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Objectives: The Concise Health Risk Tracking Self-Report (CHRT-SR) assesses the risk of suicidal behavior. We report its psychometric properties in a representative sample of adolescent outpatients., Methods: A sample (n = 657) of adolescents (<18 years of age) in primary or psychiatric care completed the 14-item version of CHRT-SR at both baseline and within 3 months. To identify an optimal brief solution for the scale, we evaluated the factor structure of CHRT-SR using multigroup confirmatory factor analysis, and testing measurement invariance across age and gender. The item response theory and classical test theory characteristics of the optimal solution were evaluated. Concurrent validity (both cross-sectional and as a change measure over time) of the optimal solution was assessed by comparing it to another suicide measure., Results: Confirmatory factor analysis identified the 9-item CHRT-SR (CHRT-SR 9 ) as the optimal solution. Classical test theory and item response theory indicated excellent fit. Concurrent validity analyses revealed that it can measure both improvement/worsening of suicidality over time., Conclusion: The CHRT-SR 9 is a brief self-report with excellent psychometric properties in a sample of adolescents that is sensitive to changes in suicidality over time. Its performance in other populations and ability to predict future suicidal events deserves study., (© 2022 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Background: This study evaluated the psychometric properties of the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR 9 ), a measure of suicidality, in adolescent psychiatric outpatients., Methods: Altogether, 933 depressed or suicidal adolescents (12-20 years of age), receiving treatment at psychiatric outpatient clinics in Texas, completed the 16-item CHRT-SR at baseline and one month later. CHRT-SR 9 was extracted from CHRT-SR 16 using multigroup confirmatory factor analysis. Sex and age measurement invariance, classical test theory, item response theory (IRT), and concurrent validity analyses (against the suicidal ideation Item 9 of Patient Health Questionnaire-Adolescent (PHQ-A)) were conducted., Results: The CHRT-SR 9 demonstrated excellent model fit with four factors (pessimism, helplessness, despair, and suicidal thoughts). Measurement invariance was upheld. Acceptable item-total correlations (0.56-0.80) and internal consistency (Spearman-Brown 0.78-0.89) were revealed. IRT analyses showed a unidimensional instrument with excellent item performance. Using the CHRT-SR 9 total score as a measure of overall suicidality and comparing it against levels of PHQ-A Item 9, the mean (standard deviation) of CHRT-SR 9 total score was 8.64 (SD = 5.97) for no-risk (0 on Item 9), 17.05 (SD = 5.00) for mild, 23.16 (SD = 5.05) for moderate, and 26.96 (SD = 5.24) for severe-risk (3 on Item 9). Significant differences (p-value<0.0001) indicated that CHRT-SR 9 total score distinguished between levels of suicidal risk. Furthermore, CHRT-SR 9 was sensitive to change over a one-month period., Limitations: Whether CHRT-SR 9 predicts actual suicidal attempts in adolescents is not well defined., Conclusion: The CHRT-SR 9 is an easy-to-administer, user-friendly self-report with good psychometric qualities which makes it an excellent screening measure of suicidal risk in adolescent psychiatric outpatients., Competing Interests: Conflict of interest Dr. Trivedi has provided consulting services to Alkermes Inc, Axsome Therapeutics, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc, Compass Pathfinder Limited, GH Research Limited, Heading Health Inc, Janssen, Legion Health Inc, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc, Merck Sharp & Dhome LLC, Naki Health, Ltd., Neurocrine Biosciences Inc, Noema Pharma AG, Orexo US Inc, Otsuka American Pharmaceutical Inc, Otsuka Canada Pharmaceutical Inc, Otsuka Pharmaceutical Development & Commercialization Inc, Praxis Precision Medicines Inc, SAGE Therapeutics, Sparian Biosciences Inc, Takeda Pharmaceutical Company Ltd, WebMD. He sits on the Scientific Advisory Board of Alto Neuroscience Inc, Cerebral Inc., Compass Pathfinder Limited, Heading Health, GreenLight VitalSign6 Inc, Legion Health Inc, Merck Sharp & Dohme Corp, Orexo US Inc, Signant Health. He holds stock in Alto Neuroscience Inc, Cerebral Inc, Circular Genomics Inc, GreenLight VitalSign6 Inc, Legion Health Inc. Additionally, he has received editorial compensation from American Psychiatric Association, and Oxford University Press. Dr. A. John Rush has received consulting fees from Compass Inc., Curbstone Consultant LLC, Emmes Corp., Evecxia Therapeutics, Inc., Holmusk Technologies, Inc., ICON, PLC, Johnson and Johnson (Janssen), Liva-Nova, MindStreet, Inc., Neurocrine Biosciences Inc., Otsuka-US; speaking fees from Liva-Nova, Johnson and Johnson (Janssen); and royalties from Wolters Kluwer Health, Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Dr. Emslie is a consultant for Lundbeck, Neuronetics and Otsuka. He receives research support from the American Foundation for Suicide Prevention, Janssen Research & Development and Pharmaceuticals, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the State of Texas. Dr. Jha has received contract research grants from Acadia Pharmaceuticals, Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development, educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network, consultant fees from Eleusis Therapeutics US, Inc., Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem, and Guidepoint Global, and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr. Brown has received consulting fees from Sage and Biogen Pharmaceuticals. Dr. Kennard receives royalties from Guilford, Press, Inc.; and serves on the board of trustees for the Jerry M. Lewis, III, MD Research Foundation. Dr. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, and Jessica Kingsley. Dr. Blader reports having received consultant and speaker's honoraria from Supernus Pharmaceuticals. Ms. Fuselier and Drs. Nandy, Garza, Gushanas, Minhajuddin, Wakefield and Slater do not have any conflicts to declare., (Copyright © 2023. Published by Elsevier B.V.)

Background: The suicide rate in youth and young adults continues to climb - we do not understand why this increase is occurring, nor do we have adequate tools to predict or prevent it. Increased efforts to treat underlying depression and other disorders that are highly associated with suicide have had limited impact, despite considerable financial investments in developing and disseminating available methods. Thus, there is a tremendous need to identify potential markers of suicide behavior for youth during this high-risk period., Methods: Funded by the American Foundation for Suicide Prevention (AFSP), this study aims to map immune dysfunction to suicidal behavior and establish a reliable immune signature of suicide risk that can 1) guide future research into fundamental pathophysiology and 2) identify targets for drug development. The study design is an observational study where blood samples and a comprehensive array of clinical measures are collected from three groups of adolescents (n = 75 each) (1) with suicidal behavior [recent (within 3 months) suicide attempt or suicidal ideation warranting urgent evaluation,] (2) at risk for mood disorders, and (3) who are healthy (no psychiatric history). Participants will complete self-report and clinical assessments, along with a blood draw, at baseline, 3 months, 6 months and 12 months, and online self-report assessments once a month., Results: The recruitment for this study is ongoing., Limitations: Observational, variability in treatment regimens., Conclusions: This study will help elucidate immune mechanisms that may play a causal role in suicide and serve as targets for future therapeutic development., Competing Interests: Conflict of interest Dr. Jha has received contract research grants from Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development, educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network, consultant fees from Eleusis Therapeutics US, Inc., Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem, and Guidepoint Global, and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr. Emslie has received research support from Duke University (Pfizer), Forest Laboratories, Inc., and Janssen Research & Development, and he has been a consultant for Allergan, Assurex Health, Lundbeck, Neuronetics, Otsuka, and Pfizer Inc. Dr. Trivedi has served as a consultant or on an advisory board for Alkermes Inc., Alto Neuroscience Inc., Axsome Therapeutics, Boegringer Ingelheim, GH Research, GreenLight VitalSign6 Inc., Heading Health, inc., Janssen Pharmaceutical, Legion Health, Merck Sharp & Dohme Corp., Mind Medicine Inc., Navitor, Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka Canada Pharmaceutical Inc., Otsuka Pharmaceutical Development & Commercialization, Inc. (MDD Section Advisor), SAGE Therapeutics, Signant Health, Takeda Pharmaceuticals Inc. He also receives editorial compensation from Oxford University Press. Drs. Chin Fatt, Ayvaci, Minhajuddin, Farrar, and Misses Gibson and Mayes have no financial disclosures to report., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: The Interpersonal Psychological Theory of Suicide proposes two constructs that serve as a final common pathway to suicidal ideation: thwarted belongingness and perceived burdensomeness. There have been few translations of this theory to clinical care. This study aimed to address this limitation by targeting burden cognitions with novel interventions., Methods: A pilot clinical trial was conducted in an evidence-based intensive outpatient program for suicidal youth. Participants were 123 adolescents who completed measures at intake, discharge, and one-month follow-up. The experimental group consisted of standard care plus study interventions, which was compared with an active control group of standard care. Feedback on intervention acceptability was gathered through qualitative interviews with parents and adolescents., Results: There was a statistically significant drop in thwarted belongingness at discharge and an improvement in perceived burdensomeness at discharge (not statistically significant, small effect size). Feedback on acceptability was favorable and supported implementation., Conclusion: This study adds to the literature by being the first to utilize the construct of perceived burdensomeness in clinical interventions for suicidal youth; illustrating one potential avenue for translating theory to practice. The unexpected effects on thwarted belongingness have implications for the role of these constructs in a treatment setting., (© 2021 American Association of Suicidology.)

Hopelessness is a well-established risk factor for suicidal ideation. Recent research has indicated that hopelessness can be split into two subsets: pessimism (PESS) and lack of optimism (LOO) and that LOO is more salient of the two in predicting suicide ideation (SI). The aim of this study was to examine the relationship of PESS and LOO to SI in the context of the Interpersonal Psychological Theory of Suicide (IPTS). Participants were 294 inpatient adolescents. LOO but not PESS was associated with SI. LOO interacted with the IPTS variable of perceived burdensomeness to differentiate between passive and active SI, partly consistent with the theory. These results support the value of separating the two components of hopelessness in understanding adolescent SI.

Background: Immune system dysfunction has been implicated in the pathophysiology of suicide behavior. Here, we conducted an exploratory analysis of immune profile differences of three groups of adolescents and young adults (ages 10-25 years): healthy controls (n = 39), at risk of major depressive disorder (MDD; at-risk, n = 33), and MDD with recent suicide behavior/ ideation (suicide behavior, n = 37)., Methods: Plasma samples were assayed for chemokines and cytokines using Bio-Plex Pro Human Chemokine 40-plex assay. Log-transformed cytokine and chemokine levels were compared after controlling for age, gender, body mass index, race, ethnicity, and C-reactive protein (CRP) levels. In post-hoc analyses to understand the effect of dysregulated immune markers identified in this exploratory analysis, their association with autoantibodies was tested in an unrelated sample (n = 166)., Results: Only levels of interleukin 4 (IL-4) differed significantly among the three groups [false discovery rate (FDR) adjusted p = 0.0007]. Participants with suicide behavior had lower IL-4 [median = 16.8 pg/ml, interquartile range (IQR) = 7.9] levels than healthy controls (median = 29.1 pg/ml, IQR = 16.1, effect size [ES] = 1.30) and those at-risk (median = 24.4 pg/ml, IQR = 16.3, ES = 1.03). IL-4 levels were negatively correlated with depression severity (r= -0.38, p = 0.024). In an unrelated sample of outpatients with MDD, levels of IL-4 were negatively correlated (all FDR p < 0.05) with several autoantibodies [54/117 in total and 12/18 against innate immune markers]., Conclusions: Adolescent and young adult patients with recent suicide behavior exhibit lower IL-4 levels. One biological consequence of reduced IL-4 levels may be increased risk of autoimmunity., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Objective: Suicide is a leading cause of death in adolescents worldwide. There is an absence of effective and low cost treatment strategies for this growing public health problem. Current practice consists of brief hospitalization of acutely suicidal youth, but many get inadequate follow-up treatment. There are few alternatives to individual outpatient services offered at too low an intensity for an acutely distressed population. This paper describes the development, feasibility, acceptability, and preliminary clinical outcomes of an intensive outpatient program (IOP) for suicidal adolescents over a two-year period., Method: 364 eligible adolescents (12-18 years) who had a worsening of suicidal ideation or a suicide attempt were enrolled in an IOP and attended at least 1 group session. Depressive symptoms and suicidality were assessed at baseline and discharge from the program and at one and six month follow-up., Results: The majority of patients completed the IOP (81.0%; average of nine sessions). Over 95% of teens and parents responded that they were mostly or very satisfied with the IOP. The condition of patients improved at the time of discharge on depressive symptoms and suicidal ideation and behavior. 286 of the 364 youth (78.6%) completed the six-month follow-up. In total, 8.7% and 27.3% of the 286 respondents reported a suicide attempt and event, respectively, within six months of discharge from the IOP., Conclusions: While limited by the lack of a control group, our findings suggest that an IOP for adolescents with suicidality is acceptable and feasible as either a step-down from or an alternative to inpatient treatment., (Copyright © 2018. Published by Elsevier Inc.)

Background: Death by suicide is one of the leading causes of mortality among adolescents, and nonsuicidal self-injury (NSSI) is one of the strongest predictors of suicide attempts (SAs). The underlying bases for this relationship are unknown. We derived two hypotheses from the Interpersonal Psychological Theory of Suicide (IPTS): unmet interpersonal needs would explain NSSI's association with suicidal ideation (SI) and increased capability for suicide would explain NSSI's relationship with SA., Methods: Adolescents hospitalized on a psychiatric inpatient unit (N = 289) provided measures of current SI, number of past SAs, unmet interpersonal needs (perceived burdensomeness and thwarted belongingness), capability for suicide (fearlessness about death [FAD] and pain tolerance), depressive symptoms, and number of NSSI methods utilized., Results: Depressive symptoms, but not unmet interpersonal needs, explained NSSI's association with SI. FAD and SI, but not depressive symptoms or pain tolerance, accounted for NSSI's relationship with SA. FAD was associated with SA, but it did not fully account for NSSI's relationship with SA., Limitations: This study utilized a cross-sectional design and retrospective, self-report measures., Conclusions: Our study provides partial support for the role of the IPTS variables in NSSI's relationship with SA in adolescents. The finding that depressive symptoms and not unmet interpersonal needs explained NSSI's relationship with SI contradicts the IPTS. However, in those with SI, FAD was linearly associated with SA, which is consistent with the IPTS. Future studies are needed to clarify the persistent basis for NSSI's relationship with SA beyond FAD and SI., (Copyright © 2018. Published by Elsevier B.V.)

Although insomnia has been repeatedly linked with suicide ideation, the reason for the linkage is not clear. The Interpersonal Psychological Theory of Suicide (IPTS) proposes that three core variables (thwarted belongingness, perceived burdensomeness, and acquired capability) are the final common pathway for all risk factors for suicide ideation and behavior. Recent research has suggested that insomnia may be associated with suicide ideation independently of the IPTS. We examined cross-sectional data from 151 psychiatric inpatients (ages 12-17) to determine if the association between insomnia symptoms and a continuous measure of suicide risk (measured as increasingly severe ideation and plan) was explained by the framework of the IPTS. When all IPTS variables and depressive symptoms were included in the model, insomnia symptoms did not contribute unique variance to suicide risk. Perceived burdensomeness and depressive symptoms were found to explain the relationship between insomnia symptoms and suicide risk. Our findings suggest that improved sleep might reduce suicide risk, that management of interpersonal need cognitions might reduce risk in the presence of insomnia symptoms, and reinforce the independent role of depressive symptoms in suicide risk in clinical samples of adolescents., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Childhood depression is often chronic and recurrent, with only modest improvements after optimal treatments. Novel approaches are needed for accurate diagnosis, timely selection of the best treatment for childhood depression, and improvement of remission rates. An important part of diagnosis is to determine how many consistent dimensions underlie childhood depression and what impact treatment may have on these dimensions., Objective: The goal of the current study is evaluate the consistency of the number of depressive symptom dimensions and examine the effect of depression treatment on the change in dimensions by seeing if this dimensional structure is the same for groups that were given a placebo and groups that were given an active drug, fluoxetine., Methods: We examined a combined sample of three clinical trials data sets with a total of 269 placebo patients and 261 fluoxetine patients at baseline, and 253 placebo patients and 249 fluoxetine patients at exit. Principal components analysis with associated parallel analysis followed by a ProMax oblique rotation was conducted on each week's scores. The similarity of the rotated structures between treatments and between weeks was then assessed using Wrigley and Neuhaus' (1955) degree of factorial similarity measure, which is a correlation-like statistic that takes two solutions based upon the same measures and assesses how similar they are., Results: Preliminary analysis indicated that mean scores of both treatment groups declined from baseline to exit, but the decline was greater for the fluoxetine group. There were four dimensions at baseline and two dimensions at exit in each treatment group. Hence the numbers of dimensions were the same in the two groups, whereas the content of the components was the same at baseline for the two groups, but was different at exit. Basically, the factorial similarities of the rotated factors were very high at baseline between the two groups for both factors (Ψ = 0.97 for factor I and 0.94 for factor II) before they were treated differently. However, at exit, the respective similarities dropped to 0.58 and -0.04 for factors I and II. Therefore, time had a large effect in changing both groups' factor structure, but it was especially large when there was an active treatment., Conclusions: In comparing the baseline and exit dimensions in a forced two factor solution of two treatment groups, it was revealed that treatment did have an impact on the change in dimensions. These results further the generality of the simplification of the factor structure of the Childhood Depression Rating Scale- Revised (CDRS-R) over time. In addition, these results show the effect of time and therapy on the factor structures. The fluoxetine group followed the trend of the content of the dimensions revealed in a previous study, whereas the placebo group had a less distinct change over time.

Objective: A randomized, double-blind, placebo-controlled flexible-dose, parallel group trial was conducted at 26 clinical investigational sites in the United States to examine the safety and efficacy of the selegiline transdermal system (STS) (EMSAM®) in adolescents (ages 12-17 years) meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for moderate to severe major depressive disorder (MDD) without psychotic features., Methods: Adolescents (n=308) with moderate to severe MDD were randomized to either STS (n=152) or placebo (n=156). Two hundred and fifteen (69.8%) subjects completed the study and 17 (5.5%) reported discontinuation because of adverse events (AEs). The primary efficacy outcome measure was the mean change from baseline to end of study (week 12 last observation carried forward [LOCF]) in the Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary outcome measures included end-point Clinical Global Impressions - Severity (CGI-S) and Clinical Global Impressions - Improvement (CGI-I)., Results: Patients on STS or placebo had a significant decline from baseline (p<0.001) on their CDRS-R total score with mean reductions±SD as follows: STS 21.4±16.6; placebo 21.5±16.5. Both groups had similar response rates (58.6% vs. 59.3%) defined as CGI-I of 1 or 2 at study end. However, these between-group efficacy findings were without statistical significance. The overall incidence of reported AEs was 62.5% for STS-treated patients and 57.7% for placebo-treated patients. Most commonly reported AEs in STS or placebo groups were application site reactions (STS=24.3%; placebo=21.8%), headache (STS=17.1%; placebo=16.7%), and nausea (STS=7.2%; placebo=7.7%). Treatment groups did not differ on any laboratory parameters, vital signs, or electrocardiogram (ECG) findings. No suspected hypertensive crises were reported in the trial., Conclusions: These data demonstrated that the STS was safe and well tolerated in this adolescent sample. However, both STS-treated and placebo-treated subjects demonstrated a decline from baseline in depressive symptoms (CDRS-R total score) over the length of the study, without statistical superiority by either group.

Background: Although acute treatments have been shown to be effective in treating early-onset depression, only one-third or thereabouts reach a remission within 3 months. Unfortunately, delayed time to remission in early-onset depression leads to poorer therapeutic outcomes. Clearly, there is a need to identify, diagnose, and provide effective treatment of a depressed patient quickly. A sophisticated understanding of depression subscales and their change over time with treatment could enhance pathways to individualized treatment approaches for childhood depression., Objective: Previous studies have found that the clinician-measured instrument, Children's Depression Rating Scale-Revised (CDRS-R) measures multiple subscales (or components) of depression. The aim of this study was to see how these subscales may change over the course of a 12-week study. This knowledge will help determine if dimensions/subscales of childhood depression (paralleling the adult literature) using the subscales derived from factor analysis procedure is useful., Methods: We examined two clinical trials in which youth (n=234) with major depressive disorder (MDD) were treated openly with fluoxetine for eight sessions spread over 12 weeks. The CDRS-R was completed based on clinician interviews with parent and child at each session. Classical test theory and component analysis with associated parallel analysis (oblique rotation) were conducted on each week's scores., Results: Although more factors were needed for the baseline and first two therapy sessions, a two-factor solution sufficed thereafter. Depressed facial affect, listless speech, and hypoactivity best defined Factor I, whereas sleep problems, appetite disturbance, physical symptoms, irritability, guilt, and weeping best defined Factor II. All other symptoms cross-loaded almost equally on the two factors. The scale's reliability (internal consistency) improved from baseline to exit sessions (α=0.65-0.91). As a result, the clinicians' assessments of the various symptoms became more highly related to one another. This caused the first eigenvalue to increase from 3.24 to 7.38 and the variance explained to increase (%) from 19% to 43% over sessions. These two factors may reflect 1) clinician-observed signs and 2) reported symptoms of depression., Conclusions: Factor analysis of CDRS-R data in a single session consistently generates a complex and difficult to interpret structure of at least three factors. This makes it very difficult to understand what these factors measure. However, when gathered over additional sessions, the CDRS-R structure tends to simplify to two factors. The reasons for this simplification are as yet unclear and in need of further study.

Rates of depression are reported to be between 22-33% in adults with HIV, which is double that of the general population. Depression negatively affects treatment adherence and health outcomes of those with medical illnesses. Further, it has been shown in adults that reducing depression may improve both adherence and health outcomes. To address the issues of depression and non-adherence, Health and Wellness (H&W) Cognitive Behavioral Therapy (CBT) and medication management (MM) treatment strategies have been developed specifically for youth living with both HIV and depression. H&W CBT is based on other studies with uninfected youth and upon research on adults with HIV. H&W CBT uses problem-solving, motivational interviewing, and cognitive-behavioral strategies to decrease adherence obstacles and increase wellness. The intervention is delivered in 14 planned sessions over a 6-month period, with three different stages of CBT. This paper summarizes the feasibility and acceptability data from an open depression trial with 8 participants, 16-24 years of age, diagnosed with HIV and with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of depression, conducted at two treatment sites in the Adolescent Trials Network (ATN). Both therapists and subjects completed a Session Evaluation Form (SEF) after each session, and results were strongly favorable. Results from The Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) also showed noteworthy improvement in depression severity. A clinical case vignette illustrates treatment response. Further research will examine the use of H&W CBT in a larger trial of youth diagnosed with both HIV and depression.

Objective: Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome., Method: TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome., Results: Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS., Conclusions: Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents., Objective: To investigate which medication to administer first to antimanic medication-naive subjects., Design, Setting, and Participants: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments., Interventions: Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg)., Main Outcome Measures: Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents., Results: There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001)., Conclusions: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects., Trial Registration: clinicaltrials.gov Identifier: NCT00057681

Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment., Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication switch, or a medication switch plus CBT. This study examined five established symptom dimensions (Child Depression Rating Scale-Revised) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment. The two indices of recovery that were evaluated were time to remission and number of depression-free days., Results: Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that anhedonia was the only dimension to predict a longer time to remission, and also the only dimension to predict fewer depression-free days. In addition, when anhedonia and CDRS-total score were evaluated simultaneously, anhedonia continued to uniquely predict longer time to remission and fewer depression-free days., Conclusions: Anhedonia may represent an important negative prognostic indicator among treatment-resistant depressed adolescents. Further research is needed to elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: To identify distinct depressive symptom trajectories in the TORDIA study and determine their correlates., Methods: Latent Class Growth Analysis (LCGA) using the Children's Depression Rating Scale-Revised (CDRS-R) through 72 weeks from intake., Results: 3 classes were identified: (1) little change in symptomatic status ("NO"), comprising 24.9% of participants, with a 72-week remission rate of 25.3%; (2) slow, steady improvement ("SLOW"), comprising 47.9% of participants, with a remission rate of 60.0%, and (3) rapid symptom response ("GO"), comprising 27.2% of participants, with a remission rate of 85.7%. Higher baseline CDRS-R (p<0.001) and poorer functioning (p=0.03) were the strongest discriminators between NO and GO. Higher baseline CDRS (p<0.001) and scores on the Mania Rating Scale (MRS) (p=0.01) were the strongest discriminators between SLOW and GO. Other variables differentiating GO from both NO and from SLOW, were better baseline functioning, lower hopelessness, and lower family conflict. Both NO and SLOW showed increases on the MRS over time compared to GO (ps ≤ 0.04), and increasing MRS was strongly associated with lack of remission by 72 weeks (p=0.02)., Limitations: High rate of open treatment by the end of the follow-up period creates difficulty in drawing clear inferences about the long-term impact of initial randomization., Conclusion: Along with depressive severity, sub-syndromal manic symptoms, at baseline, and over time emerged as important predictors and correlates of poor outcome in this sample. Further research is needed on the treatment of severe depression, and on the assessment and management of sub-syndromal manic symptoms in treatment resistant depression., (Copyright © 2011. Published by Elsevier B.V.)

Objective: This study tested whether positive response to short-term treatment for adolescent major depressive disorder (MDD) would have the secondary benefit of preventing subsequent alcohol use disorders (AUD) or substance use disorders (SUD)., Method: For 5 years, we followed 192 adolescents (56.2% female; 20.8% minority) who had participated in the Treatment for Adolescents with Depression Study (TADS; TADS Team, 2004) and who had no prior diagnoses of AUD or SUD. TADS initial treatments were cognitive behavior therapy (CBT), fluoxetine alone (FLX), the combination of CBT and FLX (COMB), or clinical management with pill placebo (PBO). We used both the original TADS treatment response rating and a more restrictive symptom count rating. During follow-up, diagnostic interviews were completed at 6- or 12-month intervals to assess onset of AUD or SUD as well as MDD recovery and recurrence., Results: Achieving a positive response to MDD treatment was unrelated to subsequent AUD but predicted a lower rate of subsequent SUD, regardless of the measure of positive response (11.65% vs. 24.72%, or 10.0% vs. 24.5%, respectively). Type of initial MDD treatment was not related to either outcome. Prior to depression treatment, greater involvement with alcohol or drugs predicted later AUD or SUD, as did older age (for AUD) and more comorbid disorders (for SUD). Among those with recurrent MDD and AUD, AUD preceded MDD recurrence in 24 of 25 cases., Conclusion: Effective short-term adolescent depression treatment significantly reduces the rate of subsequent SUD but not AUD. Alcohol or drug use should be assessed prior to adolescent MDD treatment and monitored even after MDD recovery., (PsycINFO Database Record (c) 2012 APA, all rights reserved.)

Sleep disturbances, present in more than 90% of major depressive disorder (MDD) patients, are moderated by sex in adult MDD. In particular, slow-wave electroencephalographic activity (SWA; 0.5-4 Hz) accumulation is low and dissipation impaired. This SWA abnormality in depressed adult males does not change with age, suggesting that SWA abnormality appears at early ages. The present study evaluated sex differences in SWA in adolescents with MDD compared to healthy controls. We evaluated regularized sleep-wake schedules at home for 5-7 days, followed by two consecutive nights of sleep EEG recording. The study included 104 participants, 52 symptomatic and depressed subjects (MDD: 20 males and 32 females) and 52 healthy controls (HC: 20 males and 32 females), aged 13-18 years. SWA power and dissipation, and duration and latencies to each Non-Rapid Eye Movement (NREM) sleep period were calculated for each group. Results showed that SWA accumulation in the first NREM period was lower and its dissipation across the night more irregular in MDD males compared to HC males (P<0.009). By contrast, SWA was equivalent in MDD and HC females. In conclusion, as reported in adult MDD, the accumulation and dissipation of SWA was abnormal in depressed adolescents, but only in males. SWA abnormalities in adolescent MDD may relate to different depressive symptoms in females and males. These results underscore the need to develop sex-specific therapies to enhance and restore SWA in depressed adolescents.

Objective: There is little work on the effect of school on response to treatment of depression, with available research suggesting that children and adolescents with school difficulties are less likely to respond to fluoxetine compared with those with no school difficulties., Method: Depressed adolescents in the Treatment of Resistant Depression in Adolescents study, who had not responded to a previous adequate selective serotonin reuptake inhibitor (SSRI) trial, were randomly assigned to one of the following: another SSRI, venlafaxine, another SSRI + cognitive behavior therapy (CBT), or venlafaxine + CBT. Participants were classified into four groups depending on whether their enrollment in the study and end of treatment was during school or summer vacation., Results: Controlling for baseline differences, adolescents ending their 12-week treatment during summer vacation had odds 1.7 times (95% confidence interval = 1.02-2.8, p = .04) greater to have an adequate response as those ending their treatment while being in school. In addition, adequate depression response was associated with fewer school problems at week 12 (scores <5 versus scores ≥5: odds ratio = 3.3, 95% confidence interval = 1.9-5.8, p < .001). There was a significant interaction between school difficulties and timing of treatment, with the lowest rates of response being among adolescents having school difficulties and ending their treatment during the active school year., Conclusion: School problems are relevant to treatment response in depressed adolescents and should be incorporated into the treatment plan. These findings also suggest that the time of the year might need to be taken into consideration for analysis of clinical trials in school-aged youth., Clinical Trial Registration Information: Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://www.clinicaltrials.gov; NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the clinical and prognostic significance of suicide attempts (SAs) and nonsuicidal self-injury (NSSI) in adolescents with treatment-resistant depression., Method: Depressed adolescents who did not improve with an adequate SSRI trial (N = 334) were randomized to a medication switch (SSRI or venlafaxine), with or without cognitive-behavioral therapy. NSSI and SAs were assessed at baseline and throughout the 24-week treatment period., Results: Of the youths, 47.4% reported a history of self-injurious behavior at baseline: 23.9% NSSI alone, 14% NSSI+SAs, and 9.5% SAs alone. The 24-week incidence rates of SAs and NSSI were 7% and 11%, respectively; these rates were highest among youths with NSSI+SAs at baseline. NSSI history predicted both incident SAs (hazard ratio [HR]= 5.28, 95% confidence interval [CI] = 1.80-15.47, z = 3.04, p = .002) and incident NSSI (HR = 7.31, z = 4.19, 95% CI = 2.88-18.54, p < .001) through week 24, and was a stronger predictor of future attempts than a history of SAs (HR = 1.92, 95% CI = 0.81-4.52, z = 2.29, p = .13). In the most parsimonious model predicting time to incident SAs, baseline NSSI history and hopelessness were significant predictors, adjusting for treatment effects. Parallel analyses predicting time to incident NSSI through week 24 identified baseline NSSI history and physical and/or sexual abuse history as significant predictors., Conclusions: NSSI is a common problem among youths with treatment-resistant depression and is a significant predictor of future SAs and NSSI, underscoring the critical need for strategies that target the prevention of both NSSI and suicidal behavior., Clinical Trial Registration Information: Treatment of SSRI-Resistant Depression in Adolescents (TORDIA). URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Nonadherence to antidepressant treatment may contribute to poor outcome and to suicidal adverse events in adolescent depression. We examine the relationship between adherence and both clinical response and suicidal events in participants in the Treatment of Resistant Depression in Adolescents (TORDIA) study., Method: The relationship between adherence to medication and clinical outcome was assessed in 190 treatment-resistant depressed adolescents who were randomized to one of four cells: switch to another selective serotonin reuptake inhibitor (SSRI), switch to venlafaxine, or either of these two medication switches plus cognitive behavioral therapy. Plasma levels of antidepressant drug and metabolites were determined after 6 and 12 weeks of treatment. A twofold or greater variation in the dose-adjusted concentration of drug plus metabolites (level/dose ratio [LDR]) was defined as nonadherence. Nonadherence was also determined by clinician pill counts (CPC) of the proportion of prescribed pills that were unused and was defined as having greater than 30% of the prescribed pills remaining., Results: LDR and CPC showed low concordance. LDR was unrelated to clinical response. CPC adherence was related to a higher response rate overall (adherent, 63.0% versus nonadherent, 47.2%, p = .03). Approximately half (50.8%) of the sample surveyed showed evidence of nonadherence by CPC. Neither measure of adherence was related to the occurrence of suicidal events or to the pace of decline in suicidal ideation., Conclusions: Clinician pill counts may be a relevant measure of adherence that is related to outcome under formal clinical trial conditions in depressed adolescents. Nonadherence appears to be a common and significant source of treatment nonresponse. Clinical Trial Registration Information-Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://www.clinicaltrials.gov; NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective., Objective: To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI., Design: Randomized controlled trial., Setting: Six US academic and community clinics., Patients: Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression., Intervention: Participants were randomly assigned to (1) switch to a different medication only or (2) switch to a different medication plus cognitive behavior therapy., Main Outcome Measures: Clinical outcomes were depression-free days (DFDs), depression-improvement days (DIDs), and quality-adjusted life-years based on DFDs (DFD-QALYs). Costs of intervention, nonprotocol services, and families were included., Results: Combined treatment achieved 8.3 additional DFDs (P = .03), 0.020 more DFD-QALYs (P = .03), and 11.0 more DIDs (P = .04). Combined therapy cost $1633 more (P = .01). Cost per DFD was $188 (incremental cost-effectiveness ratio [ICER] = $188; 95% confidence interval [CI], -$22 to $1613), $142 per DID (ICER = $142; 95% CI, -$14 to $2529), and $78,948 per DFD-QALY (ICER = $78,948; 95% CI, -$9261 to $677,448). Cost-effectiveness acceptability curve analyses suggest a 61% probability that combined treatment is more cost-effective at a willingness to pay $100,000 per QALY. Combined treatment had a higher net benefit for subgroups of youth without a history of abuse, with lower levels of hopelessness, and with comorbid conditions., Conclusions: For youth with SSRI-resistant depression, combined treatment decreases the number of days with depression and is more costly. Depending on a decision maker's willingness to pay, combined therapy may be cost-effective, particularly for some subgroups., Trial Registration: clinicaltrials.gov Identifier: NCT00018902.

Background: We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized trial of 334 adolescents (aged 12-18 years) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor (SSRI) treatment who were subsequently treated for 12 weeks with another SSRI, venlafaxine, another SSRI + cognitive-behavioral therapy (CBT), or venlafaxine + CBT. Responders then continued with the same treatment through week 24, while nonresponders were given open treatment., Method: For the current study, patients were reassessed 48 (n = 116) and 72 (n = 130) weeks from intake. Data were gathered from February 2001 to February 2007. Standardized diagnostic interviews and measures of depression, suicidal ideation, related psychopathology, and level of functioning were periodically administered. Remission was defined as ≥ 3 weeks with ≤ 1 clinically significant symptom and no associated functional impairment (score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [A-LIFE]), and relapse, as ≥ 2 weeks with probable or definite depressive disorder (score of 3 or 4 on the A-LIFE). Mixed-effects regression models were applied to estimate remission, relapse, and functional recovery., Results: By 72 weeks, an estimated 61.1% of the randomized youths had reached remission. Randomly assigned treatment (first 12 weeks) did not influence remission rate or time to remission, but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine (P < .03). Participants with more severe depression, greater dysfunction, and alcohol or drug use at baseline were less likely to remit. The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment (P < .001). Of the 130 participants in remission at week 24, 25.4% relapsed in the subsequent year., Conclusions: While most adolescents achieved remission, more than one-third did not, and one-fourth of remitted patients experienced a relapse. More effective interventions are needed for patients who do not show robust improvement early in treatment., Trial Registration: clinicaltrials.gov Identifier: NCT00018902., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: We previously reported that a history of abuse was associated with a poorer response to combination treatment in the Treatment of Resistant Depression in Adolescents study (TORDIA). We now report on the nature and correlates of abuse that might explain these findings., Method: Youth who did not benefit from an adequate selective serotonin re-uptake inhibitor (SSRI) trial (N = 334) were randomized to one of the following: an alternative SSRI; an alternative SSRI plus cognitive behavior therapy (CBT); venlafaxine; or venlafaxine plus CBT. Analyses examined the effect of history of abuse on response to the pharmacotherapy and combination therapy., Results: Those without a history of physical abuse (PA) or sexual abuse (SA) had a higher 12-week response rate to combination therapy compared with medication mono-therapy (62.8% versus 37.6%; odds ratio [OR] = 2.8, 95% confidence interval [CI] = 1.6-4.7, p < .001). Those with a history of SA had similar response rates to combination versus medication monotherapy (48.3% versus 42.3%; OR = 1.3, 95% CI = 0.4-3.7; p = .66), whereas those with history of PA had a much lower rate of response to combination therapy (18.4% versus 52.4%, OR = 0.1; 95% CI = 0.02-0.43). Even after adjusting for other clinical predictors, a history of PA moderated treatment outcome., Conclusion: These results should be considered within the limitations of a post hoc analysis, lack of detailed assessment of abuse and other forms of trauma, and neuropsychological status. Depressed patients with history of abuse, especially PA may require specialized clinical approaches. Further work is needed to understand by what mechanisms a history of abuse affects treatment response., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: Major depressive disorder in adolescents is common and impairing. Efficacious treatments have been developed, but little is known about longer-term outcomes, including recurrence., Objectives: To determine whether adolescents who responded to short-term treatments or who received the most efficacious short-term treatment would have lower recurrence rates, and to identify predictors of recovery and recurrence., Design: Naturalistic follow-up study., Setting: Twelve academic sites in the United States., Participants: One hundred ninety-six adolescents (86 males and 110 females) randomized to 1 of 4 short-term interventions (fluoxetine hydrochloride treatment, cognitive behavioral therapy, their combination, or placebo) in the Treatment for Adolescents With Depression Study were followed up for 5 years after study entry (44.6% of the original Treatment for Adolescents With Depression Study sample)., Main Outcome Measures: Recovery was defined as absence of clinically significant major depressive disorder symptoms on the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview for at least 8 weeks, and recurrence was defined as a new episode of major depressive disorder following recovery., Results: Almost all participants (96.4%) recovered from their index episode of major depressive disorder during the follow-up period. Recovery by 2 years was significantly more likely for short-term treatment responders (96.2%) than for partial responders or nonresponders (79.1%) (P < .001) but was not associated with having received the most efficacious short-term treatment (the combination of fluoxetine and cognitive behavioral therapy). Of the 189 participants who recovered, 88 (46.6%) had a recurrence. Recurrence was not predicted by full short-term treatment response or by original treatment. However, full or partial responders were less likely to have a recurrence (42.9%) than were nonresponders (67.6%) (P = .03). Sex predicted recurrence (57.0% among females vs 32.9% among males; P = .02)., Conclusions: Almost all depressed adolescents recovered. However, recurrence occurs in almost half of recovered adolescents, with higher probability in females in this age range. Further research should identify and address the vulnerabilities to recurrence that are more common among young women.

Objective: The article discusses a feasibility study conducted to examine whether Pay Attention!, an intervention training sustained, selective, alternating, and divided attention, could be utilized in a clinical setting with children diagnosed with ADHD, and whether children who received the intervention made attention and executive functioning gains., Method: After a diagnostic and baseline evaluation, 23 school-aged children with ADHD participate in up to 16 sessions of Pay Attention! and the outcomes are evaluated., Results: Results show the intervention is feasible to administer and acceptable to participants. Parents and clinicians rate fewer ADHD symptoms following the intervention and report improvements in executive function. Child performance on neuropsychological tests showed improvements in fluid reasoning and cognitive flexibility and working memory., Conclusion: The findings suggest that a randomized clinical trial of Pay Attention! is warranted to investigate its viability as a treatment for attention and executive functioning deficits in ADHD.

Objective: The aim of this study was to examine the impact of co-morbid illnesses on treatment outcomes in depressed children and adolescents aged 7-17 who were treated with fluoxetine., Method: This data set was drawn from two large clinical trials involving children and adolescents with depression. Subjects with a diagnosis of major depressive disorder and depressive symptoms of at least moderate severity as defined by a Children's Depression Rating Score, Revised (CDRS-R) total score >or=40 and a Clinical Global Impressions-Severity (CGI-S) rating >or=4 were included. Subjects were randomized to receive fluoxetine or placebo over an 8-week period. Predictor analyses examining two primary outcomes were conducted: (1) Response based on Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2, and (2) remission based on CDRS-R score of

Objective: Higher body mass index (BMI) has been associated with more sleep disturbance and depressive symptoms, but the combined effects of depression and BMI on sleep have not been studied in children. This study evaluated the relationship between BMI and polysomnography in children with major depressive disorder (MDD), compared to healthy controls (HCs)., Method: The sample of 104 subjects included 72 children, 8-17 years old, with MDD and 32 similarly aged HCs with no personal or family history of psychopathology. BMI was adjusted using the CDC formula for percentiles by age. Subjects were categorized as (1) normal weight (5-84th percentile) or (2) high weight, which included at risk of overweight and overweight (> or = 85th percentile). All analyses were adjusted for sex and Tanner maturational stage scores., Results: In the MDD group only, higher BMI was significantly correlated with decreased sleep efficiency, decreased percentage of rapid eye movement sleep (REM%), and higher percentage of time spent awake and moving (TSPAM). In the HC group only, higher BMI correlated with higher total sleep time. Multivariate analyses revealed significant interactions between the BMI and diagnostic groups for several REM sleep parameters, such that high-weight children from the HC and MDD groups had increases and decreases in REM sleep, respectively. TSPAM increased in the high-weight MDD group, but decreased in the high-weight HC group., Conclusions: Although limited by small sample size, these findings suggest that children and adolescents with MDD and a high BMI have more fragmented sleep than other children. The increased REM sleep patterns observed with MDD in this and other studies normalized in high-weight children with MDD. Prevention and treatment strategies should target both sleep and weight as factors that can potentially influence the development and course of MDD., (Copyright 2010 Elsevier B.V. All rights reserved.)

Objective: The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents., Method: A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression, treatment response, or suicidal events. Participants had not responded to a previous adequate trial with an antidepressant and were randomized to receive either another selective serotonin reuptake inhibitor or venlafaxine, with or without cognitive-behavioral therapy (CBT). Single-nucleotide polymorphism (SNP) analyses were conducted using PLINK with permutation procedures., Results: No relationship was observed between any polymorphism and response to treatment. The FKBP5 (which codes for a protein causing subsensitivity of the glucocorticoid receptor) rs1360780TT and rs3800373GG genotypes were associated with suicidal events (N=18), even after controlling for treatment effects and relevant covariates. These two SNPs were in significant linkage disequilibrium (r=0.91)., Conclusions: The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity. These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior. The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment.

Objective: Despite the known association between substance use disorders and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD., Method: Youths with MDD who had not improved after an adequate selective serotonin reuptake inhibitor trial (N = 334) were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents trial. Analyses examined substance use (via the Drug Use Severity Index) and changes therein in relation to treatment and depressive symptoms. Adolescents meeting substance use disorder criteria via the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version at baseline were excluded., Results: Substance use was common: 28.1% reported repeated experimentation at baseline. Substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. There was significant improvement in substance-related impairment among adolescents who responded to MDD treatment. Baseline suicidal ideation was higher among the subjects who progressed to high substance-related impairment (≥ 75th percentile) versus those whose substance-related impairment remained low (< 75th percentile), and parental depressive symptoms predicted persistence of high substance-related impairment during the study. The MDD response was best among the adolescents with low 12 week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairment. There were no significant differential effects of specific treatments, pharmacological or cognitive-behavioral therapy, on substance use., Conclusions: Substance use is common among adolescents with treatment-resistant MDD. The subjects who had persistently low substance-related impairment or who demonstrated reduced substance-related impairment had better MDD treatment response, although the direction of this association is uncertain.

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.

Objective: To examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide., Method: Adolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children's Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive-behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward., Results: Most patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p < .0001), with a Clinical Global Impression -defined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R ≤ 28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r = 0.43, p < .0001) and declined in parallel., Conclusions: When vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression., (Copyright © 2009 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the predictors of suicidal events and attempts in adolescent suicide attempters with depression treated in an open treatment trial., Method: Adolescents who had made a recent suicide attempt and had unipolar depression (n =124) were either randomized (n = 22) or given a choice (n = 102) among three conditions. Two participants withdrew before treatment assignment. The remaining 124 youths received a specialized psychotherapy for suicide attempting adolescents (n = 17), a medication algorithm (n = 14), or the combination (n = 93). The participants were followed up 6 months after intake with respect to rate, timing, and predictors of a suicidal event (attempt or acute suicidal ideation necessitating emergency referral)., Results: The morbid risks of suicidal events and attempts on 6-month follow-up were 0.19 and 0.12, respectively, with a median time to event of 44 days. Higher self-rated depression, suicidal ideation, family income, greater number of previous suicide attempts, lower maximum lethality of previous attempt, history of sexual abuse, and lower family cohesion predicted the occurrence, and earlier time to event, with similar findings for the outcome of attempts. A slower decline in suicidal ideation was associated with the occurrence of a suicidal event., Conclusions: In this open trial, the 6-month morbid risks for suicidal events and for reattempts were lower than those in other comparable samples, suggesting that this intervention should be studied further. Important treatment targets include suicidal ideation, family cohesion, and sequelae of previous abuse. Because 40% of events occurred with 4 weeks of intake, an emphasis on safety planning and increased therapeutic contact early in treatment may be warranted.

Introduction: Many children and adolescents in the community do not fit the classic Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for Bipolar Disorder, Type I., and bipolar disorder, not otherwise specified (BPNOS) is often the "catch all" diagnosis. Significant research has been conducted to better understand the phenomenology of the spectrum of bipolar disorder; however, there are presently different operational definitions for bipolar disorder, in both clinical and research settings. A recent study, The Course and Outcome of Bipolar Youth (COBY) provided preliminary validation for diagnosing BPNOS. Using these COBY research definitions for BPNOS, we examined the clinical presentation and the prior history of psychotropic medication usage of youth with BPI vs. BPNOS presenting to an outpatient clinic., Methods: The initial evaluation consisted of a direct clinical interview with the parent(s) and the patient. Standardized rating scales such as the Young Mania Rating Scale and the Quick Inventory of Depressive Symptoms were used to assess current mood states. The Clinical Global Impressions Scale-Severity was used to assess the overall functioning of bipolar youth., Results: Age, comorbidities, and family histories of 68 bipolar youth in the clinic are similar to what other studies have reported. BPNOS youth have significant functional impairment which is comparable to the BPI youth. Both bipolar groups are equally likely to have similar prior exposure to psychotropic medications., Discussion: BPNOS is a serious illness the diagnostic guidelines for which are still debatable. Until further clarification of this diagnosis, the COBY definitions for BPNOS can be used in a clinic. The use of stringent criteria for diagnosing the bipolar spectrum disorders allows for careful differential diagnoses of psychiatric illnesses.

Site differences in treatment outcomes are not often highlighted when the results of multisite randomized clinical trials (MRCTs) are reported. The primary analyses of a 6-site MRCT, the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, showed substantial variation by site in the performance of a medication-only condition and a combined medication plus cognitive-behavioral therapy (CBT) condition. Two potential primary causes of site differences in MRCT outcomes were examined in this article: sampling factors, particularly clinical characteristics of participants, and treatment protocol factors, particularly fidelity. The authors found that differences in the clinical characteristics of participants at baseline across site and within site/across conditions were the most salient explanations for site differences and differences within sites across conditions in outcome. Study findings are discussed with respect to the overall study outcomes in TORDIA as well as MRCTs in general., (Copyright 2009 APA)

Objective: To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents, we conducted a randomized controlled trial evaluating alternative treatment strategies. In primary analyses, cognitive-behavioral therapy (CBT) combined with medication change was associated with higher rates of positive response to short-term (12-week) treatment than medication alone. This study examines predictors and moderators of treatment response, with the goal of informing efforts to match youths to optimal treatment strategies., Method: Youths who had not improved during an adequate SSRI trial (N = 334) were randomized to an alternative SSRI, an alternative SSRI plus CBT, venlafaxine, or venlafaxine plus CBT. Analyses examined predictors and moderators of treatment response., Results: Less severe depression, less family conflict, and absence of nonsuicidal self-injurious behavior predicted better treatment response status. Significant moderators of response to CBT + medication (combined) treatment were number of comorbid disorders and abuse history; hopelessness was marginally significant. The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders (particularly attention-deficit/hyperactivity disorder and anxiety disorders), no abuse history, and lower hopelessness. Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer prestudy pharmacotherapy., Conclusions: Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders. Given the additional costs of adding CBT to medication, consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment.

Objective: : Less than half of youths achieve remission (minimal to no symptoms) after acute antidepressant treatment. Early identification of who will or will not respond to treatment and achieve remission may help clinicians formulate treatment decisions and shorten the time spent on ineffective treatments. In a prospective open-label fluoxetine study, we investigate indicators of acute treatment response and remission., Method: : One hundred sixty-eight children and adolescents, ages 7 to 18 years, with primary diagnoses of major depressive disorder received 12 weeks of fluoxetine treatment. The youths were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia. The outcome measure included the Children's Depression Rating Scale-Revised., Results: : Positive first-degree family history of depression was the only baseline demographic and clinical characteristic that predicted a favorable treatment response (p =.01). The rate of symptom improvement, however, is a good indicator of acute treatment response. A significant symptom reduction (approximately 50%) by week 4 is needed to achieve remission at the end of acute treatment., Conclusions: : This study demonstrated that the rate of symptom improvement during early weeks of acute fluoxetine treatment is a good indicator of remission. Treatment approach may be reevaluated and modified as early as week 4 during acute treatment.Clinical trials registration information-Determining Optimal Continuation Treatment Duration for Depressed Children and Adolescents. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00332787.

The present investigation examined neurocognitive functioning, focusing on executive functioning (EF), in 39 children and adolescents with Major Depressive Disorder (MDD) and 24 healthy control subjects all ages 8 to 17 years. The Wechsler Intelligence Scale for Children-Third Edition along with several measures of executive functioning including the Wisconsin Card Sorting Task, Trail Making Test, Controlled Oral Word Association Test, and the Stroop Color Word Test were administered. The neurocognitive profiles for the group of depressed children and adolescents were grossly intact as most scores on intellectual and EF measures fell within the average range and did not differ from the comparison group. Mental processing speed was decreased in the MDD versus normal control group and 27% of the depressed group performed below average on the Trail Making Test. This investigation provided a good base from which to compare future literature on EF in outpatients with early-onset MDD.

Context: Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy., Objective: To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI., Design, Setting, and Participants: Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006., Interventions: Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy., Main Outcome Measures: Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time., Results: Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment., Conclusions: For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects., Trial Registration: clinicaltrials.gov Identifier: NCT00018902.

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 examine the time to response for both pharmacotherapy and psychotherapy in the Treatment for Adolescents with Depression Study (TADS)., Method: Adolescents (N = 439, ages 12 to 17 years) with major depressive disorder were randomized to fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). Defining response as very much improved or much improved on the Clinical Global Impression-Improvement Scale (CGI-I), survival analyses using Cox proportional hazards models, and Kaplan-Meier curves were conducted to evaluate time to first response and time to stable response for subjects receiving pharmacotherapy (COMB, FLX, PBO) as well as for subjects receiving CBT (COMB, CBT). Direct comparisons between pharmacotherapy and CBT were not made because of differences in visit schedules., Results: Based on pharmacotherapist CGI-I scores, COMB and FLX showed faster onset of benefit than PBO on time to response and time to stable response (p < .001), and COMB was faster than FLX on time to stable response (p = .034). The probability of sustained early response was approximately threefold greater for COMB than PBO, twofold greater for FLX than PBO, and 1.5-fold greater for COMB than FLX. On the psychotherapist CGI-I scores, both first response and stable response occurred faster in COMB than CBT (p < .001), with a probability of sustained early response approximately threefold greater for COMB than CBT., Conclusions: In the acute treatment of depressed adolescents, FLX and COMB accelerate response relative to PBO, and COMB accelerates response relative to CBT alone.

Objective: To ascertain remission rates in depressed youth participating in the Treatment for Adolescents With Depression Study (TADS), a multisite clinical trial that randomized 439 adolescents with major depressive disorder (MDD) to a 12-week treatment of fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO)., Method: Using an end-of-treatment Children's Depression Rating Scale-Revised (CDRS-R) total score of 28 or below as the criterion for remission, rates of remission were examined with logistic regression, controlling for site. Loss of MDD diagnosis and residual symptoms in responders (defined as Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) were also examined across treatment groups., Results: After 12 weeks of treatment, 102 (23%) of 439 youths had reached remission. The remission rate was significantly higher in the COMB group (37%) relative to the other treatment groups (FLX, 23%; CBT, 16%; PBO, 17%), with odds ratios of 2.1 for COMB versus FLX, 3.3 for COMB versus CBT, and 3.0 for COMB versus PBO. In addition, 71% of subjects across treatment groups no longer met criteria for MDD at the end of acute treatment. Fifty percent of the youths who responded by CGI-I criteria continued to have residual symptoms, such as sleep or mood disturbances, fatigue, and poor concentration., Conclusions: The combination of FLX and CBT was superior to both monotherapy and PBO in terms of remission rates, but overall rates of remission remain low and residual symptoms are common at the end of 12 weeks of treatment.

An exploratory factor analysis was performed in a clinical sample of 314 children and adolescents to investigate the factor structure of the Children's Depression Rating Scale-Revised (CDRS-R; Poznanski et al. 1984). A maximum likelihood method followed by a Promax rotation yielded five factors: observed depressive mood, anhedonia, morbid thoughts, somatic symptoms and reported depressive mood. The age group and gender differences on the factors scores are evaluated. After controlling for gender, the adolescents had more severe depression in terms of observed depressive mood, anhedonia, and somatic symptoms. After controlling for age groups, girls had higher scores for reported depressive mood.

Objective: The purpose of this work was to develop a consensus statement on the current status and future role for pharmacologic management of insomnia in children and adolescents., Method: The National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened expert representatives involved in the study and treatment of pediatric insomnia and conducted a 2-day conference to examine the role of pharmacologic management of pediatric insomnia and to make recommendations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insomnia and its treatment alternatives, workgroups provided recommendations for the evaluation of pharmacologic treatment of insomnia in specific populations of children and adolescents and developed guidelines for the core methodologic issues relevant to the design of clinical trials. The group developed consensus recommendations for clinical trials in this area encompassing: (1) high-priority patient populations for research, (2) inclusion/exclusion criteria, (3) outcome measures, (4) ethical considerations unique to clinical trials involving children and adolescents, and (5) priorities for future research that will enhance the understanding of pediatric insomnia., Results: Conference participants unanimously agreed that there is a need for pharmacologic management of pediatric insomnia. Furthermore, the widespread use of "hypnotic" and psychotropic medications for children in the absence of safety and efficacy data indicates a knowledge gap about the best pharmacologic practices for management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of pharmacologic treatment of pediatric insomnia including agreeing on a definition of pediatric insomnia as "repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family." It was agreed that priority should be given to insomnia studies in children with attention-deficit/hyperactivity disorder and those with pervasive developmental disorders/autism spectrum disorder. There was also agreement on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate dose levels and to evaluate safety with a wide range of doses., Conclusions: The treatment of pediatric insomnia is an unmet medical need. Before appropriate pharmacologic management guidelines can be developed, rigorous, large-scale clinical trials of pediatric insomnia treatment are vitally needed to provide information to the clinician on the safety and efficacy of prescription and over-the-counter agents for the management of pediatric insomnia.