Investigating thyroid function and iodine status in adolescents with and without paediatric major depressive disorder.

Depression has been associated with subclinical hypothyroidism and altered hypothalamic-pituitary-thyroid axis functioning. Adequate iodine nutrition is essential for healthy thyroid functioning. We therefore determined associations of iodine and thyroid status with paediatric major depressive disorder (pMDD) among Swiss adolescents and explored whether associations are sex-specific and mediated by stress. We conducted a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls. We assessed depression severity using the Children's Depression Rating Scale-Revised and stress using the perceived stress scale (PSS) and measuring hair cortisol levels. We determined iodine status by measuring urinary iodine concentrations (UIC) and thyroid status by thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum. Median (IQR) UIC did not differ between cases (121 (87, 174) µg/l) and controls (114 (66, 183) µg/l, P = 0·3). Median TSH and FT4 were lower in cases than controls (TSH: 1·36 (0·91, 2·00) mlU/l v. 1·50 (1·18, 2·06) mlU/l, P = 0·039; FT4: 14·7 (12·9, 16·9) pmol/l v. 15·7 (14·3, 17·2) pmol/l, P = 0·004). The prevalence of hypothyroxinaemia (normal TSH; low FT4) was higher among female cases than controls (21 % v. 4%, P = 0·006). PSS scores were higher while hair cortisol was lower in cases than controls (PSS: 25 (20, 28) v. 11 (7, 15), P < 0·001; cortisol: 2·50 (1·34, 3·57) pg/mg v. 3·23 (1·79, 4·43) pg/mg, P = 0·044). After adjusting for confounders, the associations of TSH and hair cortisol with pMDD were no longer significant. Furthermore, TSH and FT4 were not associated with PSS scores and hair cortisol levels. Summarising, iodine nutrition was adequate for adolescents with and without pMDD. However, FT4 concentrations were lower in those with pMDD, and 1 in 5 female adolescents with pMDD were hypothyroxinaemic.

Iron status in Swiss adolescents with paediatric major depressive disorder and healthy controls: a matched case-control study.

PURPOSE: Depression is associated with low-grade systemic inflammation and impaired intestinal function, both of which may reduce dietary iron absorption. Low iron status has been associated with depression in adults and adolescents. In Swiss adolescents, we determined the associations between paediatric major depressive disorder (pMDD), inflammation, intestinal permeability and iron status. METHODS: This is a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls aged 13-17 years. We assessed depression severity using the Children's Depression Rating Scale-Revised. We measured iron status (serum ferritin (SF) and soluble transferrin receptor (sTfR)), inflammation (C-reactive protein (CRP) and alpha-1-acid-glycoprotein (AGP)), and intestinal permeability (intestinal fatty acid binding protein (I-FABP)). We assessed history of ID diagnosis and treatment with a self-reported questionnaire. RESULTS: SF concentrations did not differ between adolescents with pMDD (median (IQR) SF: 31.2 (20.2, 57.0) µg/L) and controls (32.5 (22.6, 48.3) µg/L, p = 0.4). sTfR was lower among cases than controls (4.50 (4.00, 5.50) mg/L vs 5.20 (4.75, 6.10) mg/L, p < 0.001). CRP, AGP and I-FABP were higher among cases than controls (CRP: 0.16 (0.03, 0.43) mg/L vs 0.04 (0.02, 0.30) mg/L, p = 0.003; AGP: 0.57 (0.44, 0.70) g/L vs 0.52 (0.41, 0.67) g/L, p = 0.024); I-FABP: 307 (17, 515) pg/mL vs 232 (163, 357) pg/mL, p = 0.047). Of cases, 44% reported having a history of ID diagnosis compared to 26% among controls (p = 0.020). Finally, 28% of cases had iron treatment at/close to study inclusion compared to 14% among controls. CONCLUSION: Cases had significantly higher systemic inflammation and intestinal permeability than controls but did not have lower iron status. Whether this is related to the higher rate of ID diagnosis and iron treatment in adolescents with depression is uncertain.

Anxious depression as a clinically relevant subtype of pediatric major depressive disorder.

In adults, anxious depression has been identified as a more severe form of major depressive disorder (MDD), associated with higher depression severity, more suicidal ideation and worse treatment outcome. Research in pediatric depression, however, has been sparse. 126 children and adolescents aged 8-18 years with a primary diagnosis of MDD were categorized into a MDD-only group and an anxious depression group based on clinically elevated scores on the Beck Anxiety Inventory. One-third of the sample was classified as having anxious depression with females being overrepresented in the anxious depressed compared to the MDD-only group. 42.2% of the anxious depressed youth met diagnostic criteria for a comorbid anxiety disorder. Anxious depressed youth were more likely to suffer recurrent depressive episodes, showed higher depression severity and a unique pattern of depressive symptoms characterized by more severe sleep problems, more somatic complaints, more severely depressed mood and more frequent suicidal ideations. Scores on a suicidal ideation scale were increased even when controlling for overall depression severity. However, when comparing depressed patients with and without comorbid anxiety disorders, no differences in depression severity, symptom patterns or suicidal ideations were observed. The results indicate that high anxiety levels in depressed youth are clinically relevant, and given the increase in suicidal ideation, anxiety symptoms during depressive episodes should routinely be screened in clinical practice even in the absence of a fully formed comorbid anxiety disorder.

Inverse association between slow-wave sleep and low-grade inflammation in children and adolescents with major depressive disorder.

OBJECTIVE: To investigate the relationship between both self-reported and objective sleep variables and low-grade inflammation in children and adolescents with major depressive disorder (MDD) of moderate to severe symptom severity. METHODS: In this cross-sectional study, we examined twenty-nine children and adolescents diagnosed with MDD and twenty-nine healthy controls (HC). Following a one-week actigraphy assessment, comprehensive sleep evaluations were conducted, including a one-night sleep EEG measurement and self-reported sleep data. Plasma high-sensitivity C-reactive protein (hsCRP) was employed as a marker to assess low-grade inflammation. RESULTS: No significant difference in hsCRP levels was observed between participants with MDD and HC. Furthermore, after adjusting for sleep difficulties, hsCRP exhibited no correlation with the severity of depressive symptoms. In HC, levels of hsCRP were not linked to self-reported and objective sleep variables. In contrast, depressed participants showed a significant correlation between hsCRP levels and increased subjective insomnia severity (Insomnia Severity Index; r = 0.41, p < 0.05), increased time spent in the N2 sleep stage (r = 0.47, p < 0.01), and decreased time spent in slow-wave sleep (r = - 0.61, p < 0.001). Upon additional adjustments for body mass index, tobacco use and depression severity, only the inverse association between hsCRP and time spent in slow-wave sleep retained statistical significance. Moderation analysis indicated that group status (MDD vs. HC) significantly moderates the association between slow-wave sleep and hsCRP. CONCLUSION: Our findings suggest that alterations in the architecture of slow-wave sleep may have a significant influence on modulating low-grade inflammatory processes in children and adolescents with MDD.

Associations of n-3 polyunsaturated fatty acid status and intake with paediatric major depressive disorder in Swiss adolescents: A case-control study.

BACKGROUND: Observational studies suggest a link between n-3 polyunsaturated fatty acid (PUFA) intake, n-3 PUFA status, and depression in adults, but studies in adolescents are scarce. This study aimed to determine associations of n-3 PUFA status and intake with paediatric major depressive disorder (pMDD) in Swiss adolescents. METHODS: We conducted a matched case-control study in 95 adolescents diagnosed with pMDD and 95 healthy controls aged 13 to <18 years. We analysed red blood cell (RBC) fatty acid (FA) composition (% of total FA). n-3 PUFA intake was assessed using a focused food frequency questionnaire and depression severity was assessed by the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: Mean RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower in cases than controls (EPA: 0.41 ± 0.11 vs 0.46 ± 0.12, p < 0.001; DHA: 4.07 ± 1.04 vs 4.73 ± 1.04, p < 0.001). Subsequently, the mean RBC n-3 index was lower (4.51 ± 1.10 vs 5.20 ± 1.11, p < 0.001) and the n-6/n-3 PUFA ratio higher (5.51 ± 1.25 vs 4.96 ± 1.08, p < 0.001) in cases than controls. Adolescents with a higher n-3 index had lower odds for depression (OR = 0.49 [95% CI: 0.32-0.71]). In contrast, the n-6/n-3 PUFA ratio was associated with higher odds for depression (OR = 1.58 [95% CI: 1.14-2.25]). Intake of alpha-linolenic acid, EPA and DHA did not differ between cases and controls. CONCLUSION: Our results suggest that a higher RBC n-3 PUFA status during adolescence is associated with a lower risk for pMDD, whereas a higher n-6/n-3 PUFA ratio is associated with a higher risk for pMDD. Differences in n-3 PUFA intake did not explain the observed differences in n-3 PUFA status.

Executive functions and borderline personality features in adolescents with major depressive disorder.

Background: Executive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF). Methods: We examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child's EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity. Results: Over the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries. Conclusion: On average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03167307.

Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents.

STUDY OBJECTIVES: We aimed to examine the association between self-rated and clinician-rated sleep disturbances and C-reactive protein (CRP), an objective marker of inflammation, in pediatric depression. METHODS: Two hundred fifty-six children and adolescents (15.2 ± 1.6 y, 72.3% female) with moderate to severe symptoms of depression participated in the study. Sleep disturbances were assessed by self-reports (Insomnia Severity Index) and clinician ratings (Kiddie-Schedule for Affective Disorder and Schizophrenia), inflammation by plasma CRP levels. RESULTS: Higher levels of CRP correlated positively with clinician-rated middle insomnia and hypersomnia. After adjusting for control variables (body mass index, tobacco, alcohol, stress, age, sex, antidepressants, sleep medication, depression severity), regression models confirmed the significant association of clinician-rated hypersomnia and middle insomnia symptoms with elevated CRP levels. In the adjusted regression models, other clinician-rated manifestations of sleep disturbance (eg, initial insomnia) and insomnia self-ratings were not significantly associated with CRP. Body mass index correlated positively with CRP, but body mass index had no mediating effect on the associations between sleep disturbances and CRP. We did not find an association between depression severity, assessed by the Children's Depression Rating Scale-Revised, and CRP. CONCLUSIONS: Results of the present study indicate a significant association of hypersomnia and middle insomnia symptoms with CRP in pediatric depression, not linked to alterations in the body mass index. CITATION: Strumberger MA, Häberling I, Emery S, et al. Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents. J Clin Sleep Med. 2023;19(10):1775-1784.

How Are Discrepant Parent-Child Reports Integrated? A Case of Depressed Adolescents.

Objective: Severity ratings of psychopathology in minors are often based on a composite score of the parent's and child's reports. However, parent's and child's reports often differ substantially, resulting in the integration method affecting the final scores. Nevertheless, effects of integration algorithms are seldom assessed and poorly understood. Method: The dataset is derived from the Treatment for Adolescents with Depression Study (TADS) and consists of 439 adolescents, 54% female, with a Major Depressive Disorder. The interviewer conducted the clinical interview Children's Depression Rating Scale-Revised (CDRS-R) with the parent and the adolescent and the TADS manual advised the interviewer to use the higher score as the final rating unless an informant was judged to be unreliable. Polynomial regressions, multivariate analyses, and mixed models were used to analyze the effects of this integration algorithm on the final scores and associated factors. Results: In 77% of the cases, the interviewer followed the TADS rating rule to use the higher CDRS-R item score. However, the final item scores differed significantly from the rule using the higher value, with the higher score being less often adapted at follow-up assessments and in female patients. Conclusions: The algorithm used to integrate divergent reports affects study outcomes and might introduce data-specific biases. Judgments of the validity and reliability of informants compromise the objectivity of outcomes in major clinical trials by introducing a subjective bias. Therefore, the agreement between children's and parent's reports and the method of integration should routinely be reported in research on pediatric psychopathology. ClinicalTrials.gov NCT00006286.

Omega-3 and its domain-specific effects on cognitive test performance in youths: A meta-analysis.

Omega-3 fatty acids are vital for brain development. The aim of this meta-analysis was to broaden current knowledge of the effects of omega-3 supplementation on cognitive test performance in youths. Randomized controlled trials (RCTs) meeting selection criteria were identified through two independent literature searches on PubMed, Cochrane Library, PsycARTICLES and PsycINFO (last search June 2019). Twenty-nine out of 1126 studies assessing 4247 participants met all selection criteria. A meta-analysis using random-effects model was performed for eight different cognitive domains. This first analysis revealed no main effect of omega-3 fatty acid supplementation on domain-specific cognitive test performance in youths. Subgroup analyses identified beneficial effects of eicosapentaenoic acid (EPA)-rich but not docosahexaenoic acid (DHA)-rich formulations in the domains of long-term memory, working memory and problem solving and a tendency towards beneficial effects in clinical rather than non-clinical populations. Future research should investigate differential effects of EPA and DHA and consider their baseline levels, other nutritional components and interactions with gene variations as potential predictors of response.

When parents and children disagree: Informant discrepancies in reports of depressive symptoms in clinical interviews.

BACKGROUND: Parents and their children often disagree on the existence and severity of psychopathological symptoms, especially in major depressive disorder (MDD). Discrepant estimations pose a problem for the validity of diagnoses and illness severity with major implications for treatment evaluation. METHODS: 118 adolescents aged 13-18 years and their parents were interviewed and their reports were compared regarding the presence of a MDD diagnosis. In addition, severity ratings of depression symptoms reported in the Children's Depression Rating Scale-Revised (CDRS-R) were compared between parents and their offspring using multivariate analyses and polynomial regressions. The association between borderline features, functional impairment, and treatment history variables with parent-child agreement was assessed. RESULTS: In 38% of the cases, parents and adolescents agreed on DSM-IV diagnostic MDD criteria, while in 53%, only the adolescent endorsed criteria for a MDD. A MDD that was endorsed by parents and adolescents was characterized by higher depression severity, higher number of previous treatments, and higher functional impairment. Using a polynomial approach, neither age nor borderline tendencies were associated with agreement. LIMITATIONS: We did not differentiate between mother's versus father's reports and borderline features were assessed by self-report only. CONCLUSIONS: Adolescents and their parents gave differing reports of the existence and severity of depressive symptoms. The high discrepancy levels combined with the uncertainty of previously published findings due to methodological challenges are concerning. Clinicians and researchers need to consider discrepancies in agreement in relation to diagnosis and illness severity in the context of their clinical and research decisions.

Verbal Memory Performance in Depressed Children and Adolescents: Associations with EPA but Not DHA and Depression Severity.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been described as positively associated with cognitive functioning. Current meta-analyses have identified eicosapentaenoic acid (EPA) as potentially more effective than docosahexaenoic acid (DHA). An especially vulnerable subgroup that might benefit from these beneficial effects are depressed youths. In this study, we examined associations between red blood cell (RBC) DHA and EPA levels and depression severity and verbal memory performance in a sample of 107 moderately (n = 63) and severely (n = 44) depressed youths. The findings showed that youths with high RBC EPA levels had steeper learning curves compared to those with moderate or low RBC EPA levels (Pillai's Trace = 0.195, p = 0.027, ηp2 = 0.097). No associations between RBC DHA levels or depression severity and verbal memory performance were observed. Our results further confirm previous findings indicating a more important role of EPA compared to DHA in relation to cognitive functioning. Future research should further investigate the differential role of EPA and DHA concerning cognitive functioning in depressed youths. Evidence supporting beneficial supplementation effects could potentially establish a recommendation for a natural and easily accessible intervention for cognitive improvement or remission.