The effects of isotretinoin treatment on hippocampus based learning, psychiatric disorder symptoms, theory of mind and cognitive emotion regulation skills of adolescents diagnosed with acne

ABSTRACT: Aim: The relationship between skin diseases and psychiatric disorders has long been investigated. In this thesis, it was aimed to evaluate the changes in psychopathologies according to DSM-5 criteria, depression, anxiety, obsession complaints, body perception and self-esteem, memory and visuospatial functions, cognitive emotion regulation skills, empathy, alexithymia and broad autism spectrum disorder phenotype symptoms in adolescents diagnosed with acne vulgaris (AV) and treated with isotretinoin for twelve weeks before and after treatment with a semi-structured interview. Methods: In this single-center, prospective, clinic-based study, adolescent participants aged 12-18 years who applied to Bolu Abant Izzet Baysal University Dermatology outpatient clinic between November 2023 and November 2024 were evaluated. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K- SADS-PL) and Clinical Global Impression Scale (CGI) were administered to the participants by the clinician to assess their psychopathology and severity before starting isotretinoin treatment. The Revised Child Anxiety and Depression Scale - Child Version (RCADS-CV) was used to assess subjectively reported complaints of depression and anxiety. The following scales were administered to evaluate specific psychological constructs: the Difficulties in Emotion Regulation Scale (DERS) and Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CA) for emotion regulation skills, the KA-SI Empathic Tendency Scale Adolescent Form (KA-SI-E) for empathy, the Toronto Alexithymia Scale (TAS-20) for alexithymia, the Rosenberg Self-Esteem Scale (RSES) for self-esteem levels, the Autism Spectrum Quotient (AQ)-Adolescent Form for subthreshold autism spectrum disorder (ASD) symptoms, and the Body Perception Scale (BPS) for body perceptions.The Stroop Color-Word Test (SCWT) was used to assess information processing speed and selective attention, including resistance to distractors. The Visual and Auditory Digit-Span Test (VADS, Forms A and B) was employed to evaluate auditory and verbal perception, as well as short-term memory. The Serial Digit Learning Test (SDLT-9) was utilized to measure short-term memory, while the Reading the Mind in the Eyes Test (RMET) was administered to assess theory of mind (ToM) and emotion recognition skills. In addition, Sociodemographic Data Form was used to assess sociodemographic characteristics. The tests were repeated after 12 weeks of treatment. Results: A total of 78 adolescents, mostly girls (n= 49, 62.8%) and twelfth graders (n= 36, 46.2%) were included in the study. The academic achievement of female adolescents diagnosed with acne was significantly higher than that of male adolescents. The median duration of acne was significantly higher in girls than in boys. In the entire sample, two adolescents were diagnosed with Generalized Anxiety Disorder (GAD)—one girl (50.0%) and one boy. Three adolescents met the criteria for Specific Phobia, including one girl (33.3%). Five were diagnosed with Obsessive-Compulsive Disorder (OCD), with three girls constituting 60.0% of that group. One girl was diagnosed with enuresis (100.0%), while two adolescents were diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD), with one girl representing 50.0%. Two adolescents met the criteria for Oppositional Defiant Disorder (ODD), with one girl accounting for 50.0%. Finally, one boy was diagnosed with motor tic disorder (100.0%). Additionally, four adolescents were diagnosed with Major Depressive Disorder (MDD)—three girls (75.0%) and one boy. Two adolescents were diagnosed with panic disorder, including one girl (50.0%), and two met the criteria for GAD (one girl, 50.0%). Three were diagnosed with Specific Phobia (one girl, 33.3%), and five with OCD (three girls, 60.0%). One girl was diagnosed with enuresis (100.0%), while two adolescents were diagnosed with ADHD (one girl, 50.0%) and two with ODD (one girl, 50.0%). Lastly, one boy was diagnosed with motor tic disorder (100.0%). It was observed that the median separation anxiety and panic disorder subscale scores of female adolescents were significantly higher than those of male adolescents before treatment. The rate of female adolescents reporting clinically significant panic disorder complaints was significantly higher than that of male adolescents. It was observed that the mean scores of the (ERQ-CA)-Reappraisal subscale were significantly higher than those of boys. It was observed that there was no significant difference between the mean scores of male and female adolescents diagnosed with AV in the DERS subscale and total scores. The mean scores of emotional, cognitive and total empathy scores of female adolescents were significantly higher than those of male adolescents. The mean scores of the TAS-20 subscale did not show a significant difference between genders. It was found that the mean scores of male adolescents on the AQ-Adolescent imagination subscale were significantly higher than those of girls. The mean total scores of boys and girls did not differ significantly from each other, but the proportion of girls (n= 39, 79.6%) who reported high satisfaction with body image was significantly higher than that of boys (n= 16, 55.2%). There was no significant difference between the genders in terms of the mean scores of VADS-A and B and SDLT-9 and RMET correct answers. Correlation analyses revealed that the duration of acne in adolescents with AV was significantly, positively and weakly correlated with RCADS-CV Generalized Anxiety Disorder and Major Depressive Disorder scores. In boys, acne duration did not show a significant correlation with ERQ-CA -Reappraisal scores (rho= 0.31, p=0.107) but showed a significant, positive and moderate correlation with ERQ-CA -Suppression scores (rho= 0.49, p=0.007). In boys, acne duration was significantly, negatively and weakly-moderately correlated with the AQ-Adolescent Attention Shifting subscale scores (rho= -0.40, p=0.034). A significant, negative, weak correlation was found between acne duration and Body Perception Scale (BPS) total scores in adolescents with AV (Spearman non-parametric correlation analysis, rho= -0.30, p=0.008). This relationship was not significant in men (rho= -0.30, p=0.117). It reaches significance level in girls (rho= -0.32, p=0.026). It was observed that acne duration was significantly, positively and weakly correlated with the RSES Feeling threatened in interpersonal relationships score in girls (rho= 0.29, p=0.046). Acne duration was significantly, positively and weakly correlated with SCWT-5- error count (rho= 0.23, p=0.046). In men, the correlation between acne duration and SCWT-5 error count increased to moderate (rho= 0.45, p=0.014). In the whole sample, acne duration and SCWT- Auditory Verbal test scores show a significant, positive and weak correlation (rho= 0.26, p=0.021). In girls, there was a significant, positive and weak (rho= 0.32, p=0.026) correlation between acne duration and VADS- Auditory Verbal test scores and a significant, negative and weak (rho= -0.30, p=0.035) correlation between VADS- Visual Verbal test scores. There was a significant, positive and weak correlation between the duration of acne and the number of RMET correct responses in men (rho= 0.37, p=0.046). In the second phase of the study, 31 patients participated. After 12 weeks of isotretinoin treatment, four participants met the diagnosis of MDD (all girls), two participants were diagnosed with GAD (all girls), three adolescents were diagnosed with ODD (one girl), one was diagnosed with ADHD (girl) and one was diagnosed with motor tic disorder (boy). It was observed that the RCADS-CV panic disorder subtest medians of female adolescents diagnosed with AV were significantly higher than those of male adolescents. RCADS-CV MDD subscale mean scores significantly increased in those who completed the treatment (Z= -2.2, p=0.030). DERS- Goals, Impulses and Strategies subscale score medians increased significantly after treatment. While DERS- Awareness subscale score medians tended to decrease after treatment, DERS- total score medians tended to increase after treatment. Adolescents who completed isotretinoin treatment had significantly lower median scores of Cognitive and Total Empathy on the KASI-E after treatment compared to before treatment. There was no significant difference between the median scores of the TAS-20 subscales before and after isotretinoin treatment. After treatment, the median scores of AQ-Adolescent attention to detail subscale were significantly higher than before treatment. Post-treatment BPS median scores did not show a significant difference between genders. After completing the twelfth week of isotretinoin treatment, female adolescents had significantly lower SCWT-4 error and correction number medians than male adolescents. Among the adolescents diagnosed with AV, those who completed isotretinoin treatment had significantly lower median SCWT-2 and 5 times after treatment than before treatment. The median of RMET total correct responses after completion of isotretinoin treatment was significantly lower than before treatment (Wilcoxon Signed-Ranks test, Z= - 4.1, p=0.000). Conclusion: Our findings suggest that AV diagnosis in adolescents may be associated with internalizing problems both before and after isotretinoin treatment and Isotretinoin treatment has a negative effect on emotion regulation, is associated with decreased empathy skills, and negatively affects theory of mind skills. In addition to dermatologic treatment, it may be recommended to evaluate their mental and psychosocial functioning and to intervene early in case of detected problems. Additional studies are needed to evaluate the long-term effects of isotretinoin treatment on psychopathology, body perception and self-esteem, memory and visuospatial functions, cognitive emotion regulation skills, empathy, alexithymia, and symptoms of the broad autism spectrum disorder phenotype.