The development and validation of an algorithm to predict future depression onset in unselected youth.

BACKGROUND: Universal depression screening in youth typically focuses on strategies for identifying current distress and impairment. However, these protocols also play a critical role in primary prevention initiatives that depend on correctly estimating future depression risk. Thus, the present study aimed to identify the best screening approach for predicting depression onset in youth. METHODS: Two multi-wave longitudinal studies (N = 591, AgeM = 11.74; N = 348, AgeM = 12.56) were used as the 'test' and 'validation' datasets among youth who did not present with a history of clinical depression. Youth and caregivers completed inventories for depressive symptoms, adversity exposure (including maternal depression), social/academic impairment, cognitive vulnerabilities (rumination, dysfunctional attitudes, and negative cognitive style), and emotional predispositions (negative and positive affect) at baseline. Subsequently, multi-informant diagnostic interviews were completed every 6 months for 2 years. RESULTS: Self-reported rumination, social/academic impairment, and negative affect best predicted first depression onsets in youth across both samples. Self- and parent-reported depressive symptoms did not consistently predict depression onset after controlling for other predictors. Youth with high scores on the three inventories were approximately twice as likely to experience a future first depressive episode compared to the sample average. Results suggested that one's likelihood of developing depression could be estimated based on subthreshold and threshold risk scores. CONCLUSIONS: Most pediatric depression screening protocols assess current manifestations of depressive symptoms. Screening for prospective first onsets of depressive episodes can be better accomplished via an algorithm incorporating rumination, negative affect, and impairment.

Brain and behavioral correlates of insulin resistance in youth with depression and obesity.

Depression, together with insulin resistance, is increasingly prevalent among youth. These conditions have traditionally been compartmentalized, but recent evidence suggests that a shared brain motivational network underlies their co-occurrence. We posit that, in the context of depressive symptoms, insulin resistance is associated with aberrant structure and functional connectivity in the Anterior Cingulate Cortex (ACC) and hippocampus. This motivational neural circuit underlies dysfunctional behavioral responses and increased sensitivity to rewarding aspects of ingesting high calorie food that lead to disinhibition of eating even when satiated. To investigate this shared mechanism, we evaluated a sample of forty-two depressed and overweight (BMI > 85th%) youth aged 9 to 17. Using ACC and hippocampus structural and seed-based regions of interest, we investigated associations between insulin resistance, depression, structure (ACC thickness, and ACC and hippocampal area), and resting-state functional connectivity (RSFC). We predicted that aberrant associations among these neural and behavioral characteristics would be stronger in insulin resistant compared to insulin sensitive youth. We found that youth with greater insulin resistance had higher levels of anhedonia and more food seeking behaviors, reduced hippocampal and ACC volumes, and greater levels of ACC and hippocampal dysconnectivity to fronto-limbic reward networks at rest. For youth with high levels of insulin resistance, thinner ACC and smaller hippocampal volumes were associated with more severe depressive symptoms, whereas the opposite was true for youth with low levels of insulin resistance. The ACC-hippocampal motivational network that subserves depression and insulin resistance separately, may represent a critical neural interaction that link these syndromes together.

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.

Parenting mediates the impact of maternal depression on child internalizing symptoms.

BACKGROUND: To examine the potential mediating role of parenting behaviors in the longitudinal, bidirectional relationships between maternal depression and child internalizing symptoms (i.e. depression and anxiety). METHODS: We analyzed data from 4,581 mother-child dyads from the Fragile Families and Child Wellbeing Study, assessed when the child was 3, 5, and 9 years old. Data included maternal depression diagnosis, child internalizing symptoms, and parenting behaviors (i.e. psychological aggression, nonviolent discipline, and physical assault). Data were analyzed using cross-lagged panel models. RESULTS: Results indicated bidirectional relationships between maternal depression and child internalizing symptoms over childhood. Mediation analyses suggested that maternal depression led to subsequent increased psychological aggression toward their child, which in turn led to increased child internalizing symptoms. Nonviolent discipline and physical assault did not mediate this relationship. However, greater use of nonviolent discipline at age 5 among all parents predicted higher child internalizing symptoms at age 9. No parenting behaviors were both predicted by earlier child internalizing symptoms and predictive of subsequent maternal depression. CONCLUSIONS: Our results suggest a bidirectional relationship between child and maternal internalizing psychopathology that is partially explained by depressed mothers' greater use of psychological aggression toward their children. It is important to note that the size of these effects were small, suggesting that the relationship between parent and child psychopathology is likely additionally explained by factors not assessed in the current study. Nonetheless, these results have implications for prevention and intervention strategies targeting child anxiety and depression.

Incidence of Mood or Anxiety Disorders in Children of Parents with Multiple Sclerosis.

BACKGROUND: Although parental multiple sclerosis (MS) may put children at increased risk for mental health disorders such as anxiety and depression, the incidence and determinants of such disorders have not been examined. METHOD: We carried out a retrospective cohort study in British Columbia, Canada, among children of parents with MS and age-matched children of unaffected parents. Cox regression was used to estimate the association between parental MS and mood or anxiety disorders in children. RESULTS: The study included 1028 children of MS parents, 4010 children of unaffected parents, and 25 464 child-years of follow-up (median follow-up of 4 years). Mental health morbidity was more common among MS parents vs. unaffected parents (50.4% vs. 33.1%) and among MS-affected mothers vs. unaffected mothers (54.6% vs. 38.0%, P < 0.001). The incidence of child mood or anxiety disorders was 8.3 and 6.3 per 1000 child-years among children of parents with and without MS respectively. Sex of the MS-affected parent modified the relationship between parental MS and mood or anxiety disorders in children (P = 0.04). Compared with children of unaffected mothers, children of mothers affected by MS had higher rates of mood or anxiety disorders (HR 1.7, 95% CI 1.1, 2.4), whereas children of MS-affected fathers did not (HR 0.5, 95% CI 0.2, 1.7). Adjustment for mental health morbidity in mothers diminished the association between maternal MS and child mood or anxiety disorders. CONCLUSION: Maternal MS is associated with a higher rate of mood or anxiety disorders in children and this association appeared to be mediated by maternal mental health morbidity.

Identifying symptoms of depression and anxiety in students in the school setting.

Early detection of mental health problems in school-age children offers the opportunity for prompt referral to treatment which is critical to their success in school. School nurses are in a key position to screen for mental health issues in the school setting. This article discusses how school nurses began a new initiative to use two validated screening tools, the Patient Health Questionnaire-9 item for detecting depression and the 5-item Screen for Child Anxiety Related Emotional Disorders for detecting anxiety in middle school/high school-aged children in selected urban schools. Students having positive screens were referred to the multidisciplinary school-based Student Assistance Program team for further evaluation and referral. These screens improved the identification and referral for treatment of children suffering from anxiety and/or depression by expediting the connection to services.

The Quick Inventory of Depressive Symptomatology, Adolescent Version (QIDS-A17): A Psychometric Evaluation.

Objective: The current study aimed to evaluate the psychometric features of the Quick Inventory of Depressive Symptomatology, Adolescent version (QIDS-A17) and the clinician-rated Children's Depression Rating Scale-Revised (CDRS-R). Methods: Altogether, 103 outpatients (8 to 17 years) completed the self-report QIDS-A17-SR. Clinician interviews of adolescents (QIDS-A17-C (Adolescent)) and of parents (QIDS-A17-C (Parent)) were combined to create the QIDS-A17-C(Composite) and the CDRS-R. Results: All QIDS-A17 measures and the CDRS-R evidenced high total score correlations and internal consistency. Factor analysis found all four measures to be unidimensional. Item Response Theory (IRT) analysis found results that complemented the reliability results found in CTT. All four also demonstrated discriminant diagnostic validity based on logistic regression and ANOVA analyses. Conclusion: The psychometric properties of the self-report and composite versions of the QIDS-A17 suggest acceptability as a measure of depression in adolescents either as a measure of depressive symptoms or severity of illness in adolescents. The self-report version may be a helpful tool in busy clinical practices.

Antidepressants in children and adolescents with major depressive disorder and the influence of placebo response: A meta-analysis.

BACKGROUND: There are few available antidepressants for pediatric Major Depressive Disorder (MDD). The objective of this systematic review and meta-analysis was to review industry-funded studies of antidepressants in children and adolescents with MDD, and to better understand the contribution of study design and placebo response to the findings of these studies. METHODS: Randomized, double-blind, placebo-controlled clinical trials that compared antidepressant with placebo for the acute treatment of MDD in children and/or adolescents were selected. Estimates of the standardized mean difference (SMD) in change in Children's Depression Rating Scale-Revised scores were pooled, after examining for heterogeneity. A random-effects meta-analysis was completed. RESULTS: Thirty-four antidepressant-placebo comparisons, involving 6161 subjects, were included. The SMD among all studies was 0.12 (CI 0.08, 0.17; p < 0.001), a very small effect size, lower than that seen in studies of adults with MDD. When the meta-analysis was limited to studies with a low mean placebo response, the SMD increased to 0.19 and further increased to 0.22 when studies with at least a 50% chance of receiving placebo were included. LIMITATIONS: Many studies focused on older children and younger adolescents. Our findings may not reflect antidepressant efficacy in older adolescents. CONCLUSIONS: The modest SMD identified in this analysis may reflect study design factors and the application of antidepressants developed for adults to pediatric patients. Given the urgent clinical need for more pediatric MDD treatments, the influence of placebo response and the need for drug development tailored to this population should be considered in pediatric MDD trial design.

The Management of Anxiety and Depression in Pediatrics.

Anxiety and depression are among the most common psychiatric conditions affecting children and adolescents, and physicians in primary care settings often represent the first point of contact for these patients. Therefore, it is critical to provide these clinicians with an overview of current, evidence-based approaches for treating these conditions in pediatric and adolescent patients. Cognitive behavioral therapy (CBT) is an appropriate and effective first-line intervention for anxiety disorders in children and adolescents. For depressive disorders, treatment guidelines recommend either CBT or interpersonal therapy (IPT) as frontline treatment approaches. Pharmacologically, selective serotonin reuptake inhibitors (SSRIs) represent the most efficacious treatment for anxiety and depressive disorders in young persons. Combination therapies consisting of a psychotherapy plus an SSRI have produced greater therapeutic effects than either treatment alone. In particular, CBT plus sertraline is most effective in those with anxiety, whereas combining CBT or IPT with fluoxetine has been identified as the most effective treatment for depression in this population. Clinically, these combination therapies are especially useful in patients showing an insufficient response to treatment with only an SSRI or psychotherapy. A physician should also recommend lifestyle alterations to aid in the management of anxiety and depression, including diet, exercise, adequate sleep, limiting screen time, and spending time in nature. When used to complement standard treatment approaches, these interventions may provide the patient with additional symptom reduction while decreasing the return of symptoms in the long term.

Medication Management of Anxiety and Depression by Primary Care Pediatrics Providers: A Retrospective Electronic Health Record Study.

Objectives: To describe medication management of children diagnosed with anxiety and/or depression by primary care providers within a primary care network. Study Design/Methods: We performed a retrospective cross-sectional analysis of electronic health record (EHR) structured data from all children seen at least twice in a 4-year observation period within a network of primary care clinics in Northern California. For children who had visit diagnoses of anxiety, depression, anxiety+depression or symptoms characteristic of these conditions, we analyzed the rates and types of medications prescribed. A logistic regression model considered patient variables for the combined sample. Results: Of all patients 6-18 years old (N = 59,484), 4.4% (n = 2,635) had a diagnosis of anxiety only, 2.4% (n = 1,433) depression only, and 1.2% (n = 737) both anxiety and depression (anxiety + depression); 18% of children with anxiety and/or depression had comorbid ADHD. A total of 15.0% with anxiety only (n = 357), 20.5% with depression only (n = 285), and 47.4% with anxiety+depression (n=343) were prescribed a psychoactive non-stimulant medication. For anxiety and depression only, the top three medications prescribed were sertraline, fluoxetine, and citalopram. For anxiety + depression, the top three medications prescribed were citalopram, sertraline, and escitalopram. Frequently prescribed medications also included benzodiazepines. Logistic regression modeling showed that the depression only and anxety + depression categories had increased likelihood of medication prescription. Older age and mental health comorbidities were independently associated with increased likelihood of medication prescription. Conclusions: In this network, ~8% of children carried a diagnosis of anxiety and/or depression. Medication choices generally aligned with current recommendations with the exception of use of benzodiazepines.

Association between frontal cortico-limbic white-matter microstructure and risk for pediatric depression.

This study aimed to identify white-matter microstructural characteristics associated with risk for pediatric major depressive disorder (MDD) measured by the Child Behavior Checklist (CBCL) Anxiety/Depression scores. Children (N = 32) of both sexes, aged 6-12, underwent T1-weighted whole-head anatomical and diffusion-weighted imaging. Each participant's mean diffusion measure image was generated and thinned to create an alignment-invariant tract representation. Voxel-wise analysis on the resulting map was carried out in Track Based Spatial Statistics (TBSS) using general linear models by regressing the CBCL-Anxiety/Depression score against measures of diffusion tensor imaging (DTI). We also compared these results with prior DTI findings from the same children associated with CBCL-Emotion Dysregulation profile, an indicator for bipolar disorder. TBSS voxel-wise analysis showed a significant negative correlation between fractional anisotropy (FA) and CBCL-Anxiety/Depression scores localized in the right anterior cingulum and connected corpus callosal region. The negative FA correlations in these regions were greater in CBCL-Anxiety/ Depression scores compared to CBCL-Emotional Dysregulation scores. Reduced white-matter connectivity in the anterior cingulum and connected corpus callosal region may represent a biomarker of risk for pediatric MDD. These results may help identify brain differences associated with the development of MDD, and assist with earlier clinical identification of pediatric MDD.

Drivers of and Solutions for the Overuse of Antidepressant Medication in Pediatric Populations.

Children in the United States and internationally are increasingly being diagnosed with depression and related psychiatric conditions and a recent study found that antidepressant (ADM) use in children and adolescents rose substantially in youth cohorts in five Western countries from 2005 to 2012. However, there has been ongoing controversy over the effectiveness and safety of ADM use in children, including concerns about ADM increasing suicidality and self-harm. In addition to the increase in the diagnosis of depression, commercially driven off-label prescriptions have been cited as a significant reason for high rates of pediatric ADM prescribing. In this commentary, we discuss two drivers of the overuse of ADM, both of which are products of an increasingly medicalized approach to mental health: 1) the demand for mental health and depression screening in youth, despite the lack of evidence to support it, and 2) the renewed momentum of the Global Mental Health Movement and concomitant calls to "scale up" the diagnosis and treatment of mental illness. Using the lens of institutional corruption, we identify the ways in which both guild and financial conflicts of interest create obstacles to rational prescribing practices in pediatric populations and offer suggestions for reform.

The Relationship between Flourishing and Depression in Children in the U.S. Using a Socioecological Perspective.

Children's flourishing is likely to be associated with achieving a positive mental and physical quality of life, which is considered as an important factor for helping children to overcome psychological adversity during the critical stage of emotional development. This study examined the relationships between children's flourishing and childhood depression. This was a cross-sectional study using the 2011-2012 National Children's Health Survey in the U.S. The conceptual framework that guided this study was a modified ecological system theory model. Multiple regressions were performed to investigate the associations between flourishing and pediatric depression, controlling for demographics, physical activity-related behaviors, family and environmental conditions. A total of 45,309 children (representing 33,293,823 children at the population level) were identified in this study (mean age: 13.63 years; female: 48.7%). Children's childhood depression was highly related to direct parenting functions, individual needs and environmental availabilities and accessibilities from a socioecological perspective. This study revealed multiple dimensions of how sociological factors influence children's flourishing and mental health. Parents' involvement in children's physical activities and family and social support are crucial for children's flourishing and mental health status. More attention needs to be paid to provide children with family and social support to help them to overcome and reduce childhood depression.

Emotion Regulation Among Adolescents With Pediatric Depression As a Function of Anxiety Comorbidity.

Background: Both depression and anxiety (two of the most common internalizing psychopathologies among youths) are associated with difficulties in emotion regulation (ER). Little is known about whether anxiety as a comorbid condition has an effect on the habitual use of different ER strategies in youngsters with depression histories. We aimed 1) to compare ER in adolescents with histories of childhood onset major depressive disorder (MDD) with and without comorbid anxiety and 2) to examine whether certain ER response clusters (Cognitive, Social, and Behavioral/Physical) characterize comorbid children and adolescents. Methods: We analyzed data on 217 youth (11-18 years old) with depression history: 85 subjects with lifetime anxiety comorbidity (comorbid group) and 132 without lifetime anxiety (non-comorbid group). Psychiatric diagnosis was established by a comprehensive Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-based diagnostic procedure. ER strategies were examined via the self-rated "Feelings and Me" Child version questionnaire (FAM-C). Results: The comorbid group used maladaptive ER strategies significantly more frequently than the non-comorbid youngsters. The Behavioral/Physical and Social ER skills, especially those reflecting social withdrawal and self-harm, were responsible for the higher maladaptive scores. Limitations: Because our study is a cross-sectional analysis, we have no information about the development or the onset of maladaptive ER strategies. Therefore, we were unable to examine whether maladaptive ER was a risk factor or a consequence of the internalizing psychopathology and comorbidity. Conclusions: Comorbid anxiety worsens the impaired use of ER strategies in depression-prone youths. Further longitudinal research is needed to explore the causal role of dysfunctional ER in the development of internalizing psychopathology.

Omega-3 Fatty Acids as a Treatment for Pediatric Depression. A Phase III, 36 Weeks, Multi-Center, Double-Blind, Placebo-Controlled Randomized Superiority Study.

Background: Depressive disorders in childhood and adolescence are a major health problem and often follow a chronic course with severe consequences in later life. Depressive disorders cause the highest burden of disease in this age group across all medical conditions. Treatment adherence is usually very poor, and the use of antidepressant drugs is heavily debated, as suicidal ideations may increase, in particular in the early phase of treatment. Omega-3 fatty acids rich in eicosapentaenoic acid have shown some promising results in over a dozen small scale randomized controlled trials (RCTs) in adult major depressive disorders, with only very few published RCTs in children and adolescents. High-quality phase III RCTs are missing. Methods and Design: The omega-3-pMDD trial is a carefully designed phase III RCT to assess the efficacy and safety of omega-3 fatty acids in the early course of pediatric major depressive disorder (MDD). The study is designed as a multi-center, double-blinded, placebo-controlled, randomized clinical trial enrolling 220 patients aged 8 to 17 years meeting DSM-IV criteria for major depressive disorder of at least moderate symptom severity. After a single-blinded placebo-lead-in phase (7 to 10 days) patients are randomly assigned to omega-3 fatty acids or placebo over 36 weeks. Primary outcomes are changes in depression severity, as well as remission and recovery rates. Secondary outcome measures include the omega-3 index and inflammatory parameters as predictors of response. Data analysis will be performed in the intention-to-treat sample using a (generalized) linear random intercept regression model. Through sampling of blood, hair, saliva, and urine, further putative biological markers for depression and omega-3 fatty response will be investigated. Discussion: This trial addresses if omega-3 fatty acids play a role in the pathogenesis of pediatric MDDs and have antidepressant properties, in particular in clinically depressed children and adolescents with a pre-existing omega-3 fatty acid deficiency, increased markers of oxidative stress, and/or markers of (low grade) inflammation. Ethics and Dissemination: The study was approved by the local ethics committees. The results will be published in peer-reviewed journals irrespective of specific outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03167307.

Limbic Intrinsic Connectivity in Depressed and High-Risk Youth.

OBJECTIVE: Depression runs in families and has been associated with dysfunctional limbic connectivity. Whether aberrant limbic connectivity is a risk factor for or a consequence of depression is unclear. To examine this question, we compared resting state functional connectivity (RSFC) in youth with depressive disorders (DEP), healthy offspring of parents with depression (DEP-risk), and healthy comparison (HC) youth. METHOD: Magnetic resonance imaging at rest was acquired from 119 youth, aged 8 to 17 years (DEP, n = 41, DEP-risk, n = 39, and HC, n = 39) and analyzed using seed-based RSFC in bilateral amygdala and nucleus accumbens (NAcc), covarying for age, IQ, and sex. RESULTS: We found distinct risk- and disorder-specific patterns of RSFC across groups. DEP-risk and DEP youth shared reduced negative amygdala-right frontal cortex RSFC and reduced positive amygdala-lingual gyrus RSFC compared to HC youth (p < .001). DEP-risk youth had weaker negative amygdala-precuneus RSFC compared to DEP and HC youth (p < .001), suggesting a resilience marker for depression. In contrast, DEP youth had increased positive NAcc-left frontal cortex RSFC and reduced positive NAcc-insula RSFC compared to DEP-risk and HC youth (p < .001), suggestive of disorder-specific features of depression. Greater depression severity was correlated with disorder-specific amygdala and NAcc RSFC (p < .05). CONCLUSION: RSFC in the amygdala and NAcc may represent selective disorder- and risk-specific markers in youth with, and at familial risk for, depression. Longitudinal studies are needed to determine whether these patterns predict long-term clinical outcomes.

Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity.

Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.