Measurement-Based Care for Depression in Youth: Practical Considerations for Selecting Measures to Assess Depression, Associated Features and Functioning.

Identification and management of major depressive disorder (MDD) in children and adolescents remains a significant area of public health need. The process for identifying depression (e.g. screening) and management (e.g. measurement based care [MBC]) is substantially enhanced by utilization of clinical measures and rating scales. Measures can be self- or caregiver reported or clinician rated. They can aid recognition of at-risk individuals for future assessment and assist in clinical diagnosis and management of depression. In addition to assessing symptoms of depression, rating scales can be used to assess important associated features (e.g. anxiety, trauma) and functional outcomes (e.g. quality of life, performance/productivity). In this manuscript, we discuss practical considerations for clinicians and researchers when selecting rating instruments for assessing depression, associated factors, functioning, and treatment outcomes (i.e. adherence and side effects) as part of MBC in youth and provide a summary of rating scales commonly used in research and clinical settings.

Evidence for machine learning guided early prediction of acute outcomes in the treatment of depressed children and adolescents with antidepressants.

BACKGROUND: The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo. METHODS: The study samples included training datasets (N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine (N = 255) or placebo (N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment. RESULTS: Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self-esteem, and depressed feelings) assessed with the Children's Depression Rating Scale-Revised at 4-6 weeks predicted treatment outcomes with fluoxetine at 10-12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10-12 week outcomes at 4-6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo-treated patients with accuracies of 67%. In placebo-treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants. CONCLUSIONS: PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression.

Fearlessness about death and suicide planning predict lethality of adolescent suicide attempts during and following treatment.

INTRODUCTION: The rate of adolescent suicide attempt has increased drastically over the past 10 years. However, little is known regarding what predicts a more versus less lethal attempt, which is of critical interest to clinicians managing this at-risk population. We sought to extend the study of lethality in adolescents by exploring its relationship with two recognized risk-factors for suicide attempt: fearlessness about death (FAD) and suicide planning. METHODS: Participants (N = 254) were administered measures of FAD and depressive symptoms upon entering intensive outpatient treatment for adolescents exhibiting suicidal thoughts and behaviors. Attempts made between treatment entry and 6 months following discharge (n = 47) were scored on a 4-point ordinal scale of lethality. The resulting continuum ranged from no attempt to attempts of low to moderate levels of lethality. RESULTS: FAD and suicide planning distinguished between levels of lethality of future attempt at the bivariate and multivariate level. FAD's predictive relationship with lethality while controlling for age, sex, depression, and prior attempt diminished when suicide planning was covaried. CONCLUSION: FAD and suicide planning significantly predicted more versus less lethal future attempts in our sample of adolescents in a clinical setting. Our findings suggest that FAD influences the lethality of a future attempt by promoting planning for suicide. More studies are needed to assess whether the brief FAD scale might be a valuable adjunct in the clinical management of youth with suicidal thoughts and behaviors.

Psychotic symptoms and suicidal ideation in child and adolescent bipolar I disorder.

OBJECTIVES: The purpose of this study was to explore associations between specific types of hallucinations and delusions and suicidal ideation in a sample of children and adolescents with bipolar I disorder. METHODS: Participants (N = 379) were children and adolescents aged 6-15 years (M = 10.2, SD = 2.7) with DSM-IV diagnoses of bipolar I disorder, mixed or manic phase. The study sample was 53.8% female and primarily White (73.6% White, 17.9% Black, and 8.5% Other). Presence and nature of psychotic symptoms, suicidal ideation, and functioning level were assessed through clinician-administered measures. A series of logistic regressions was performed to assess the contribution of each subtype of psychotic symptom to the presence of suicidal ideation above and beyond age, sex, socio-economic status, age at bipolar disorder onset, and global level of functioning. RESULTS: Hallucinations overall, delusions of guilt, and number of different psychotic symptom types were uniquely associated with increased odds of suicidal ideation after accounting for covariates. Other forms of delusions (eg, grandiose) and specific types of hallucinations (eg, auditory) were not significantly uniquely associated with the presence of suicidal ideation. CONCLUSIONS: Findings of this study suggest the presence of hallucinations as a whole, delusions of guilt specifically, and having multiple concurrent types of psychotic symptoms are associated with the presence of suicidal ideation in children and adolescents with bipolar I disorder. Psychotic symptom subtypes, as opposed to psychosis as a whole, are an under-examined, potentially important, area for consideration regarding suicidal ideation in pediatric bipolar I disorder.

Treatment of Adolescent Depression: Comparison of Psychiatric and Pediatric Settings at an Academic Medical Center Using the VitalSign6 Application.

Background: Similar outcomes and remission rates have been found for the treatment of depression in adults in primary and psychiatric care settings. However, comparatively little is known about how pediatric depression is managed across different settings. This study aims to address this gap by comparing depression treatment in pediatric and psychiatric settings. We hypothesized that pediatric care settings would be more likely to treat individuals with lower depression severity and would select pharmacotherapy less frequently as a treatment option. Methods: Patients (n = 3498) were screened for depression at a children's hospital from May 2017 to May 2022 as part of the VitalSign6 project, a web-based application for depression management. The two-item patient health questionnaire (PHQ) was used for screening, and the data set contains patient-reported measures and provider-reported diagnoses and treatment selections at each clinic visit. Patients with nine-item PHQ (PHQ-9) scores ≥10 at baseline were included in the analysis to compare diagnosis and treatment recommendations between pediatric and psychiatric settings. Results: Among the 1323 patients who screened positive for depression, those in psychiatric settings had higher PHQ-9 scores (15.9 ± 5.0 vs. 12.1 ± 5.5; p < 0.0001). Patients with PHQ-9 ≥ 10 in psychiatric settings were more likely to be diagnosed with major depressive disorder (60.6% vs. 24.7%, p < 0.0001) and receive pharmacotherapy (54.8% vs. 6.6%) than those in pediatric settings. Pediatric setting patients were more likely to receive nonpharmacological treatment alone (36.3% vs. 4.3%) or an outside referral (27.7% vs. 5.7%). Remission rates did not significantly differ between the two settings. Conclusions: Youth in psychiatric settings are more likely to screen positive for depression and to have greater depression severity than those in pediatric settings. Both settings provide treatment recommendations for moderate-to-severe depression, but treatment types vary substantially. Yet, remission rates remain similar. Further research is needed to understand the nuances of treatment differences and their implications.

Problematic substance use in depressed adolescents: Prevalence and clinical correlates.

Background: Substance use among adolescents is common and associated with significant consequences, including depression. Adolescents can experience myriad problems related to early onset substance use and depression, making further understanding of this comorbidity necessary. Method: Participants were a subset from a large-scale performance improvement project and consisted of adolescents aged 12-18 who screened positive for depression during their routine medical or psychiatric appointment and who then completed the substance use assessment Car, Relax, Alone, Forget, Friends, Trouble Version 2.1 (CRAFFT). Participants with problematic substance use had a CRAFFT score ≥2. Results: A total of 621 participants were included in this study, and 105 (16.9%) reported problematic substance use. Compared with participants without problematic substance use, those with problematic use were more likely to have moderate to severe depression and anxiety, as well as significantly higher irritability, impulsivity, suicidal propensity, and suicidal thoughts scores. Controlling for age at screening, sex, race, and ethnicity, problematic substance use remained a significant predictor of depression severity, impulsivity, suicidal propensity, and suicidal thoughts. Limitations: Participants were from a large, metropolitan area of the Southwest United States who must have screened positive for depression, so results may not generalize. Because all participants were underage, they may have been wary in responding to the substance use assessment accurately. Conclusions: By using a large, diverse sample in a real-world clinical setting, findings strengthen the association between problematic substance use and depression and depression-associated symptoms among adolescents, highlighting the need for early detection and universal depression screening.

The effect of parent-adolescent discrepancies in reports of familial dysfunction and depression on suicidal ideation in adolescents.

INTRODUCTION: Parents and adolescents are often discrepant in their reports of adolescent psychosocial factors. Few studies have addressed parent-adolescent discrepancies in subjective ratings of familial dysfunction and depression as longitudinal predictor variables, and none have done so in a treatment setting for adolescents with acute suicidality. This study examined how parent-adolescent discrepancies in familial dysfunction and depression impact adolescent treatment response in an intensive outpatient program for suicidality. METHODS: Adolescents (N = 315) were assessed at treatment entry and exit for familial dysfunction, depression, and suicidal ideation. Parents received parallel assessments of familial dysfunction and adolescent depression at each time point. A polynomial regression was conducted to determine whether parent-adolescent discrepancies in reports of familial dysfunction and depression at entry related to the treatment outcome of adolescent-reported depression and suicide ideation at exit. RESULTS: Significant discrepancies were present with on average adolescents reporting more depression and familial dysfunction than parents. Entry discrepancy in familial dysfunction (but not depression) predicted suicide ideation at exit. CONCLUSIONS: Our results suggest that parent-adolescent discrepancies in perception of familial dysfunction is a risk factor for poor outcomes in suicidal youth and might be a fruitful target in treatment programs.

Editorial: Novel Approaches to the Treatment of Suicidality and Depression in Youth.

Suicide continues to be a major cause of mortality in adolescents with limited treatment options.1,2 Effective treatments, both therapy and medication, are available for treating depression, but even with the best combination, treatment remission rates are low.3 The most common approach to treating suicidality, which includes suicidal ideation and suicidal behavior, is to address concomitant depression. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with MDD, and intranasal esketamine is approved for treating treatment-resistant depression (TRD) in adults.4,5 The effectiveness of ketamine for the treatment of depression frequently lags behind the treatment of suicidality. There are also many methodological differences and barriers to assessing the effectiveness of short-term treatments. These include measurement of change over short time frames, measurement of suicidality, and so forth. Finally, the use of novel short-term treatments in treating chronic depression and suicidality in real-world situations is unclear.

The Concise Health Risk Tracking - Self-Report (CHRT-SR)-A measure of suicidal risk: Performance in adolescent outpatients.

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-SR9 ) 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-SR9 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.

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

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

Predicting Remission From Depression in Youth Receiving Outpatient Medication Management.

Objective: To examine 6-month remission rates of adolescents treated for depression in a university-based clinic and examine predictors of eventual remission.Methods: All patients aged 11-18 years treated in the clinic completed self-report measures assessing depression, suicidal ideation, anxiety, and associated symptoms. Remission was operationalized as a total score of ≤ 4 on the Patient Health Questionnaire-9 (PHQ-9) within 6 months of entering treatment.Results: Of the 430 patients, (76.74% female, 65.34% Caucasian, mean ± SD age 14.65 ± 1.69 years), 26.74% achieved remission within 6 months. Mean ± SD scores on the PHQ-9 at visit 1 (clinic entry) were 11.97 ± 4.76 for remitters (n = 115) and 15.03 ± 5.21 for non-remitters (n = 315). Predicted odds of remitting decreased as depressive symptom severity at visit 1 increased (OR = 0.941; 95% CI, 0.886 to 1.000; P = .051) and as scores on the Concise Associated Symptoms Tracking scale at treatment entry increased (OR = 0.971; 95% CI, 0.948 to 0.995; P = .017). As depression severity increased between visits, odds of remitting decreased (OR = 0.873; 95% CI, 0.827 to 0.921; P < .0001). Finally, adolescent males were more likely to achieve remission than females within 6 months (OR = 2.257; 95% CI, 1.351 to 3.771; P = .002).Conclusions: This study reports remission rates for depressed youth receiving medication management in a naturalistic outpatient setting. Results confirm that depression severity at treatment initiation and over time is a strong predictor of remission status. Additionally, monitoring associated symptoms via measurement-based care can provide important clinical information to inform treatment decisions.

Characterizing inflammatory profiles of suicidal behavior in adolescents: Rationale and design.

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.

Predicting suicidal events: A comparison of the Concise Health Risk Tracking Self-Report (CHRT-SR) and the Columbia Suicide Severity Rating Scale (C-SSRS).

This report examines the predictive capabilities of two scales of suicidality in high-risk adolescents. Charts of adolescents with severe suicidality participating in an intensive outpatient program were reviewed. Self-report data from the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9) and clinician-completed data from the Columbia Suicide Severity Risk Scale (C-SSRS) were obtained at entry. Scales' performances in predicting suicide attempts and suicidal events were evaluated using logistic regression models and ROC analyses. Of 539 adolescents, 53 had events of which 19 were attempts. The CHRT-SR9 total score predicted events (OR=1.05) and attempts (OR=1.09), as did the C-SSRS Suicide Ideation (SI) Intensity Composite for events (OR=1.10) and attempts (OR=1.16). The CHRT-SR9 AUC was 0.70 (84.2% sensitivity; 41.7% specificity; PPV=5.0%; NPV=98.6%) for attempts. The C-SSRS Intensity Composite AUC was 0.62 (89.5% sensitivity; 24.1% specificity; PPV=4.2%; NPV=98.4%) for attempts. Both the CHRT-SR9 and C-SSRS capture important parameters related to suicidal events or attempts that can help assess suicidal risk in adolescents.

A Comparison of Depressive Symptom Self-Reported Measures in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

Objective: To evaluate psychometrically and provide crosswalks between 3 self-report measures of depressive symptomatology in youth in psychiatric care settings. Ratings included the Patient Health Questionnaire for Adolescents (PHQ-A), a widely used 9-item self-report; the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and the 5-item Very Quick Inventory of Depressive Symptomatology-Self-Report (VQIDS-SR5), a recent effort to create a bridge from the QIDS-SR16 to clinical practice.Methods: Data from the Texas Youth Depression and Suicide Research Network Registry (August 26, 2020-May 11, 2022) were included in this work. At first visit, 795 depressed or suicidal adolescent (12-20 years of age) psychiatric outpatients completed the PHQ-A, QIDS-SR16, and VQIDS-SR5. Classical test theory and item-response theory (IRT) analyses were conducted. Crosswalks among total scales were created. Sensitivity to change over 1-month follow-up was assessed for all 3 scales (n = 682).Results: Cronbach alphas were 0.86 (PHQ-A), 0.80 (QIDS-SR16), and 0.76 (VQIDS-SR5). Item total correlations were 0.49-0.72, 0.29-0.64, and 0.43-0.61, respectively. All 3 scales were unidimensional and sensitive to change over a 1-month period. IRT analyses revealed satisfactory item performance. Modest but significant associations were found between baseline to 1-month changes in PHQ-A and VQIDS-SR5 total scores (r = 0.50, P < .0001) and between PHQ-A and QIDS-SR16 total scores (r = 0.56; P < .0001). Categorical thresholds of severity (ie, mild, moderate, severe, and very severe) were comparable between PHQ-A and QIDS-SR16.Conclusions: The PHQ-A, QIDS-SR16, and VQIDS-SR5 are unidimensional, psychometrically acceptable self-reports of depressive prevalence or severity in adolescents and young adults in this sample. Total scale scores on any measure can be converted reliably to those on any other.

Psychometric evaluation of the 9-item Concise Health Risk Tracking - Self-Report (CHRT-SR9) (a measure of suicidal risk) in adolescent psychiatric outpatients in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: This study evaluated the psychometric properties of the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9), 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-SR9 was extracted from CHRT-SR16 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-SR9 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-SR9 total score as a measure of overall suicidality and comparing it against levels of PHQ-A Item 9, the mean (standard deviation) of CHRT-SR9 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-SR9 total score distinguished between levels of suicidal risk. Furthermore, CHRT-SR9 was sensitive to change over a one-month period. LIMITATIONS: Whether CHRT-SR9 predicts actual suicidal attempts in adolescents is not well defined. CONCLUSION: The CHRT-SR9 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.

Borderline personality features influence treatment response to suicide prevention.

BACKGROUND: Suicide is a notable risk for individuals with features of borderline personality disorder. Given the centrality of interpersonal difficulties in this disorder, we proposed that the negative interpersonal cognitions (perceived burdensomeness and thwarted belongingness) identified by the Interpersonal Theory of Suicide (IPTS) may explain the associations between suicidal ideation and borderline personality features. METHOD: Participants were 322 suicidal youth (74% girls) aged 11-18 years (M, SD = 14.74, 1.6) in an intensive outpatient program in the southwest United States. Youth completed measures assessing borderline personality features at program entry, and suicidal ideation and IPTS variables at entry and exit. RESULTS: Borderline personality features did not moderate associations of IPTS variables and suicidal ideation. For the entire sample, changes in suicidal ideation from entry to discharge occurred in tandem with changes in perceived burdensomeness and depressive symptoms, but not thwarted belongingness. Youth with elevated borderline personality features entered with greater suicidal ideation, but improved more from treatment entry to exit. Regardless of level of borderline personality features, changes in negative interpersonal cognitions over treatment were associated with changes in suicidal ideation. LIMITATIONS: Self-report measures and lack of sample diversity are study limitations. CONCLUSIONS: This research highlights the clinical utility of the IPTS variables and the importance of promoting competence and interpersonal connectedness when treating this population. Findings indicate that the IPTS variables carry the same fundamental information for contributing to suicidal ideation, regardless of level of borderline personality features.

Vortioxetine for Major Depressive Disorder in Adolescents: 12-Week Randomized, Placebo-Controlled, Fluoxetine-Referenced, Fixed-Dose Study.

OBJECTIVE: To evaluate the efficacy and safety of vortioxetine in adolescents with major depressive disorder (MDD). METHOD: After 4 weeks of single-blind lead-in treatment with a Brief Psychosocial Intervention (BPI) plus placebo, patients (aged 12-17 years) with MDD (DSM-5) who did not meet response criteria (Children's Depression Rating Scale-Revised [CDRS-R]; total score ≥40 plus <40% reduction and a Parent Global Assessment score >2) were randomized 1:1:1:1 to 8 weeks of BPI plus double-blind treatment with vortioxetine 10 mg, vortioxetine 20 mg, fluoxetine 20 mg, or placebo. The primary endpoint was change from randomization in CDRS-R total score at week 8; the primary comparison was the average effect of 2 vortioxetine doses vs placebo. RESULTS: Of 784 patients enrolled in the lead-in, 616 were randomized. At week 8, the mean change in CDRS-R total score averaged for vortioxetine doses was -18.01 (SE = 0.98) and the mean difference vs placebo was 0.21 (P = .878; not significant). For fluoxetine, the mean change in CDRS-R total score was -21.95 and the mean difference vs placebo was -3.73 (P = .015). Treatment-emergent adverse events occurring in ≥5% of patients in either vortioxetine arm and at least twice more frequently than placebo were nausea, headache, vomiting, and dizziness. CONCLUSION: Patients in all groups showed reduction in CDRS-R scores by the end of the study, with no difference between combined doses of vortioxetine and placebo. The primary endpoint was not met, thereby rendering the study negative. The overall favorable safety profile of vortioxetine in an adolescent patient population was consistent with that seen in adults. CLINICAL TRIAL REGISTRATION INFORMATION: Active Reference (Fluoxetine) Fixed-Dose Study of Vortioxetine in Paediatric Patients Aged 12 to 17 Years With Major Depressive Disorder (MDD); http://clinicaltrials.gov; NCT02709746.

A Characterization of the Clinical Global Impression Scale Thresholds in the Treatment of Adolescent Depression Across Multiple Rating Scales.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%-95% change in CDRS-R scores at 4-6 weeks across three datasets. CGI-I scores of 2 mapped to 56%-94% change in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 3 mapped to 30%-68% changes in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%-44% at 4-6 weeks across three studies. There was no significant difference (p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference (p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Forty-Eight Week Outcomes of a Site-Randomized Trial of Combined Cognitive Behavioral Therapy and Medication Management Algorithm for Treatment of Depression Among Youth With HIV in the United States.

BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

Antidepressant exposure as a predictor of clinical outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.