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Abstract 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.

Objectives: Antidepressant treatment for major depressive disorder (MDD) has been a topic of continued interest with a number of placebo randomized-controlled trials (RCTs) being published in the past decade. We review the updated literature since the 2007 Bridge meta-analysis, and reassess safety data looking at signals of treatment-emergent suicidality with the Columbia Suicide Severity Rating Scale (CSSR-S). Methods: PubMed literature review was performed searching for RCTs published since the 2007 article and supplemented with manual search. Results: Findings from seven trials (five industry sponsored, one NIMH funded, and one other) were included in this systematic review, which showed high medication and placebo response rates, with only fluoxetine and escitalopram treatment reaching statistical significance. Fluoxetine was also shown to prevent relapse of MDD with continued treatment with an odds ratio of 3.2 for prevention of relapse compared with placebo. There were no increases in treatment-emergent suicidality associated with antidepressant medication in any trial measuring suicidality systematically using the CSSR-S. Conclusions: Depressed pediatric patients respond similarly in these trials to antidepressant intervention and placebo, with recent studies showing that newer agents did not clearly demonstrate benefit above placebo. The evidence continues to support fluoxetine and escitalopram as first-line treatment and demonstrated effect to prevent relapse. Use of newer rating scales reveals similar rates of treatment-emergent suicidality in patients on antidepressants as placebo, in contrast to increased suicide signal suggested by past research using adverse events data. Antidepressant treatment is generally safe and well tolerated in this age group.

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., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: We report active treatment group differences on response and remission rates and changes in anxiety severity at weeks 24 and 36 for the Child/Adolescent Anxiety Multimodal Study (CAMS)., Method: CAMS youth (N = 488; 74% ≤ 12 years of age) with DSM-IV separation, generalized, or social anxiety disorder were randomized to 12 weeks of cognitive-behavioral therapy (CBT), sertraline (SRT), CBT+SRT (COMB), or medication management/pill placebo (PBO). Responders attended 6 monthly booster sessions in their assigned treatment arm; youth in COMB and SRT continued on their medication throughout this period. Efficacy of COMB, SRT, and CBT (n = 412) was assessed at 24 and 36 weeks postrandomization. Youth randomized to PBO (n = 76) were offered active CAMS treatment if nonresponsive at week 12 or over follow-up and were not included here. Independent evaluators blind to study condition assessed anxiety severity, functioning, and treatment response. Concomitant treatments were allowed but monitored over follow-up., Results: The majority (>80%) of acute responders maintained positive response at both weeks 24 and 36. Consistent with acute outcomes, COMB maintained advantage over CBT and SRT, which did not differ, on dimensional outcomes; the 3 treatments did not differ on most categorical outcomes over follow-up. Compared to COMB and CBT, youth in SRT obtained more concomitant psychosocial treatments, whereas those in SRT and CBT obtained more concomitant combined (medication plus psychosocial) treatment., Conclusions: COMB maintained advantage over CBT and SRT on some measures over follow-up, whereas the 2 monotherapies remained indistinguishable. The observed convergence of COMB and monotherapy may be related to greater use of concomitant treatment during follow-up among youth receiving the monotherapies, although other explanations are possible. Although outcomes were variable, most CAMS-treated youth experienced sustained treatment benefit. Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); URL: http://clinicaltrials.gov. Unique identifier: NCT00052078., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period., Method: The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Children's Depression Rating Scale-Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure., Results: Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality., Conclusions: In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.

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.), (2008 Massachusetts Medical Society)

Objective: We examined the extent to which parents and adolescents participating in the Treatment for Adolescents With Depression Study (TADS) understood key aspects of the study., Method: TADS was a clinical trial comparing the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), their combination, and placebo in 439 adolescents (12-17 years old) with major depressive disorder. Six weeks after starting treatment, adolescents and their parents were asked to complete a questionnaire about critical elements of the trial., Results: Completion rate was 67.2% for adolescents (N = 295) and 73.6% for parents (N = 323). More than 90% of the completers knew of the main purpose of the trial, possible assignment to placebo, and their right to withdraw participation at any time. However, about one third overall (and 49% in the CBT group) described TADS as "education" rather than "research." Of 12 questions, the mean number of correct answers was 10.3 (SD 1.7) among adolescents and 11.2 (SD 1.2) among parents (p <.0001). The most frequently stated reason for TADS participation was the pursuit of high-quality care., Conclusions: Most parents and adolescents were well-informed research participants. Difficulties in appreciating the research nature of the trial, however, emerged, especially among participants assigned to psychotherapy. Parents were overall better informed than adolescents.

Objective: To compare the rates of physical, psychiatric, and suicide-related events in adolescents with MDD treated with fluoxetine alone (FLX), cognitive-behavioral therapy (CBT), combination treatment (COMB), or placebo (PBO)., Method: Safety assessments included adverse events (AEs) collected by spontaneous report, as well as systematic measures for specific physical and psychiatric symptoms. Suicidal ideation and suicidal behavior were systematically assessed by self- and clinician reports. Suicidal events were also reanalyzed by the Columbia Group and expert raters using the Columbia-Classification Algorithm for Suicidal Assessment used in the U.S. Food and Drug Administration reclassification effort., Results: Depressed adolescents reported high rates of physical symptoms at baseline, which improved as depression improved. Sedation, insomnia, vomiting, and upper abdominal pain occurred in at least 2% of those treated with FLX and/or COMB and at twice the rate of placebo. The rate of psychiatric AEs was 11% in FLX, 5.6% in COMB, 4.5% in PBO, and 0.9% in CBT. Suicidal ideation improved overall, with greatest improvement in COMB. Twenty-four suicide-related events occurred during the 12-week period: 5 patients (4.7%) in COMB, 10 (9.2%) in FLX, 5 (4.5%) in CBT, and 3 (2.7%) in placebo. Statistically, only FLX had more suicide-related events than PBO (p =.0402, odds ratio (OR) = 3.7, 95% CI 1.00-63.7). Only five actual attempts occurred (2 COMB, 2 FLX, 1 CBT, 0 PBO). There were no suicide completions., Conclusions: Different methods for eliciting AEs produce different results. In general, as depression improves, physical complaints and suicidal ideation decrease in proportion to treatment benefit. In this study, psychiatric AEs and suicide-related events are more common in FLX-treated patients. COMB treatment may offer a more favorable safety profile than medication alone in adolescent depression.

Objective: To test whether 12-week treatment of major depression improved the level of functioning, global health, and quality of life of adolescents., Method: The Treatment for Adolescents With Depression Study was a multisite, randomized clinical trial of fluoxetine, cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with placebo in 439 adolescents with major depression. Functioning was measured with the Children's Global Assessment Scale (CGAS), global health with the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA), and quality of life with the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). Random-effects regression models were applied to the data., Results: Compared with placebo, COMB was effective on the CGAS (p < .0001), HoNOSCA (p < .05), and PQ-LES-Q (p < .001), whereas fluoxetine was superior to placebo on the CGAS only (p < .05). COMB was superior to fluoxetine on the CGAS (p < .05) and PQ-LES-Q (p = .001). Fluoxetine was superior to CBT on the CGAS (p < .01). CBT monotherapy was not statistically different from the placebo group on any of the measures assessed. Treatment effects were mediated by improvement in depressive symptoms measured on the Child Depression Rating Scale-Revised., Conclusions: The combination of fluoxetine and CBT was effective in improving functioning, global health, and quality of life in depressed adolescents. Fluoxetine monotherapy improved functioning.

This article reviews mood disorders in children and adolescents, the diagnostic criteria, and important differential diagnoses to be considered. Critical points in the treatment of mood disorders and comorbid conditions and the important role the primary care provider can play in their management are stressed. Warning signs to identify adolescents who may be at risk of attempting suicide are discussed.

Pediatric anxiety disorders are commonly occurring mental health disorders of childhood and are associated with significant distress, impairment, and risk for ongoing morbidity. During the past decade, significant progress has been made in developing safe and effective therapeutic approaches to these disorders. This article focuses on the scientific literature supporting the use of a variety of medication approaches to the treatment of the various anxiety disorders of childhood and adolescence.

Background: Chronic depressions commonly present in youth and cause significant morbidity. No treatment studies in this age group are currently available., Methods: 19 pediatric subjects with dysthymic disorder or 'double depression' were recruited. After four weeks of psychosocial treatment, subjects failing to improve began open treatment with fluoxetine (20 mg) for eight weeks. Subjects were then reassessed for treatment response., Results: Fifteen subjects entered the medication phase, and eleven (73%) no longer met criteria for dysthymic disorder or Major Depression at final assessment., Conclusions: Fluoxetine shows promise as a safe and effective treatment for youth with chronic depressions. Controlled trials are indicated., Limitations: Open label design, no comparison treatment condition., Clinical Relevance: As in adults, treatment with antidepressants may prove to be a useful intervention with children and adolescents with chronic forms of depression.

Objective: To examine the impact of age on the effects of desipramine (DMI) on autonomic input to the heart., Method: Twenty-four-hour electrocardiograms were obtained from 42 subjects, aged 7 to 66 years, while off and on DMI. To obtain measures of autonomic input to the heart, heart rate variability was assessed via spectral analysis of RR interval variability., Results: DMI treatment was associated with a significant increase in 24-hour mean heart rate and significant decreases in RR interval variability in all spectral bands, including in the high-frequency band, which provides a measure of parasympathetic input to the heart. RR interval variability was greater in younger individuals both off and on DMI., Conclusions: DMI treatment was associated with a marked decline in RR interval variability, indicating that DMI affects autonomic input to the heart. Specifically, DMI reduced parasympathetic input, which, in theory, may increase vulnerability to arrhythmias. However, the magnitude of DMI's impact on RR interval variability did not vary with age.

Objective: In light of recent reports of sudden death in children being treated with desipramine (DMI), 3 of which were associated with physical exercise, the authors examined the effects of DMI on exercise in children and adults before and during DMI treatment., Method: Before treatment, 22 subjects (9 children, 13 adults) participated in a graded treadmill exercise test. Outcome measures included exercise tolerance, cardiovascular, and electrocardiographic parameters at progressive intensity levels and serum norepinephrine (NE) levels before and after exercise testing. Subjects were then treated with DMI, titrated to an average DMI dosage of 3 mg/kg, and underwent repeated exercise testing., Results: DMI treatment was associated with a significant elevation of circulating NE levels in the pre-exercise assessment. Exercise tolerance was not affected by DMI, and blood pressure and heart rate effects were modest. The cardiovascular impact of DMI treatment was similar in children and adults. One 31-year-old subject exhibited a brief episode of ventricular tachycardia associated with exercise during DMI treatment., Conclusions: DMI has only minor effects on the cardiovascular response to exercise, and these effects do not appear age-related. However, DMI may increase the risk of exercise-associated arrhythmias in rare individuals.

Multiple dependent variables were graphed for 29 subjects who participated in a double-blind evaluation of 4 doses of Adderall, plus positive (methylphenidate) and placebo control conditions. Five judges ranked the conditions for each subject, and analyses of individual subjects indicated that these rankings were concordant (reliable) across judges. Consensus rankings were assigned to each subject, and an analysis of these ranks showed that the conditions differed significantly. The choice of best conditions were judged to be across 3 doses of Adderall (10, 15, and 20 mg). This confirms the clinical impression of individual differences in optimal dose of stimulant medication. The methodological, graphical, and statistical methods presented in this article provide a systematic, reliable procedure for evaluating relative response of individuals to different doses of stimulant medication.

In a randomized double-blind crossover study of children with attention deficit hyperactivity disorder (ADHD), the time course effects of four doses of Adderall (5, 10, 15, and 20 mg) and an inactive (placebo) control, and an active (Ritalin) control were evaluated. A laboratory classroom setting was established in which subjective (teacher ratings of deportment and attention) and objective (scores on math tests) measurements were taken every 1.5 hours across the day. In addition to significant time and dose effects of Adderall, significant time-of-day effects were documented in the placebo condition for the subjective measure of deportment and objective measures of performance. Regression analyses were used to estimate the magnitude of these baseline effects. Correlations across time were used to evaluate the test-retest reliability of each measure in the face of these time-dependent placebo effects. After placebo/time adjustments, within-subject correlations between pairs of measures were used to evaluate the validity of the math test as a measure of response to stimulant medication.

Many therapeutic approaches to managing suicidal behavior among youth have been used, including in-school education programs, screening programs, telephone hotlines, cognitive behavioral therapies, medication management, and inpatient milieux treatment programs. These interventions have been applied based on educational and therapeutic principles drawn from prior work with adolescents in varied scholastic and psychiatric settings. This article reviews: the assessment of risk factors among suicide attempters, emotional states, family, social isolation, interpersonal loss, substance and alcohol abuse, and treatment strategies.