The Impact of Failed Antidepressant Trials on Outcomes in Children and Adolescents with Anxiety and Depression: A Systematic Review and Meta-Analysis.

Objective: To identify predictors of medication-placebo differences in double-blind placebo-controlled antidepressant trials in children and adolescents with anxiety and depression. Methods: Clinical trials in patients <18 years of age with major depressive disorder or generalized, separation or social anxiety disorders were obtained from PubMed, the Cochrane Database and clinicaltrials.gov searches from inception through 2019. Forty-nine trials (43 published and 6 unpublished) of anxiety (κ = 13) and depression (κ = 36) evaluated 19 antidepressants in 8642 child and adolescent patients; placebo and medication response rates, trial characteristics, disorder, medication class, and funding source were extracted. Antidepressant-placebo differences were examined using Bayesian hierarchical models and estimates of response were determined for trial design, disorder, and medication class variables. Using meta-regression, correlates of antidepressant-placebo difference and placebo response were examined. Results: Funding source differentiated medication-placebo differences regardless of disorder. Industry trials had larger placebo response rates (mean difference: 0.189 ± 0.066, credible interval [CrI]: 0.067 to 0.33, p = 0.0008) and smaller medication-placebo differences (-0.235 ± 0.078, CrI: -0.397 to -0.086, p = 0.005) compared with federally funded trials. However, medication response was similar for industry- and federally-funded studies (-0.046 ± 0.042, CrI: -0.130 to 0.038, p = 0.252). Conclusions: The impact of study sponsorship on trial outcome supports the assertion that industry-funded trials with high placebo response rates and small drug-placebo differences are "failed trials" and should not be described as "negative trials" or used to determine public health estimates of antidepressant efficacy in children and adolescents with anxiety and depression. Identifying the proper role and value of industry-funded trials is critical to establishing the evidence base for antidepressants in youth.

Do Children with Special Health Care Needs with Anxiety have Unmet Health Care Needs? An Analysis of a National Survey.

OBJECTIVE: To describe differences in health care needs between Children with Special Health Care Needs (CSHCN) with and without anxiety and examine the association between anxiety and unmet health care needs. METHODS: We analyzed data from the 2009/2010 national survey of CSHCN. The independent variable was anxiety. The main outcomes were health care needs and unmet needs. Covariates included demographics, other co-morbid conditions, and the presence and quality of a medical home. We used bivariate analyses and multivariable logistic regression to assess the relationships among anxiety, covariates, and the outcomes. We stratified our analysis by age (6-11 years, 12-17 years). Propensity score matched paired analysis was used as a sensitivity analysis. RESULTS: Our final sample included 14,713 6-11 year-olds and 15,842 12-17-year-olds. Anxiety was present in 16% of 6-11 year-olds and 23% or 12-17 year-olds. In bivariate analyses, CSHCN with anxiety had increased health care needs and unmet needs, compared to CSHCN without anxiety. In multivariable analyses, only children 12-17 years old with anxiety had increased odds of having an unmet health care need compared to those children without anxiety (OR 1.44 [95% CI 1.17-1.78]). This was confirmed in the propensity score matching analysis (OR 1.12, [95% CI 1.02-1.22]). The specific unmet needs for older CSHCN with anxiety were mental health care (OR 1.54 [95% CI 1.09-2.17]) and well child checkups (OR 2.01 [95% CI 1.18-3.44]). CONCLUSION: Better integration of the care for mental and physical health is needed to ensure CSHCN with anxiety have all of their health care needs met.

Integrating evidence-based assessment into clinical practice for pediatric anxiety disorders.

BACKGROUND: Although evidence-based assessments are the cornerstone of evidence-based treatments, it remains unknown whether incorporating evidence-based assessments into clinical practice enhances therapists' judgment of therapeutic improvement. This study examined whether the inclusion of youth- and parent-reported anxiety rating scales improved therapists' judgment of treatment response and remission compared to the judgment of treatment-masked independent evaluators (IEs) after (a) weekly/biweekly acute treatment and (b) monthly follow-up care. METHODS: Four hundred thirty six youth received cognitive-behavioral therapy (CBT), medication, CBT with medication, or pill placebo through the Child/Adolescent Anxiety Multimodal Study. Participants and parents completed the following anxiety scales at pretreatment, posttreatment, and follow-up: Screen for Childhood Anxiety and Related Disorders (SCARED) and Multidimensional Anxiety Scale for Children (MASC). IEs rated anxiety on the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) at posttreatment and follow-up. Therapists rated anxiety severity and improvement using scales that paralleled IE measures. RESULTS: Fair-to-moderate agreement was found between therapists and IEs after acute treatment (κ = 0.38-0.48), with only slight-to-fair agreement found after follow-up care (κ = 0.07-0.33). Optimal algorithms for determining treatment response and remission included the combination of therapists' ratings and the parent-reported SCARED after acute (κ = 0.52-0.54) and follow-up care (κ = 0.43-0.48), with significant improvement in the precision of judgments after follow-up care (p < .02-.001). CONCLUSION: Therapists are good at detecting treatment response and remission, but the inclusion of the parent-report SCARED optimized agreement with IE rating-especially when contact was less frequent. Findings suggest that utilizing parent-report measures of anxiety in clinical practice improves the precision of therapists' judgment.

Epidemiology and Impact of Health Care Provider-Diagnosed Anxiety and Depression Among US Children.

OBJECTIVE: This study documents the prevalence and impact of anxiety and depression in US children based on the parent report of health care provider diagnosis. METHODS: National Survey of Children's Health data from 2003, 2007, and 2011-2012 were analyzed to estimate the prevalence of anxiety or depression among children aged 6 to 17 years. Estimates were based on the parent report of being told by a health care provider that their child had the specified condition. Sociodemographic characteristics, co-occurrence of other conditions, health care use, school measures, and parenting aggravation were estimated using 2011-2012 data. RESULTS: Based on the parent report, lifetime diagnosis of anxiety or depression among children aged 6 to 17 years increased from 5.4% in 2003 to 8.4% in 2011-2012. Current anxiety or depression increased from 4.7% in 2007 to 5.3% in 2011-2012; current anxiety increased significantly, whereas current depression did not change. Anxiety and depression were associated with increased risk of co-occurring conditions, health care use, school problems, and having parents with high parenting aggravation. Children with anxiety or depression with effective care coordination or a medical home were less likely to have unmet health care needs or parents with high parenting aggravation. CONCLUSION: By parent report, more than 1 in 20 US children had current anxiety or depression in 2011-2012. Both were associated with significant comorbidity and impact on children and families. These findings may inform efforts to improve the health and well-being of children with internalizing disorders. Future research is needed to determine why child anxiety diagnoses seem to have increased from 2007 to 2012.

Antidepressant Efficacy for Depression in Children and Adolescents: Industry- and NIMH-Funded Studies.

Significant controversy surrounds the efficacy of the newer antidepressants for children and adolescents with depression. The controversy largely hinges on meta-analyses of studies that suggest that antidepressants are minimally effective, not effective, or equivalent to placebo. In this review, the author discusses several scientific and clinical complexities that are important to understand in reviewing the antidepressant literature: the strengths and weaknesses of meta-analyses; the scientific and regulatory context for the large number of antidepressant trials in the late 1990s and early 2000s; and the distinction between a negative trial, where the treatment does not demonstrate efficacy, and a failed trial, where methodological problems make it impossible to draw any conclusion about efficacy. It is the premise of this review that meta-analyses that include the large number of industry-sponsored antidepressant trials distort the picture of antidepressant efficacy for teen depression. Industry-sponsored child and adolescent depression trials suffer from a number of implementation challenges and should be considered failed trials that are largely uninformative and not eligible to be included in efficacy meta-analyses. In contrast to the industry-sponsored trials, depression trials funded by the National Institute of Mental Health (NIMH) (N=2) are characterized by many methodological strengths, lower placebo response rates (30%-35%), and meaningful between-group differences (25%-30%) that support antidepressant efficacy. The NIMH-funded trials, taken together with the demonstrated efficacy of the serotonin reuptake inhibitors for childhood-onset obsessive-compulsive disorder and the anxiety disorders, suggest a broad and important role for antidepressant medications in pediatric internalizing conditions.

Development and piloting of a brief intervention for suicidal American Indian adolescents.

American Indian (AI) adolescents have the highest suicide death and attempt rates of any U.S. group, yet few interventions have been developed or evaluated for this population. This paper presents the first adaptation of a brief evidence-based intervention for AI adolescents from one reservation who made a suicide attempt. We describe our community-driven approach to intervention development and a small pilot study (n = 13). Preliminary findings indicate reductions in adolescents' negative thinking, depression, and suicidal ideation, and an increase in psychological service utilization. Key innovations include delivery by AI paraprofessionals and potential to strengthen the continuum of care between emergency department and outpatient settings.

SMARTer discontinuation trial designs for developing an adaptive treatment strategy.

OBJECTIVE: Developing evidenced-based practices for the management of childhood psychiatric disorders requires research studies that address how to treat children during both the acute phase of the disorder and beyond. Given the selection of a medication for acute treatment, discontinuation trials are used to evaluate the effects of treatment duration (e.g., time on medication) and/or maintenance strategies following successful acute-phase treatment. Recently, sequential multiple assignment randomized trials (SMART) have been proposed for use in informing sequences of critical clinical decisions such as those mentioned. The objective of this article is to illustrate how a SMART study is related to the standard discontinuation trial design, while addressing additional clinically important questions with similar trial resources. METHOD: The recently completed Child/Adolescent Anxiety Multimodal Study (CAMS), a randomized trial that examined the relative efficacy of three acute-phase treatments for pediatric anxiety disorders, along with a next logical step, a standard discontinuation trial design, is used to clarify the ideas. This example is used to compare the discontinuation trial design relative to the SMART design. RESULTS: We find that the standard discontinuation trial can be modified slightly using a SMART design to yield high-quality data that can be used to address a wider variety of questions in addition to the impact of treatment duration. We discuss how this innovative trial design is ultimately more efficient and less costly than the standard discontinuation trial, and may result in more representative comparisons between treatments. CONCLUSIONS: Mental health researchers who are interested in addressing questions concerning the effects of continued treatment (for different durations) following successful acute-phase treatment should consider SMART designs in place of discontinuation trial designs in their research. SMART designs can be used to address these and other questions concerning individualized sequences of treatment, such as the choice of a rescue treatment in case of postacute phase relapse.

Understanding the relationship between substance use and self-injury in American Indian youth.

BACKGROUND: American Indian communities compared to other US populations are challenged by the largest health disparities in substance abuse and suicidal behavior among youth ages 15-24. OBJECTIVES: This article examines the co-occurrence of substance use and self-injury among reservation-based youth in the US. METHODS: White Mountain Apache tribal leaders and Johns Hopkins University formed a partnership to address self-injury and substance abuse among Apache youth. Data on suicide (deaths, attempts, ideation), non-suicidal self-injury, and substance use were analyzed from the White Mountain Apache tribally mandated self-injury surveillance registry from 2007 to 2010, including 567 validated incidents from 352 individuals aged 15-24 years. Findings regarding characteristics of co-occurrence - including differences in the type of self-harm behavior, gender, and reported reasons for the act - were interpreted through a community-based participatory research process. RESULTS: From 2007 to 2010, 64% (n = 7/11) of Apache youth ages 15-24 were "drunk or high" at the time of suicide death with data missing for 2/11 deaths; 75.7% (n = 118/156) were "drunk or high" during suicide attempt; 49.4% (n = 83/168) during suicidal ideation; and 49.4% (81/166) during non-suicidal self-injury. Co-occurrence of substance use was higher for more lethal acts and among males. CONCLUSION: High rates of co-occurring self-injury and substance use within this population highlight the importance of research to understand relationships between these behaviors to design preemptive and integrated interventions. SCIENTIFIC SIGNIFICANCE: Tribal-specific and culturally informed data on the co-occurrence of self-injury and substance use hold promise for reducing the combined toll of years of productive life lost among American Indian youth.

A phenomenological investigation of women with Tourette or other chronic tic disorders.

There are little data concerning clinical characteristics of women with Tourette disorder and chronic tic disorders in the extant literature and what is available mostly focuses on treatment-seeking individuals. The present research was conducted to provide a phenomenological characterization of tic disorders among 185 adult women with tic disorders. In addition to providing a descriptive overview of specific tic symptoms, tic severity, self-reported history of other psychiatric conditions, and impairment/lifestyle impact due to tics, this study compares 185 women and 275 men between 18 and 79 years old with tic disorders (who completed an identical battery of measures) based on demographic, social/economic status indicators, psychiatric variables (comorbidity, family psychiatric history, symptom presentation), adaptive functioning/quality of life, and impairment variables among a nonclinical adult sample. Finally, this research examines the relationship between tic severity and impairment indicators among women with tics. Sixty-eight percent of women in our sample reported severe motor tics and 40% reported severe phonic tics. Our exploratory data suggest that a sizeable number of adult women with persistent tics are suffering from psychiatric comorbidity and psychosocial consequences such as underachievement and social distress. Tic severity in women may be associated with lifestyle interference as well as with symptoms of depression and anxiety, and such symptoms may be more common among women with tics than in men with tics.

Nonsuicidal self-injury in an American Indian reservation community: results from the White Mountain Apache surveillance system, 2007-2008.

OBJECTIVE: To describe characteristics and correlates of nonsuicidal self-injury (NSSI) among the White Mountain Apache Tribe. NSSI has not been studied before in American Indian samples despite associated risks for suicide, which disproportionately affect American Indian youth. METHOD: Apache case managers collected data through a tribally mandated surveillance system. Data from 2007 and 2008 (N = 182) were examined for rates, methods, precipitants, functions, past history of self-injury and service use, by age and gender. RESULTS: The rate of NSSI among all ages was 600 in 100,000, with individuals 10 to 14 years old disproportionately affected at a rate of 3,000 in 100,000. More females (65%) reported NSSI, and cutting was the preferred method (98%) for both genders combined. Most frequently reported precipitants were peer pressure/copying, conflict with boy/girlfriend and "depression." A substantial proportion (22%) was intoxicated/high at the time. More reported the function of NSSI was to "effect internal state" (45%) than "effect circumstances" (15%). More than one-third (39%) received ED treatment and referrals for aftercare (36%). Of those referred, only 30% followed up with services. Most (79%) reported past NSSI; 30% reported past suicidal ideation and 25% attempts. CONCLUSIONS: NSSI is a significant, largely unaddressed mental health problem among the White Mountain Apache Tribe and likely other reservation communities, especially as NSSI could serve as a precursor to suicide in this population. Interestingly, another self-destructive behavior, severe substance use, was reported to the surveillance system by Apaches and described in terms similar to NSSI, an important preliminary finding worth further exploration.

Patterns and correlates of tic disorder diagnoses in privately and publicly insured youth.

OBJECTIVE: This study examined the prevalence and demographic and clinical correlates of children diagnosed with Tourette disorder, chronic motor or vocal tic disorder, and other tic disorders in public and private insurance plans over the course of a 1-year period. METHOD: Claims were reviewed of Medicaid (n = 10,247,827) and privately (n = 16,128,828) insured youth (4-18 years old) focusing on tic disorder diagnoses during a 1-year period. Rates are presented for children with each tic disorder diagnosis overall and stratified by demographic characteristics and co-identified mental disorders. Mental health service use, including medications prescribed, and co-existing psychiatric disorders were also examined. RESULTS: In Medicaid-insured children, rates of diagnosis per 1,000 were 0.53 (95% confidence interval [CI] 0.51-0.55) for Tourette disorder, 0.08 (95% CI 0.07-0.08) for chronic motor or vocal tic disorder, and 0.43 (95% CI 0.41-0.44) for other tic disorders. In privately insured children, comparable rates were 0.50 (95% CI 0.49-0.52), 0.10 (95% CI 0.10-0.11), and 0.59 (95% CI 0.58-0.61). In 1 year, children diagnosed with tic disorders also frequently received other psychiatric disorder diagnoses. Compared with privately insured youth, children under Medicaid diagnosed with Tourette disorder had higher rates of attention-deficit/hyperactivity disorder (50.2% versus 25.9%), other disruptive behavior (20.6% versus 5.6%), and depression (14.6% versus 9.8%) diagnoses and higher rates of antipsychotic medication use (53.6% versus 33.2%). CONCLUSIONS: Despite similarities in annual rates of tic disorder diagnoses in publicly and privately insured children, important differences exist in patient characteristics and service use of publicly and privately insured youth who are diagnosed with tic disorders.

Pediatric generalized anxiety disorder: epidemiology, diagnosis, and management.

Pediatric generalized anxiety disorder (GAD) is characterized by excessive and uncontrollable worry about a variety of events and is accompanied by physical symptoms such as headaches, tension, restlessness, gastrointestinal distress, and heart palpitations. Symptoms impose marked distress and interfere with social, emotional, and educational functioning. GAD occurs in over 10% of children and adolescents, has an average age of onset of 8.5 years, and is more often reported in girls. Common co-occurring conditions include separation anxiety disorder and social phobia. Assessment involves a multi-informant, multi-method approach involving the child, parents, and school teachers. A clinical interview should be conducted to assess for the three primary ways anxiety presents: behaviors, thoughts, and somatic symptoms. Several semi-structured diagnostic interviews are available, and the Anxiety Disorders Interview Schedule is increasingly used. Rating scales completed by the patient, caregivers, and teachers provide useful information for diagnosis and symptom monitoring. Several scales are available to assess patients for the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) GAD diagnosis; however, instruments generally cannot distinguish children with GAD from children with similar anxiety disorders. Both cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy for the treatment of pediatric anxiety disorders including GAD. Evidence suggests that the combination of CBT plus sertraline offers additional benefit compared with either treatment alone. With pharmacotherapy, systematic tracking of treatment-emergent adverse events such as headaches, stomach aches, behavioral activation, worsening symptoms, and emerging suicidal thoughts is important. Recommended starting doses are fluvoxamine 25 mg/day, fluoxetine 10 mg/day, and sertraline 25 mg/day, though lower starting doses are possible. Dosing can be adjusted as often as weekly with the goal of achieving a high-quality response, while minimizing side effects. Long-term treatment with medication has not been well studied; however, to achieve optimal long-term outcome extended use of medication may be required. It is recommended to continue medication for approximately 1 year following remission in symptoms, and when discontinuing medication to choose a stress-free time of the year. If symptoms return, medication re-initiation should be considered seriously.

Review of safety assessment methods used in pediatric psychopharmacology.

OBJECTIVE: Elicitation is an essential and critical step in ascertaining adverse events (AEs). This report reviews elicitation methods used in published clinical trials of psychopharmacological agents in children. METHOD: Pediatric psychopharmacology reports were reviewed for safety methods in the Medline database. Studies were included if they were published 1980 or later, provided data on AEs, and described the ascertainment methodology used for determining them. RESULTS: A review of 196 pediatric psychopharmacology articles depicting safety assessments in clinical studies over the past 22 years revealed that there was no common method used for eliciting or reporting AE data. CONCLUSION: The current inconsistency in safety data ascertainment is a major limitation that likely impairs the ability to promptly and accurately identify drug-induced AEs. Research on how best to standardize safety methods should be considered a priority in pediatric psychopharmacology.

How can we improve the assessment of safety in child and adolescent psychopharmacology?

OBJECTIVE: To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. METHOD: Strengths and limitations of current methodology were reviewed and possible alternatives examined. RESULTS: Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. CONCLUSION: The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.