Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa.

Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

[Trans* Youth and Young Adults in Healthcare: A Qualitative Study About Experiences, Challenges, andWishes]. / Trans* Jugendliche und junge Erwachsene im Gesundheitswesen: Eine qualitative Interviewstudie über Erfahrungen, Herausforderungen undWünsche.

The number of adolescents who present themselves to the healthcare system due to the aspect of trans* is rising internationally as well as nationally. Studies, especially from the international area, point next to appropriate treatment situations increasingly to aversively experienced situations.These are characterized by lack of knowledge of the professionals, incorrect naming and pronoun naming as well as inappropriate questions and comments. In order to shed light on the situation in Germany, semi-structured interviews were conducted with ten adolescents and evaluated using qualitative content analysis. Overall, a balanced ratio of positive, appropriate and negative, aversive experiences emerged. Themes were gender-sensitive language, ways of interacting, support/networking and knowledge. The adolescents named parental support and connection to self-help groups as supportive instances in dealing with the healthcare system, but also mentioned structural hurdles such as long waiting times. Overall, the adolescents had a positive outlook on the future and would like to see a sensitization of healthcare workers. Educationalmeasures and further training should be implemented in order to meet these wishes and to ensure needs-based care for trans* adolescents.

[Parents Health Care Experiences of a Child or Adolescent with Gender Incongruence and Gender Dysphoria: A Qualitative Study]. / Erfahrungen im Gesundheitswesen von Sorgeberechtigten eines Kindes oder Jugendlichen mit Geschlechtsinkongruenz und Geschlechtsdysphorie: Eine qualitative Studie.

In general, little is known about the experiences of parents of a transgender child or adolescent when seeking health care services. In addition, there is little research on how parents interact with their child in the health care system. International studies show high vulnerability and psychological distress among those children and adolescents who assign themselves to a gender other than the one assigned at birth. Parental support represents a protective factor related to mental health. The aim of this study is to investigate parental interaction processes in medical-psychological treatment settings. For this purpose, guided qualitative interviews were conducted throughout Germany with twelve fathers and mothers of transgender children/adolescents. Most parents faced a number of challenges and barriers to their children's health care. A lack of knowledge and insecurities on the part of the health care practitioners up to psychopathologization of identity were ascertainable. At the same time, accepting, affectionate and supportive encounters were evident from the reports. Furthermore, it was found that the parents took an essential protective and supportive stance towards their children in the treatments. For improved health care, sensitization and education regarding gender variance in childhood and adolescence is necessary for health care practitioners in the health care system. The study can contribute to expanding the scientific discourse on life biographies of young trans* people and their parents.

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

Healthcare Professionals' Conflicts When Treating Transgender Youth: Is It Necessary to Prioritize Protection Over Respect?

Increasingly, transgender minors are seeking medical care such as puberty-suppressing or gender-affirming hormone therapies. Yet, whether these interventions should be performed at all is highly controversial. Some healthcare practitioners oppose irreversible interventions, considering it their duty to protect children from harm. Others view minors, like adults, as transgender individuals who must be protected from discrimination. The underlying ethical question is presented as a problem of priority. Is it primarily relevant that minors are involved? Or should decision makers focus on the fact that they treat transgender individuals? The paper explores the relevance for medical practice. We provide results of an interview study with German healthcare professionals. We discuss the general question whether prioritization among different group memberships of the same person is ethically defensible. We conclude that priority conflicts between group memberships of the same person can be deceptive and should be addressed by an intersectional approach. Eventually, we discuss practical implications.

Expression of CXCR4 on CD4+ T cells predicts body composition parameters in female adolescents with anorexia nervosa.

Anorexia nervosa (AN) is a severe eating disorder characterized by excessive weight loss and lack of recognition of the seriousness of the current low body weight. Individuals with AN frequently exhibit an enhanced inflammatory state and altered blood levels of cytokines and chemokines. However, the expression of chemokine receptors in AN and the association with body composition parameters and treatment effects are still unknown. In this study, we examined the expression of CCR4, CCR6, CXCR3, and CXCR4 on peripheral blood T cells in female adolescents with AN before (T0, n = 24) and after 6 weeks of multimodal therapy (T1, n = 20). We also investigated their value to predict body mass index (BMI) and fat mass index (FMI) at baseline. Using multi-parameter flow cytometry, we found increased expression of CCR4, CXCR3, and CXCR4, but not CCR6, on CD4+ T cells in AN at T0 when compared to healthy controls (HC, n = 20). At T1, CXCR3 and CXCR4 expression decreased in AN. We found a close link between CCR4, CCR6 and CXCR4 expression and the adolescent mental health status in the study cohort as determined by the Strengths and Difficulties Questionnaire (SDQ). Specifically, CXCR4 expression correlated positively with emotional symptoms and peer relationship problems, as well as with the total sum score of the SDQ. In addition, CXCR4 expression on CD4+ T cells was a significant predictor of BMI and FMI in female adolescents. Our findings that CXCR4 expression on T cells is altered in adolescents with AN and predicts body composition parameters in adolescents suggest an impact of this chemokine receptor in the pathogenesis of AN.

Age at menarche relates to depression in adolescent girls: Comparing a clinical sample to the general pediatric population.

CONTEXT: The timing of puberty, physical features of pubertal development, and hormones are closely intertwined but may also individually contribute to the risk for depression and depression severity. Additionally, their effects on mood may depend on depression severity, but previously this has only been studied in mostly subclinical depression. METHODS: In 184 girls from a single psychiatric hospital with significant depressive symptoms (Beck Depression Inventory-II score > 13), the relationship between depression severity and age at menarche (AAM), pubertal status, and gonadal/adrenal hormones (estradiol, progesterone, DHEA-S, androstenedione, testosterone, dihydrotestosterone) was investigated. Moreover, AAM in depressed girls was compared to that from a representative sample of German adolescents without a psychiatric disorder (N = 1674). Androgen levels were compared to those of age- and sex-matched controls (N = 59). RESULTS: AAM but not pubertal stage or biochemical parameters related to depression. Girls with AAM at the lower normative range of pubertal development were 61 % more likely to develop depression and scored 4.9 points higher on the depression scale than girls experiencing menarche at the population average. Androstenedione levels were increased in the psychiatric sample, but neither androgen nor gonadal hormone levels were associated with depression severity. LIMITATIONS: The study is cross-sectional. CONCLUSIONS: These observations confirm previous studies in mostly subclinical depression and highlight the importance of AAM for adolescent depression. Thus, AAM could be considered a prognostic factor for a clinical risk score assessing the probability of adolescent depression. Moreover, these findings suggest fostering efforts that address risk factors that contribute to an earlier AAM.

[Dialectical BehaviouralTherapy for Adolescent Patients with Anorexia Nervosa]. / Dialektisch Behaviorale Therapie (DBT-A) bei jugendlichen Patient/innen mit Anorexia nervosa.

Dialectical behavioural therapy (DBT) has become the gold standard in the treatment of patients with borderline personality disorder. This therapy includes the combination of stance and techniques, which are characterized by the dialectic of acceptance and change. In the meantime, this method has also been successfully applied to other psychiatric disorders. In the case of anorexia nervosa - a disorder with a tendency to chronification and a considerably increased mortality risk - the work on treatment motivation increases. Traditional concepts in clinics are increasingly being questioned and tested for their suitability for everyday use. Here, DBT offers a set of tools with which positive experiences of effectiveness have already been made in some clinics. Evidence based on randomized controlled trials is still lacking. In this article, the basic principles of DBT treatment for adolescent patients with anorexia nervosa are explained and experiences with the treatment concept are reported.

Influence of Identity Development on Weight Gain in Adolescent Anorexia Nervosa.

Background: Anorexia Nervosa (AN) typically begins during early adolescence, an important phase of personality development. A substantial proportion of adolescent AN patients shows impaired personality functioning, which might be a relevant but understudied aspect of illness severity. The developmental status of identity as key element of personality is suggested to influence inpatient treatment outcome in adolescents with AN. Methods: This study analyzed existing data of N = 60 adolescents with AN. Multilevel models assessed the influence of identity functioning, measured by the Assessment of Identity Development in Adolescence (AIDA) at admission, on weight gain [BMI (body mass index), BMI-SDS (BMI standard deviation score)] during 10 weeks of inpatient treatment. Moreover, the influence of other indicators of illness severity, i.e., eating disorders and comorbid psychopathologies, was explored. Results: As expected, higher AIDA scores negatively influenced the course of weight gain. A similar effect was observed for other psychopathology measures, especially body image distortion. In general, higher weight at admission was associated with less weight gain. Higher weight at admission was also predicted by higher other psychopathology measures, but not AIDA scores. Conclusion: The course of weight gain during inpatient treatment was hampered in adolescent AN patients who have difficulties developing a stable identity. Unlike other aspects of psychopathology, this was independent of the initial weight. Thus, in addition to the level of underweight and other aspects of psychopathology, difficulties in identity development constitute a relevant aspect of illness severity in AN. This recommends consideration of identity development during treatment.

The adrenal steroid profile in adolescent depression: a valuable bio-readout?

There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus-pituitary-adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.

PTBP2 - a gene with relevance for both Anorexia nervosa and body weight regulation.

Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5'UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.

Changes in patterns of eating habits and food intake during the first German COVID-19 lockdown: results of a cross-sectional online survey.

PURPOSE: The COVID-19 pandemic and public measures have a direct impact on the nutrition situation; studies show changes in food consumption, eating behavior or body weight but complex pattern analyses of changes rarely exist. METHODS: During the first German lockdown, a web-based survey was conducted among adults. It included 33 questions about changes in food intake, eating habits and physical activity, as well as anthropometrics and sociodemographic factors. Patterns of change were calculated based on changes in food intake and eating habits using two-step cluster analysis. To identify influencing factors for assignment to the patterns of change, binary logistic regression analyses were performed. RESULTS: Data from 2103 participants (81% female, 40 ± 14 years) were considered for analysis. Increased stockpiling, cooking, and variation in preparation was reported by 50-70%. The constant pattern (C-P, 36%) reported little change besides the above. The health-oriented pattern (HO-P; 37%) reported eating more healthy foods, avoiding unhealthy foods, and eating less and less frequently. The emotional-driven pattern (ED-P; 28%) exhibits higher influence of emotions on eating behavior, less avoidance of unhealthy foods, and increased consumption of sweets, pastries, and alcohol. The odds of changing eating behavior either to HO-P or ED-P were higher in women, people with migration background, younger participants, and increased with BMI categories. CONCLUSION: Both, the ED-P and HO-P, exhibit distinctive reactions in eating habits and food intake when dealing with a distressing experience. In subgroups, these may lead to disturbances in eating behavior and increase the risk for eating disorders and obesity.

COVID-19: Effects of Pandemic Related Restrictions on Physical Activity, Screen Time, and Mental Well-being in German adolescents.

Objective: To describe the impact of the COVID-19 pandemic-related restrictions (PR) in April and May 2020 on physical activity (PA), sedentary screen time (SST), and mental well-being (MWB) in German adolescents, and to analyze associations between these variables. Methods: The Münster District Government invited all secondary school students (aged 11-17) in the region to take part in the online survey that assessed PA, SST, and MWB. For data analysis, we calculated descriptive statistics and ran linear regression analysis. Results: 1,038 students (627 [60.4%] female; 14.18 [± 1.97] years) were included in the analysis. During the PR, a marked decline in overall PA (p < .001) and a significant increase (p < .001) in SST were observed. One-third of the students reported worrying more and being less satisfied with their lives since PR. A decrease in life satisfaction (ß = -.524, p < .001) as well as an increase in general worrying (ß = -.336, p = .015) were associated with a decrease in PA during PR. Conclusion: The results show that the restrictions led to a decrease in physical activity, which may have detrimental effects on the students' mental and physical health.

Reasons for admission and variance of body weight at referral in female inpatients with anorexia nervosa in Germany.

BACKGROUND: Body mass index (BMI) at hospital admission in patients with anorexia nervosa (AN) represents a prognostic marker for mortality, chronicity and future body weight. The current study focused on the associations between BMI standard deviation score (BMI-SDS) at admission and reasons for seeking inpatient treatment. Further interest was given to the relationship between premorbid weight and weight at admission, as well as the effect of both weight at referral and reasons for admission on treatment outcome. METHODS: Data ascertained in the German Register of Children and Adolescents with AN were analysed to assess the parental and patient overlap for 23 predefined reasons for admission, using factor analyses and regressions models. RESULTS: Complete parent-patient data sets were available for 360 patients out of 769. The highest consensus rates between parents and patients were obtained for weight and eating behavior related reasons and hyperactivity. Based on factor analysis, four factors emerged. Premorbid BMI-SDS, age and 'low body weight' as stated by patients or parents explained almost 40% of the variance of the BMI-SDS at admission. CONCLUSIONS: Results underscore the relevance of age and premorbid BMI for BMI at admission. Only single reasons for admission explained further variance, with 'low body weight' having the largest effect. Approximately 40% of the variance of BMI-SDS was explained. For the first time, the effect of premorbid BMI for BMI at admission was robustly demonstrated in a multicenter study. Of the variance in BMI-SDS at discharge, our model could explain 37%, with reasons for admission having a small effect. Further investigation of the reasons for admission would be worthwhile to improve treatment and prognosis.

Size Matters: The CAG Repeat Length of the Androgen Receptor Gene, Testosterone, and Male Adolescent Depression Severity.

There is a distinct increase in the prevalence of depression with the onset of puberty. The role of peripubertal testosterone levels in boys in this context is insufficiently understood and may be modulated by a functional polymorphism of the androgen receptor gene (AR), a variable number of CAG repeats. Moreover, there is preliminary evidence that the relationship between testosterone, CAG repeat length, and the severity of depressive symptoms may differ between subclinical and overt depression, but this has neither been studied in a clinical sample of adolescents with depression nor compared between subclinical and overt depression in an adequately powered study. To investigate the relationship between free testosterone, CAG repeat length of the AR, depression status (subclinical vs. overt), and the severity of depressive symptoms, 118 boys treated as in- or daycare patients at a single psychiatric hospital were studied. Of these, 73 boys had at least mild depressive symptoms according to the Beck Depression Inventory-II (BDI-II > 13). Higher-order moderation analysis in the multiple regression framework revealed a constant relationship between free testosterone and depression severity irrespective of the number of CAG repeats in adolescents with a BDI-II score ≤ 13. In adolescents with a BDI-II score > 13, however, there was a significant negative relationship between free testosterone and BDI-II score in patients with <19 CAG repeats and a significant positive relationship regarding free testosterone and BDI-II score in those with more than 28 CAG repeats, even when considering important covariates. These results suggest that the effects of testosterone on mood in male adolescents with depression depend on the genetic make-up of the AR as well as on depression status. This complex relationship should be considered by future studies addressing mental health issues against an endocrine background and may, moreover, contribute to tailored treatment concepts in psychiatric medicine, especially in adults.