P- Reviewer: Belli H, Yap FBB S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK
Published online Mar 22, 2016. doi: 10.5498/wjp.v6.i1.136
Peer-review started: September 21, 2015
First decision: October 30, 2015
Revised: December 9, 2015
Accepted: December 29, 2015
Article in press: January 4, 2016
Published online: March 22, 2016
AIM: To investigate the frequency and severity of depression and/or anxiety in isotretinoin (ITT)-treated subjects and in a non-ITT control group.
METHODS: Sixty consecutively-admitted non-psychiatric outpatients with acne were assigned to either ITT at a fixed dose of 30 mg/d (n = 36) or “other treatment” group (OT; n = 24). The Zung depression or anxiety scales (with cut-off points), two locally developed scales for depression (GeDepr) and anxiety (Ansilet) (without cut-off points) and clinical global impression scales of acne severity were administered at baseline and at weeks 6 and 12 of treatment. Data was analyzed with the chi-squared test and covariance analysis.
RESULTS: Gender distribution, age, marital status and education level did not differ between both treatment groups. The frequency of depression, as defined by the Zung scale cut-off points was similar in the ITT and in the non-ITT groups: Weeks 6 and 12: 8.3% in both groups, P = 0.9. The frequency of anxiety was similar in the groups as well: Week 6: ITT = 8.3%; OT = 0.0%, P > 0.05; week 12: ITT = 11.1%, OT = 4.2%, P > 0.05. The scores in both scales’ sets did not differ between the treatment groups at any evaluation time point (P > 0.05). Five ITT-treated subjects (13.8%) and two from the OT-treated group (8.3%) developed clinically significant anxiety and/or depression during treatment (P > 0.05).
CONCLUSION: Our study confirms the safety of ITT regarding psychological side effects in regular dermatological patients. Susceptible subjects may exist but their identification requires additional strategies.
Core tip: Isotretinoin (ITT) is frequently used for acne therapy, particularly in young people, but concerns exist regarding the risk of depression and suicide attempts. We conducted a 12-wk prospective study administering a fixed ITT dose in non-psychiatric acne patients an in a non-ITT control group. We used categorical and continuous scales for the assessment of depression and anxiety. The frequency and severity of psychopathology was similar in both treatment groups, stressing the safety of ITT in typical dermatological patients. However, 13.8% ITT subjects and 8.3% of the non-ITT developed clinically significant anxiety and/or depression. Hence, susceptible subjects exist, who deserve further investigation and assistance.
- Citation: Suarez B, Serrano A, Cova Y, Baptista T. Isotretinoin was not associated with depression or anxiety: A twelve-week study. World J Psychiatr 2016; 6(1): 136-142
- URL: https://www.wjgnet.com/2220-3206/full/v6/i1/136.htm
- DOI: https://dx.doi.org/10.5498/wjp.v6.i1.136
Isotretinoin (ITT) is a vitamin A-related compound widely used in the treatment of severe cystic acne vulgaris. It is less frequently used to treat squamous-cell carcinoma, brain or pancreatic cancer and severe ichtyosis.
The safety of ITT on mental functioning has been a concern since its introduction into clinical practice. For example, as early as in 1983, clinically significant depression was reported in a case series.
The association between ITT treatment and psychopathology, particularly with depressive symptoms, comes from accumulated evidence of case reports, temporal association, challenge-re-challenge tests, dose response/class effect studies, and biological plausibility. As a matter of fact, ITT was among the top five drugs with the most frequent spontaneous reports of depression in a recent survey conducted in the United Kingdom. Collectively, these results have been criticized for not discriminating between the worsening of pre-existing psychopathology and the development of de novo psychopathology.
The frequency of depression during ITT administration observed in group studies ranges from 1% to 11%. The low frequency of depression obtained in some studies has been associated with protocols based on self-reports of psychological symptoms. Research has shown that patients tend to underestimate the magnitude of depression in comparison to their family controls. Besides, numerous negative studies lacked standardized diagnostic protocols and/or control groups.
Current research trends suggest that the risk of ITT-related depression maybe particularly relevant in a minority of patients who are also susceptible to other ITT neural side effects, such as headache[4,7]. Besides, subjects with bipolar, anxiety or obsessive-compulsive disorders may be at risk of clinical worsening during ITT administration[4,8]. By contrast, numerous practitioners and research studies report that ITT may rather improve the psychological status in patients with severe acne. These results are not in contradiction with the finding of a specific minority of subjects with increased susceptibility to ITT-related psychological side effects.
In this longitudinal 12-wk study, we evaluated depression and anxiety symptoms in acne patients receiving either ITT or antibiotics by using not only the well-known Zung scales for depression/anxiety but also a set of instruments developed and previously validated at Los Andes University, Mérida, Venezuela.
This is a naturalistic, longitudinal, open-labeled study conducted in a non-probabilistic sample from February 2013 to June 2013 at the Dermatology Department of Los Andes University Hospital in Mérida, Venezuela. It was approved by the Ethics Committee and by the Institutional Review Board of the Department of Psychiatry, Los Andes University Medical School, Mérida, Venezuela. No formal trial registration system exists in this country.
Consecutively admitted patients consulting for acne were invited to participate in the study and filled an informed consent of voluntary participation. Treatments were assigned by a dermatologist (YC) according to disease severity and patient’s income. The participating subjects were assigned either to the ITT-group (30-40 mg/d) or to the OT-group that consisted in the administration of a combination of oral or topic antibiotics and the antibacterial agent benzoil peroxide. Exclusion criteria were previous administration or intolerance to ITT, < 18 years of age, and/or explicit refusal to participate in the study.
Acne severity was assessed by the dermatologist at baseline only by using a 5-point, likert-type, clinical global impression scale, from 0 as “minimally severe” to 5 as “very severe”. At weeks 6 and 12, the patients and the treating physician assessed the changes in acne severity compared to baseline by using a 7-point, likert-type scale, from 0 as “markedly worst” to 7 as “very much improved”.
Depression and anxiety were evaluated at baseline and at weeks 6 and 12 with categorical and continuous self-administered scales. The former consisted in the validated Spanish versions of the Zung depression and anxiety scales that provided a categorical classification[9-11]. Every scale consisted of 20 items with positive or negative valence that explored the frequency of depression or anxiety signs and symptoms, as follows: From 1 = rarely to 4 = always. Each subject was then classified as non-depressed or non-anxious when scoring < 50 points, or slightly, moderately or severely depressed and/or anxious when scoring 50-59, 60-69 and ≥ 70 points, respectively.
The continuous scales corresponded to the previously mentioned Zung scales plus the following two scales for continuous quantification of depression or anxiety levels. The “Ge-Depr” is a two-factor scale consisting of 16 depression-related items. It was validated in 249 Venezuelan subjects and reported a Cronbach alpha coefficient of 0.88 and Pearson correlation coefficients of 0.65 vs an aggression scale, of 0.68 vs an anxiety scale, and of 0.65 vs a general scale of psychological maladjustment.
The “Ansilet” is a one-factor scale consisting of 15 anxiety-related items. It was validated in 264 Venezuelan university students and reported a Cronbach alpha coefficient of 0.82 and a Pearson correlation coefficient of 0.59 vs the self-esteem Rosemberg scale.
Both local scales were scored with a 6-point likert-type scale from 0 = complete disagreement to 6 = complete agreement and no neutral score. These scales did not include a cut-off point but are aimed to assess changes over time in a continuous scale.
A separate analysis was conducted with the Zung depression scale items that explore suicide-related ideation (items 17 and 19).
Categorical data (frequency of depression or anxiety according to the Zung scales from baseline to week 12 with intra-group and inter-group comparisons) were analyzed with the χ2 test.
Continuous data (depression and anxiety scores) were analyzed with the univariate general linear model with treatment and time as between- and within-group variables, respectively, and age as covariate.
Bivariate correlation analysis was conducted with the Pearson correlation coefficient. Results were considered significant when P < 0.05.
Sixty consecutively admitted patients were assigned either to the ITT-group (n = 36) or to the OT-group (n = 24). No subject was excluded in any group. Gender distribution and education level were similar in both groups, but the ITT-treated males tended to be younger, and the proportion of single (unmarried) subjects was significantly higher in the ITT group (Table 1). Most patients (35 out of 36) received 30 mg/d of ITT; hence, the treatment protocol consisted of a fixed-dose schedule.
|Isotretinoine (n = 36)||Other treatments (n = 24)|
|Gender [n (%)]1|
|16 (44.4)||20 (55.6)||11 (45.8)||13 (54.2)|
|Age (mean ± SD)2|
|23.0 ± 3.2||20.3 ± 2.9||22.9 ± 3.8||23.4 ± 4.4|
|Marital status [n (%)]3|
|34 (94.4)||2 (5.6)||15 (62.5)||9 (37.5)|
|Education [n (%)]4|
|6 (16.6)||35 (83.4)||4 (16.7)||(83.3)|
Acne severity was higher in the ITT - than in the control group. Severe and very severe acne was only observed in the ITT group: 9 subjects (25%) vs 0 subjects (0%): Mann Whitney test: Z = 2.6, P = 0.008.
The frequency of depression or anxiety categorically defined according to the Zung scales and the scores obtained in the continuous scale analysis were similar in both treatment groups at baseline and did not display significant changes over time (Tables 2 and 3). The scores in the depression Zung scale suicide related items were similar in both treatment groups at baseline and at weeks 6 and 12: Item 17: F (1) = 0.001, P = 0.9; item 19: F (1) = 0.5, P = 0.5 (data not shown).
|Categorical level of depression [n (%)]1|
|Basal||Week 6||Week 12||Basal||Week 6||Week 12|
|Mild||1 (2.8)||3 (8.3)||3 (8.3)||2 (8.3)||2 (8.3)||2 (8.3)|
|Moderate||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|Severe||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|Total||1 (2.8)||3 (8.3)||3 (8.3)||2 (8.3)||2 (8.3)||2 (8.3)|
|Categorical level of anxiety [n (%)]2|
|Basal||Week 6||Week 12||Basal||Week 6||Week 12|
|Mild||1 (2.8)||2 (5.5)||1 (2.8)||1 (4.2)||0 (0.0)||0 (0.0)|
|Moderate||0 (0.0)||1 (2.8)||2 (5.5)||0 (0.0)||0 (0.0)||0 (0.0)|
|Severe||0 (0.0)||0 (0.0)||1 (2.8)||0 (0.0)||0 (0.0)||1 (4.2)|
|Total||1 (2.8)||3 (8.3)||4 (11.1)||1 (4.2)||0 (0.0)||1 (4.2)|
|Basal||Week 6||Week 12||Basal||Week 6||Week 12|
|GeDep scale1||38.3 ± 2.5||38.1 ± 2.3||36.8 ± 2.3||36.9 ± 3.1||34.9 ± 2.9||34.9 ± 2.9|
|Zung scale2||35.2 ± 1.3||33.8 ± 1.4||34.2 ± 1.4||34.9 ± 1.6||34.6 ± 1.7||35.0 ± 1.7|
|Basal||Week 6||Week 12||Basal||Week 6||Week 12|
|GegDep scale3||43.3 ± 2.4||41.9 ± 2.3||40.8 ± 2.3||40.9 ± 2.9||38.1 ± 2.9||36.8 ± 2.9|
|Zung scale4||37.2 ± 1.1||36.7 ± 1.4||36.6 ± 1.6||34.5 ± 1.4||32.4 ± 1.7||32.8 ± 1.9|
The Zung depression and anxiety scale scores showed a highly significant positive correlation with the GeDepr and Ansilet scale scores, respectively: The r coefficient value was over 0.60, P = 0.000 in all the analyses (data not shown).
Clinical assessment of acne severity and depression/anxiety scores: For the sake of concision, we only present the data related to the GeDepr and Ansilet scale scores.
No significant correlations were observed between the clinical severity assessment of acne at baseline and the depression and anxiety scores at any time-point in the ITT group. However, in the OT group, significant correlations were observed in the depression scores, and marginally significant correlations were detected in the anxiety value sets (Table 4).
|Treatment group||Depression score (baseline)||Depression score (week 6)||Depression score (week 12)||Anxiety score (baseline)||Anxiety score (week 6)||Anxiety score (week 12)|
|ITT||PAB vs||0.1 (0.4)||0.08 (0.6)||0.02 (0.9)||0.1 (0.5)||0.1 (0.4)||0.05 (0.8)|
|OT||PAB vs||0.48 (0.01)1||0.5 (0.01)1||0.5 (0.01)1||0.25 (0.2)||0.39 (0.054)||0.37 (0.07)|
Patient and physician perceived changes in acne severity vs depression/anxiety scores: Several negative correlations reached statistical significance in the ITT group but not in the OT group (Table 5). The negative correlations reveal the improvement in psychological symptoms (decreased depression or anxiety scores) along with the decrease in acne severity (magnitude of the improvement perceived by the patient and the physician at a given time point).
|Treatment group||Depression score(week 6)||Depression score(week 12)||Anxiety score(week 6)||Anxiety score(week 12)|
|ITT||Patient evaluation vs||-0.31 (0.067)||-0.43 (0.009)1||-0.43 (0.01)1||-0.38 (0.02)1|
|Physician evaluation vs||-0.28 (0.1)||-0.33 (0.049)1||-0.35 (0.03)1||-0.32 (0.057)|
|OT||Patient evaluation vs||-0.1 (0.6)||-0.-08 (0.7)||-0.3 (0.9)||0.25 (0.2)|
|Physician evaluation vs||-0.15 (0.5)||-0.18 (0.4)||-0.03 (0.9)||-0.08 (0.7)|
Five ITT-treated subjects (13.8% of the ITT group) and two receiving other treatments (8.3% of the OT group patients) developed clinically significant anxiety and/or depression during treatment [χ2 (1) = 0.06, P = 0.8] (Table 6). In the five subjects of the ITT group, three were females (60%) and two (40%) reported previous symptoms of depression and/or anxiety.
|Treatment||Age (yr)||Gender||Personal history of depression||Personal history of anxiety||Diagnosis before treatment (categorical Zung scales)||Diagnosis during treatment (categorical Zung scales)|
|ITT||28||M||No||Yes||Anxiety and depression||Anxiety and depression|
|ITT||25||F||No||No||-||Anxiety and depression|
|OT||18||M||Yes||Yes||Anxiety and depression||Anxiety and depression|
One subject in each group increased their scores in the suicide-related items in the Zung depression scale (items 17 and 19, data not shown). However, because of the very small number of subjects (5 only), an association between gender and previous psychiatric disorders with ITT-induced psychopathology cannot be inferred.
This study showed that oral ITT in a fixed-dose schedule of 30 mg/d, compared to a control group of subjects treated with antibiotics or antibacterial agents, was not associated with a significant increase in the frequency of depression or anxiety or in the scores of the corresponding scales up to 12 wk of treatment. This result points to a safe profile of short-term ITT administration in a typical group of non-psychiatric outpatients with acne.
The correlation analysis showed complex results in both treatment groups: On the one hand, only the OT group showed significant correlations (positive ones, mainly in the depression scores) between the physician basal evaluation of acne severity and the psychopathological scales over time (Table 4). This may reveal a poor response to OT because one might have expected a trend toward negative correlations, that is the greater the physician appreciation of the acne severity at baseline, the lower the depression or anxiety scores after successful treatment.
On the other hand, only the ITT-treated patients showed the expected negative correlations between the changes in acne severity observed by the physician and those perceived by the patients (higher scores over time) and the scores in depression and anxiety at each evaluation time point (lower punctuations along time (Table 5). As the correlation data in Table 4 show, this result may imply a better response of the ITT-treated group. However, this is only speculative, because the present investigation was not designed to properly assess the comparative treatment response.
Five ITT-treated subjects developed clinically significant psychopathology: Two patients with pure anxiety, one with pure depression and two with both diagnoses. Personal antecedents of depression or anxiety or significant symptoms at baseline were observed only in two of these five ITT-treated patients. Hence, this small sub-sample of patients does not allow us to explore the predisposing features that favored the development of psychopathology during ITT administration.
The frequency of depression in the ITT group, alone or in combination with anxiety, was 8.3% (3 out of 36 subjects). This value is within the range reported in the literature which is between 1% and 11%.
Most research on the psychological deleterious effects of ITT has focused on depression development or aggravation and suicide ideation and/or suicide attempts during treatment[4,5,15-27]. Most recent reviews point to a safe profile of ITT regarding depression and/or suicide[28-31] with the exception of a study conducted by an Australian research group. According to a comprehensive review, important methodological differences among the studies would explain the divergent results.
The present research agrees with the conclusion that depression occurs in a minority of ITT-treated patients. Recent studies suggest that these depression-prone patients may be susceptible to other neural side effects of ITT, such as headache. Interestingly, preliminary data suggest that subjects with bipolar disorders may be particularly susceptible of symptom worsening during ITT treatment[33,34]. Since migraine is common in bipolar disorder, particularly in the predominantly depressive type, and since psychoses, panic attacks and obsessive doubting worsening have also being reported during ITT treatment[8,36-38], the predictive value of headache as a relatively specific marker for ITT-induced depression should be assessed in future studies.
This research field would also benefit from animal studies that would explore the pathways involved in the induction of depression-related behaviors in rodents, such as changes in brain monoamine transmission and corticotrophin-releasing hormone[39,40]. Finally, it is worthwhile mentioning that genetic studies are currently under way to identify genetic polymorphisms in the retinoic receptors that may predispose to or protect from ITT-unintended effects.
The present study has the following strengths: A longitudinal evaluation, a control group, the administration of scales for psychopathological assessment that provided categorical and continuous evaluation and the use of locally-developed scales that provided an adequate wording for this specific clinical population. However, it has several limitations: A relatively small sample size and a relatively short period of psychological assessment; the patients were older than those who typically request acne therapy (i.e., adolescents); evaluations were not blind; treatment assignment was not random, and hence, the acne severity was higher in the ITT group than in the control group, and there was no formal scale to assess such a severity.
Further research should take into account that, while random treatment assignment appears problematic from an ethical point of view, semi-quantitative scales for acne severity have been developed. Since severe acne is in many cases a chronic and severe condition and since ITT is often prescribed in doses higher than 30 mg/d and for prolonged periods, long-term studies with high ITT doses are also needed. In those studies, other physical ITT side effects must be assessed. The influence of ethnicity and previous psychiatric disorders on ITT safety should also be examined in further research.
We are grateful to the patients for their cooperation and to Françoise Salager-Meyer for her editorial assistance. The authors did not receive any funding for the conduction of this study.
Concerns exist about the risk of depression, suicide risk and/or anxiety during isotretinoin (ITT) administration in acne-treated patients.
Limited information exists about the psychopathology background and the pretreatment mental status of subjects who developed clinically significant depression/anxiety during ITT administration.
Few studies in ITT-treated subjects include an adequate control group, locally-developed psychopathological scales and a pretreatment evaluation. The authors aimed to overcome these limitations in the present study.
Approximately one out of ten subjects treated for acne either with ITT or antibiotics in the short term may develop clinically-significant depression or anxiety. Subjects at risk for psychopathology must be identified before starting ITT administration.
ITT is a vitamin. A-related compound widely used in the treatment of severe cystic acne vulgaris.
Well written manuscript.
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