mean 2.55 1.30 0.69 6.11 4.13 3.25 9.77 7.55 5.86 7.00 6.11 5.02 5.33 4.44 3.41 12.38 10.58 8.30 SD 0.60 0.66 0.62 4.13 3.27 3.48 6.62 6.27 5.16 3.33 3.50 3.76 3.51 3.00 3.08 6.24 5.80 6.13 Topical group (n = 29) Mean 2.00 1.68 1.31 5.17 7.10 7.17 9.20 10.6 10.6 6.89 7.72 7.58 5.27 6.27 6.31 12.20 13.93 13.89 SD 0.59 0.60 0.66 3.49 3.77 2.59 7.52 6.07 5.49 3.17 3.28 3.21 3.30 3.48 3.23 6.01 6.12 5.91 z 3.50 2.49 3.48 0.74 3.21 5.17 0.45 1.89 3.32 0.40 1.93 3.03 0.02 1.78 3.40 0.15 1.93 3.42 P 0.001* 0.013* 0.001* 0.45 0.001* 0.001* 0.65 0.058 0.01* 0.68 0.053 0.002* 0.98 0.07 0.001* 0.87 0.053 0.001*

Analysis Comparisons with respect to categorical measures were performed by using 2-tests, corrected for continuity, or by using Fishers exact tests if there were cells with expected frequencies of less than ve. The difference of the means of the DLQI, BDI, HAD and disease severity scores at the baseline, second and fourth months between treatment groups were compared using the MannWhitney U-test. Comparison of the test scores and disease severity within groups was done using the KruskalWallis test. Comparisons between pairs of treatments were made using t-tests, in which the overall analysis of covariance showed signicant differences. All statistics are reported two-tailed; standard deviations are reported throughout. Results of the dependent variables were expressed as mean values SD, with a P-value of < 0.05 being considered signicant. spss 10.0 was used for statistical analysis.

Results Twenty-nine patients in the topical treatment group and 36 patients in the isotretinoin group were able to complete the study. Most of the drop-outs in the topical treatment group happened after the first visit for unknown reasons, and the rest discontinued treatment on their own wishes due to a lack of effectiveness of the treatment. One patient in the isotretinoin group discontinued treatment after one month due to muscle pain and headaches. The mean ages, duration of disease and previous duration of acne treatment in the isotretinoin and topical treatment groups were 20.61 1.87 / 20.51 2.01, 4.86 2.81 / 3.93 2.86, and 3.12 1.70 / 4.35 2.80, respectively. Overall, 11 males and 25 females were present in the isotretinoin group, and 9 males and 20 females were present in the topical treatment group. The isotretinoin treatment group and the topical treatment group did not differ from each other in terms of age (z = 0.33, P = 0.73), gender (2 = 0.02, P = 0.967), duration of disease (z = 1.73, P = 0.08) and previous duration of acne treatment (z = 1.35, P = 0.17). Baseline disease severity was significantly higher in patients in the isotretinoin group compared to that in the topical treatment group, as expected (P < 0.05). Both groups were not different from each other in terms of DLQI, BDI, HADA, HAD-D, and total HAD scores at baseline. However, at the end of the second month quality of life was more impaired
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DS, Disease Severity; DLQI, Dermatology Life Quality Index; BDI, Beck Depression Inventory; HAD-A, Hospital Anxiety and Depression scaleAnxiety; HAD-D, Hospital Anxiety and Depression scaleDepression; HAD-T, Hospital Anxiety and Depression scale-total (*p < 0.05).

in the topical treatment group compared to the isotretinoin group (P < 0.05), and there were no differences between the two groups in terms of BDI, HAD-A, HAD-D, and total HAD scores (P > 0.05). At the end of the fourth month, quality of life and all psychological test scores had improved more in the isotretinoin group compared to the topical treatment group (P < 0.05). The means and standard deviations, and the comparison of the treatment groups in terms of disease severity, life quality and psychological test scores throughout the follow-up are presented in Table 1. There was a significant reduction in disease severity both in the isotretinoin and the topical treatment group over time (P < 0.05). The isotretinoin treatment group showed an improvement in DLQI scores and a reduction in BDI, HADA, HAD-D, and total HAD scores over time in the second and fourth months compared to the baseline. However, the topical treatment group showed either no improvement or a reduction in life quality over time and showed either no change or an increase in BDI, HAD-A, HAD-D and total HAD scores over time. The comparison of the change in measurements over time within groups is presented in Table 2. The mean values and standard deviations are presented in Table 1. Psychopathology regarding cut-off scores of psychological tests in treatment groups were not different from each other
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Table 2 Comparison of the change in measures by time within

Table 3 Comparison of the treatment groups with regard to cut-

groups
Isotretinoin group (n = 36) Measures DS 0-2 DS 0-4 DS 2-4 DLQI 0-2 DLQI 0-4 DLQI 2-4 BDI 0-2 BDI 0-4 BDI 2-4 HAD-A 0-2 HAD-A 0-4 HAD-A 2-4 HAD-D 0-2 HAD-D 0-4 HAD-D 2-4 HAD-T 0-2 HAD-T 0-4 HAD-T 2-4 z 5.30 5.37 4.30 3.69 3.86 2.93 3.27 3.75 2.66 2.39 3.28 3.22 2.24 3.57 2.70 2.87 3.91 3.51 P 0.001* 0.001* 0.001* 0.001* 0.001* 0.003* 0.001* 0.001* 0.008* 0.017* 0.001* 0.001* 0.025* 0.001* 0.007* 0.004* 0.001* 0.001* Topical group (n = 29) z 3.00 3.87 3.31 3.43 2.87 0.57 2.95 2.83 0.36 2.37 1.89 0.32 2.79 2.53 0.25 2.72 2.39 0.41 P 0.003* 0.001* 0.001* 0.001* 0.004* 0.56 0.003* 0.005* 0.719 0.18 0.058 0.74 0.005* 0.011 0.801 0.006* 0.01* 0.67

off scores of measures

Isotretinoin (n = 36) 12 7 4 4 4 4 9 5 4 Topical (n = 29) 6 6 10 5 7 4 10 12 10

Measures BDI 0 BDI 2 BDI 4 HAD-A 0 HAD-A 2 HAD-A 4 HAD-D 0 HAD-D 2 HAD-D 4

2 1.282 0.016 5.192 0.506 1.939 0.107 0.698 6.285 5.192

P 0.257 0.91 0.033* 0.497 0.196 1.00 0.403 0.012* 0.023*

BDI, Beck Depression Inventory; HAD-A, Hospital Anxiety and Depression scale-Anxiety; HAD-D, Hospital Anxiety and Depression scale-Depression; HAD-T, Hospital Anxiety and Depression scale-total (*P < 0.05).

Table 4 Comparison of some demographic variables and school

success between groups based on cut off scores of baseline BDI

Variables BDI 13 Female Male Good Bad Present Absent Present Absent 14 4 14 4 3 15 3 15 BDI < 13 16 31 40 7 2 45 0 47 2 0.85 0.49 2.82 8.21 P 0.54 0.48 0.12 0.019*

DS, Disease Severity; DLQI, Dermatology Life Quality Index; BDI, Beck Depression Inventory; HAD-A, Hospital Anxiety and Depression scale- Anxiety; HAD-D, Hospital Anxiety and Depression scale-Depression; HAD-T, Hospital Anxiety and Depression scale-total (*P < 0.05).

Gender School success Family history of psychiatric disorder History of psychiatric disorder

at the baseline. There were significantly more patients with BDI scores over 13 in the topical treatment group compared to the isotretinoin group at the end of the fourth month. With regard to the cut-off scores of HAD-D, the number of patients in the topical treatment group was significantly more than the number of patients in the isotretinoin group at the end of the second and fourth months (P < 0.05). The number of patients and test values are presented in Table 3. The baseline BDI and HAD-D (r = 0.678, P = 0.001) and fourth month BDI and HAD-D (r = 0.767, P = 0.001) are highly correlated. With regard to the cut-off scores of baseline BDI, 18 patients in the whole sample had depressive symptoms. Comparison of the patients based on BDI scores over 13, and patients with BDI scores under 13, according to DLQI scores (z = 0.42, P = 0.67) and disease severity (z = 0.40, P = 0.68) revealed no difference between the groups. Also, the groups based on cut-off scores of baseline HAD-D did not differ from each other regarding DLQI scores (z = 0.86, P = 0.38) and disease severity (z = 0.20, P = 0.83). Groups based on cut-off scores of BDI did not differ from each other regarding sex, school success and family history of psychiatric disease (P > 0.05). History of psychiatric disease was significantly higher in patients with BDI over 13 compared to that in patients with
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BDI, Beck Depression Inventory (*P < 0.05).

BDI under 13 (P < 0.05). The test scores and number of patients are presented in Table 4. Comment The results of the present study indicate that there was no increase in depressive symptoms in the isotretinoin treatment group compared to that in the topical group. The use of isotretinoin in adolescent and young adults did not increase depressive and anxiety symptoms as measured by psychiatric tests. On the contrary, the present study reveals that successful treatment of acne alleviates depressive symptoms. Poor improvement in the symptoms of acne in patients under topical treatment might have resulted in poor compliance of the patients and drop outs. Therefore, we can conclude that depressive symptoms related to acne were resolved with proper treatment of acne, particularly in the isotretinoin group. These results are in accord with the former studies which report that clinically significant depression was not more
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prevalent in the isotretinoin group than in the conservative therapy group and in some cases isotretinoin treatment may actually improve depressive symptoms in acne patients.16,2326 From the entire sample, 27.7% of the patients were in the range of clinically significant depression (> 8) on the HAD-D scale before either isotretinoin or topical therapy use. The number of patients who remained in the depressive range after 4 months was significantly reduced in the isotretinoin group compared to the topical therapy group, indicating the effect of successful treatment of acne on psychiatric symptoms, and this is consistent with the literature.25 In the present study, at the end of 4 months, a similar improvement in depressive symptoms was found in terms of BDI scores in the isotretinoin group which was not observed in the topical group. These findings were consistent with the previous study which reported a significant decrease in the mean score of the BDI at the end of isotretinoin treatment among patients who had scores in the range of clinically significant depression before treatment.27 All patients with a previous history of depression also had depressive symptoms at the onset of treatment. This may indicate that patients with a prior history of psychiatric disorder may be more vulnerable to experiencing psychiatric symptoms with the emergence of acne which acts as a stressful condition. Therefore, these patients should be identified and closely observed for the possible exacerbation of the psychiatric symptoms. A limitation of the study is its relatively small sample size, which limits statistical power and increases the chance of missing small associations or effects, either beneficial or deleterious. Additional studies are needed to clarify the association or otherwise of isotretinoin with depression. In the meantime, physicians are advised to inform patients prescribed isotretinoin (and parents) immediately to report mood swings and symptoms suggestive of depression such as sadness, crying, loss of appetite, unusual fatigue, withdrawal, and inability to concentrate, so that patients can be promptly evaluated for appropriate treatment, including consideration of drug discontinuation and referral for psychiatric care. Almost one fifth of patients with acne have psychiatric symptoms; therefore, it is necessary in caring for patients with acne to not only monitor the physical changes but also monitor the patients psychological status with self-administered, easily applicable tools such as HAD. Conclusion The results of the present study indicate that there is no increase in depressive and anxiety symptoms in the isotretinoin treatment group compared to that in the topical group. On the contrary, the present study reveals that successful treatment of acne improves both depressive and anxiety symptoms and improve quality of life.
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References
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20 Aydemir , Gvenir T, Key L, et al. The validity and reliability of the Turkish version of Hospital anxiety and depression scale (in Turkish). Turk Psikiyatri Derg 1997; 8: 280287. 21 Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch General Psychiatry 1961; 4: 561571. 22 Lasa L, Ayuso-Mateos JL, Vazquez-Barquero JL, et al. The use of Beck Depression Inventory to screen for depression in the general population: a preliminary analysis. J Affect Disord 2000; 57: 261265. 23 Cohen J, Adams S, Patten S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can J Clin Pharmacol 2007; 14: 227233.

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