Trends in Children's Mental Health Services Research Funding: Response to Hoagwood and Colleagues' Commentary.

In their recent JAACAP Commentary, Hoagwood et al.1 examined data extracted from the National Institutes of Health Research Portfolio Online Reporting Tools (RePORT) and concluded there has been a decrease in National Institute of Mental Health (NIMH) funding for child and adolescent services and intervention research during the 10-year period from 2005 to 2015. They eloquently argued for the importance of research that can guide practice and inform the organization and delivery of children's mental health services in the current context of unmet need and the state of mental health service delivery.

Secondary Outcomes From the Child/Adolescent Anxiety Multimodal Study: Implications for Clinical Practice.

BACKGROUND: Controlled evaluations comparing medication, cognitive-behavioral therapy (CBT), and their combination in the treatment of youth anxiety have predominantly focused on global ratings by independent evaluators. Such ratings are resource-intensive, may be of limited generalizability, and do not directly inform our understanding of treatment responses from the perspective of treated families. We examined outcomes from the perspective of treated youth and parents in the Child/Adolescent Anxiety Multimodal Study (CAMS). METHODS: Participants (N=488; ages 7-17 years) who had a primary diagnosis of separation, social, and/or generalized anxiety disorder were randomly assigned to a treatment condition in the CAMS trial. Linear mixed-effects and ANCOVA models examined parent- and youth-reported anxiety symptoms, impact of anxiety, broader internalizing and externalizing psychopathology, depressive symptoms, and family burden throughout the 12-week acute treatment phase and 6-month follow-up. RESULTS: At week 12, combination treatment showed superiority over placebo, sertraline, and CBT with regard to parent-reported youth anxiety symptoms, and sertraline and CBT as monotherapies showed superiority over placebo with regard to parent-reported youth anxiety. Combination therapy and sertraline also showed week 12 superiority over placebo with regard to parent-reported internalizing psychopathology, and superiority over placebo and CBT with regard to parent-reported impact of anxiety, family burden, and youth depressive symptoms. By week 36, parent reports of many youth outcomes were comparable across active conditions. Youth measures tracked parent measures on many outcomes. CONCLUSIONS: Findings were drawn on brief, readily available questionnaires that in conjunction with clinician measures can inform patient-centered care and collaborative decision-making.Trial Registry Name: Child and Adolescent Anxiety Disorders (CAMS)Registry identification number: NCT00052078Registry URL: https://www.clinicaltrials.gov/ct2/show/NCT00052078.

Adaptive Treatment Strategies in Youth Mental Health: A Commentary on Advantages, Challenges, and Potential Directions.

This commentary underscores the importance and potential of the research approaches and intervention strategies described in the JCCAP special issue on the Science of Adaptive Treatment Strategies in Child and Adolescent Mental Health for addressing the widely observed heterogeneity in response to even our most promising research-informed interventions. First, the commentary briefly summarizes the advantages of these approaches and highlights how these programs of research are responsive to widely agreed-upon calls for more personalized, prescriptive interventions. Next, the commentary briefly discusses key common challenges and gaps in our knowledge that might be addressed to advance the development, testing, and implementation of adaptive intervention strategies. For example, research to identify robust moderators that might serve as potential tailoring variables for initial assignment and sequencing of interventions, efforts to operationalize surrogate endpoints for early identification of individuals who are unlikely to respond to first-line interventions, and research that helps define what constitutes an adequate exposure (i.e., dose) or response threshold (e.g., response that suggests the need to intensify, switch, or augment interventions) would inform decision rules for adaptive algorithms. The commentary concludes with a discussion of potential strategies and current initiatives that might ultimately help facilitate research on more targeted, prescriptive approaches to intervening, including efforts to encourage investigators to use common data elements, to share and integrate data across trials, and to employ a more mechanism-based approach to intervention development and testing.

Child/Adolescent anxiety multimodal study: evaluating safety.

OBJECTIVE: To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents. METHOD: Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC). RESULTS: There were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (≤12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups. CONCLUSION: The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (≤12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078.

A strategic approach for prioritizing research and action to prevent suicide.

It is time to strategically apply science and accountability to the public health problem of preventable suicide. U.S. suicide rates have remained stable for decades. More than 36,000 individuals now die by suicide each year. A public health-based approach to quickly and substantially reduce suicides requires strategic deployment of existing evidence-based interventions, rapid development of new interventions, and measures to increase accountability for results. The purpose of this Open Forum is to galvanize researchers to further develop and consolidate knowledge needed to guide these actions. As researchers overcome data limitations and methodological challenges, they enable better prioritization of high-risk subgroups for targeted suicide prevention efforts, identification of effective interventions ready for deployment, estimation of the implementation impact of effective interventions in real-world settings, and assessment of time horizons for taking implementation to scale. This new knowledge will permit decision makers to take strategic action to reduce suicide and stakeholders to hold them accountable for results.

Therapist Factors and Outcomes in CBT for Anxiety in Youth.

This study examined the relationship between therapist factors and child outcomes in anxious youth who received cognitive-behavioral therapy (CBT) as part of the Child-Adolescent Anxiety Multimodal Study (CAMS). Of the 488 youth who participated in the CAMS project, 279 were randomly assigned to one of the CBT conditions (CBT only or CBT plus sertraline). Participants included youth (ages 7-17; M = 10.76) who met criteria for a principal anxiety disorder. Therapists included 38 cognitive-behavioral therapists. Therapist style, treatment integrity, and therapist experience were examined in relation to child outcome. Child outcome was measured via child, parent, and independent evaluator report. Therapists who were more collaborative and empathic, followed the treatment manual, and implemented it in a developmentally appropriate way had youth with better treatment outcomes. Therapist "coach" style was a significant predictor of child-reported outcome, with the collaborative "coach" style predicting fewer child-reported symptoms. Higher levels of therapist prior clinical experience and lower levels of prior anxiety-specific experience were significant predictors of better treatment outcome. Findings suggest that although all therapists used the same manual-guided treatment, therapist style, experience, and clinical skills were related to differences in child outcome. Clinical implications and recommendations for future research are discussed.

Child/Adolescent Anxiety Multimodal Study (CAMS): rationale, design, and methods.

OBJECTIVE: To present the design, methods, and rationale of the Child/Adolescent Anxiety Multimodal Study (CAMS), a recently completed federally-funded, multi-site, randomized placebo-controlled trial that examined the relative efficacy of cognitive-behavior therapy (CBT), sertraline (SRT), and their combination (COMB) against pill placebo (PBO) for the treatment of separation anxiety disorder (SAD), generalized anxiety disorder (GAD) and social phobia (SoP) in children and adolescents. METHODS: Following a brief review of the acute outcomes of the CAMS trial, as well as the psychosocial and pharmacologic treatment literature for pediatric anxiety disorders, the design and methods of the CAMS trial are described. RESULTS: CAMS was a six-year, six-site, randomized controlled trial. Four hundred eighty-eight (N = 488) children and adolescents (ages 7-17 years) with DSM-IV-TR diagnoses of SAD, GAD, or SoP were randomly assigned to one of four treatment conditions: CBT, SRT, COMB, or PBO. Assessments of anxiety symptoms, safety, and functional outcomes, as well as putative mediators and moderators of treatment response were completed in a multi-measure, multi-informant fashion. Manual-based therapies, trained clinicians and independent evaluators were used to ensure treatment and assessment fidelity. A multi-layered administrative structure with representation from all sites facilitated cross-site coordination of the entire trial, study protocols and quality assurance. CONCLUSIONS: CAMS offers a model for clinical trials methods applicable to psychosocial and psychopharmacological comparative treatment trials by using state-of-the-art methods and rigorous cross-site quality controls. CAMS also provided a large-scale examination of the relative and combined efficacy and safety of the best evidenced-based psychosocial (CBT) and pharmacologic (SSRI) treatments to date for the most commonly occurring pediatric anxiety disorders. Primary and secondary results of CAMS will hold important implications for informing practice-relevant decisions regarding the initial treatment of youth with anxiety disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT00052078.

Integrating statistical and clinical research elements in intervention-related grant applications: summary from an NIMH workshop.

OBJECTIVE: The authors summarize points for consideration generated in a National Institute of Mental Health (NIMH) workshop convened to provide an opportunity for reviewers from different disciplines-specifically clinical researchers and statisticians-to discuss how their differing and complementary expertise can be well integrated in the review of intervention-related grant applications. METHODS: A 1-day workshop was convened in October, 2004. The workshop featured panel presentations on key topics followed by interactive discussion. This article summarizes the workshop and subsequent discussions, which centered on topics including weighting the statistics/data analysis elements of an application in the assessment of the application's overall merit; the level of statistical sophistication appropriate to different stages of research and for different funding mechanisms; some key considerations in the design and analysis portions of applications; appropriate statistical methods for addressing essential questions posed by an application; and the role of the statistician in the application's development, study conduct, and interpretation and dissemination of results. RESULTS: A number of key elements crucial to the construction and review of grant applications were identified. It was acknowledged that intervention-related studies unavoidably involve trade-offs. Reviewers are helped when applications acknowledge such trade-offs and provide good rationale for their choices. Clear linkage among the design, aims, hypotheses, and data analysis plan and avoidance of disconnections among these elements also strengthens applications. CONCLUSION: The authors identify multiple points to consider when constructing intervention-related grant applications. The points are presented here as questions and do not reflect institute policy or comprise a list of best practices, but rather represent points for consideration.

Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety.

BACKGROUND: Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. METHODS: In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12. RESULTS: The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. CONCLUSIONS: Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.)

Nonsomatic treatment of depression.

Clinicians who treat depressed children and adolescents are faced with substantial challenges. Although to date the results of controlled psychotherapy trials with depressed youths offer limited guidance regarding choice of treatment, some general guidelines can be culled from the available data. Interventions or elements of therapies that are structured and directed towards cognitive behavioral or relationship issues show promise for the treatment of juvenile depression. Group interventions seem to be as effective as the more traditional individual therapy. Parental participation in empiric treatment trials of pediatric depression has been limited to either separate parent groups as an adjunct or to family therapy,but for various practical and clinical reasons it may be wise to involve parents directly. Parents may be critical to the success of interventions with depressed children and should be regarded as potentially important agents of change.

Nonsomatic treatment of depression.

There is solid evidence that active and goal-oriented cognitive-behavioral or relationship-focused therapies are generally superior to more generic therapies or to no treatment for clinically diagnosed and for undiagnosed but symptomatic youths. Between 50% to 87% of diagnosed youths who received a targeted treatment had recovered from their depressive episodes, in comparison to 21% to 75% of those who received some other generic therapy and 5% to 48% of wait-listed youths. The cognitive behavioral and relationship-oriented interventions that were tested tended to be even more successful in reducing depressive symptoms in school-based samples, possibly because the participants in the school-based studies may have been less disturbed than the clinically diagnosed cases. Although the targeted treatments generally yielded better results than the comparison conditions, the targeted interventions seem to be similarly successful in ameliorating depression. Determining which psychosocial therapy works best for a given depressed youngster remains problematic. As noted in recent reviews [30,46,47], little attention has been devoted to which interventions, or parts of an intervention, are likely to be effective with children with various characteristics. This issue acquires added importance because in some diagnosed samples half or more of the treated participants were still in a depressive episode at the end of the trial. Likewise, in intervention studies involving symptomatic, school-based youngsters, not all children improved, and gains were not uniform across domains of functioning (e.g., severity of depression, self-esteem, global functioning). Possibly, for some of the nonresponders, the participant's characteristics and relevant problems and the target interventions were mismatched. For example, a depressed youth with a long history of highly dysfunctional relationships may not respond optimally to a therapy focusing on negative cognitions; alternatively, interpersonal therapy may not be the most effective treatment for a youth dispositionally inclined to negative ruminations about the self and for whom relationship issues are not the most relevant. Empiric information about the relationship between the underlying processes presumed to account for the onset and maintenance of depression and recovery from depression is limited. Few studies of youths provide direct evidence tht cognitive-behavioral interventions change depressogenic cognitions, explanatory style, and pleasent events, among others, that relationship-focused approaches predictably alter relevant interpersonal processes, or that improvements in these domains relate to overall depression outcomes. Admittedly, the designs of extent studies typically preclude conclusions about the relationship between changes in target processes and improvement in depression or about treatment specificity. More compelling evidence linking changes in targeted mechanisms to decreases in depressive symptoms comes from a controlled prevention trial involving 10- to 13-year-olds that used cognitive restructuring, social problem-solving, or a combination intervention [48]. According to the results, changes in explanatory style were related to decreased depression and accounted for a significant portion of the variance in changes in depression even after controlling for treatment assignment. Further research along such lines may help identify which treatment may be most effective for a patient with a given set of characteristics. To improve patients' response rates to specific treatments, it also would be helpful to understand better the impact of other attributes, such as psychiatric comorbidity, and contextual factors, such as parental psychopathology, on the process of recovery. With few exceptions [25], however, such variable have not yet received sufficient attention. Recent reviews also have noted that researchers typically use multi-component interventions in treatmenttrials [46,47]. This design an make it difficult to identify which particular treatment ingredient is instrumental in general or among children with specific characteristics. Thus, empiric initiatives also are needed to determine the active ingredients of experimental therapies for depressed youths. Existing models include component-analysis or dismantling studies of multi-faceted treatments for depressed adults [49,50]. Once the improtant prognostic factors and active ingredients of therapies have been identified, it will be possible to conduct studies in which children are either "matched" or "mismatched" to treatment conditions. To achieve meaningful results and to enroll sufficient numbers of youths, collaborative, multisite efforts may be required. What treatment should be endorsed for depressed youths from the perspective of health services policy? When the criteria of the Task Force on Promotion and Dissemination of Psychological Procedures [1] are applied broadly, both cognitive behavioral and interpersonally oriented therapies can be deemed efficacious. Both approaches have been tested in different samples by two independent teams and thus may be regarded as well-established treatments for depression in youths. If the criteria are applied more stringently, so that exactly the same intervention is tested independently by two or more research teams, interpersonal therapy and cognitive behavioral therapy would be regarded as "probably efficacious". Namely, the two trials of interpersonal therapy apparently used somewhat different versions because of cultural differences in the samples. The complete CWD course has been tested and the results replicated only by its originators [20,21]. Other trials of cognitive behavioral therapy entail various different study-specific approaches and consequently cannot serve as replications [46,47]. A next step in psychotherapy research might therefore involve further independent replication of standardized, previously studies therapies. In their landmark meta-analytic study of the efficacy of psychotherapy for adults, Smith et al [51] concluded that all psychotherapies are about equally beneficial and that distinctions among them, although "cherished by those who draw them ... make no important differences: (p. 186). Likewise, the various psychotherapies for depresed youths that have been examined seem to produce similar rates of improvement ( or alternatively, similar limits in efficacy) across the tested therapies and the scant data regarding meaningful prognostic factors might indicate that at present it does not matter what type of brief, goal-oriented nonsomatic therapy is used to treat pediatric depression. Alternatively, one might conclude that patients who fail to respond may have been mismatched to a therapy that was not focused on their primary depression-related deficits. Thus, clinicians who treat depressed children and adolescents are faced with substantial challenges, and to date, results of controlled psychotherapy trials with depressed youths offer limited guidance regarding choice of treatment. Nonetheless, some general guidelines can be culled from the available data. For example, interventions of elements of therapies that are structured and directed towards cognitive, behavioral or relationship issues show promise for the treatment of juvenile depression. It also appears that group interventions may be used as profitably as the more traditional individual therapy formats. And although parental participation in empiric treatment trials of pediatric depression has been limited to either separate parent groups as an adjunct [20,21 or family therapy [7], it can be argued that for various practical and clinical reasons [30] direct involvement of parents may be a wise choice. Parents may be critical to the success of interventions with depressed children and should be regarded as potential important agents of change.

Regional patterns of brain activity in adults with a history of childhood-onset depression: gender differences and clinical variability.

OBJECTIVE: The study investigated the hypothesis that EEG asymmetry scores (indicating higher right and lower left frontal brain activity) are associated with vulnerability to negative mood states and depressive disorders. Gender and clinical history variables were examined as factors that may influence the relation between EEG and depression. METHOD: EEG measures of asymmetrical alpha frequency (7.5-12.5 Hz) suppression were analyzed in 55 young adults with a documented clinical history of childhood-onset depression and 55 comparison subjects with no history of major psychopathology. EEG patterns were examined in relation to operational diagnoses of mental disorders during childhood and adulthood. RESULTS: Differences in EEG asymmetry between childhood depression probands and comparison subjects varied with gender, diagnostic history, and current symptoms. Women with childhood depression had higher right midfrontal alpha suppression, and men with childhood depression had higher left midfrontal alpha suppression, relative to comparison subjects. At all scalp sites, women showed greater alpha power than men. Probands with a bipolar spectrum course had the most extreme midfrontal asymmetry. Frontal asymmetry was more extreme in probands with current depressive symptoms than in those without current symptoms. CONCLUSIONS: Regional brain activity is influenced by gender and variability in clinical course. The findings have implications for investigating brain correlates of mood disorder and may help to develop more refined phenotypes.