Rachel H. Jacobs

Recovery and Recurrence Following Treatment for Adolescent Major Depression

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.

The Treatment for Adolescents With Depression Study (TADS): outcomes over 1 year of naturalistic follow-up.

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 Childrens 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.

Social problem-solving among adolescents treated for depression.

Studies suggest that deficits in social problem-solving may be associated with increased risk of depression and suicidality in children and adolescents. It is unclear, however, which specific dimensions of social problem-solving are related to depression and suicidality among youth. Moreover, rational problem-solving strategies and problem-solving motivation may moderate or predict change in depression and suicidality among children and adolescents receiving treatment. The effect of social problem-solving on acute treatment outcomes were explored in a randomized controlled trial of 439 clinically depressed adolescents enrolled in the Treatment for Adolescents with Depression Study (TADS). Measures included the Childrens Depression Rating Scale-Revised (CDRS-R), the Suicidal Ideation Questionnaire--Grades 7-9 (SIQ-Jr), and the Social Problem-Solving Inventory-Revised (SPSI-R). A random coefficients regression model was conducted to examine main and interaction effects of treatment and SPSI-R subscale scores on outcomes during the 12-week acute treatment stage. Negative problem orientation, positive problem orientation, and avoidant problem-solving style were non-specific predictors of depression severity. In terms of suicidality, avoidant problem-solving style and impulsiveness/carelessness style were predictors, whereas negative problem orientation and positive problem orientation were moderators of treatment outcome. Implications of these findings, limitations, and directions for future research are discussed.

Increased Coupling of Intrinsic Networks in Remitted Depressed Youth Predicts Rumination and Cognitive Control

Objective Functional connectivity MRI (fcMRI) studies of individuals currently diagnosed with major depressive disorder (MDD) document hyperconnectivities within the default mode network (DMN) and between the DMN and salience networks (SN) with regions of the cognitive control network (CCN). Studies of individuals in the remitted state are needed to address whether effects derive from trait, and not state or chronic burden features of MDD. Method fcMRI data from two 3.0 Tesla GE scanners were collected from 30 unmedicated (47% medication naïve) youth (aged 18–23, modal depressive episodes = 1, mean age of onset = 16.2, SD = 2.6) with remitted MDD (rMDD; modal years well = 4) and compared with data from 23 healthy controls (HCs) using four bilateral seeds in the DMN and SN (posterior cingulate cortex (PCC), subgenual anterior cingulate (sgACC), and amygdala), followed by voxel-based comparisons of the whole brain. Results Compared to HCs, rMDD youth exhibited hyperconnectivities from both PCC and sgACC seeds with lateral, parietal, and frontal regions of the CCN, extending to the dorsal medial wall. A factor analysis reduced extracted data and a PCC factor was inversely correlated with rumination among rMDD youth. Two factors from the sgACC hyperconnectivity clusters were related to performance in cognitive control on a Go/NoGo task, one positively and one inversely. Conclusions Findings document hyperconnectivities of the DMN and SN with the CCN (BA 8/10), which were related to rumination and sustained attention. Given these cognitive markers are known predictors of response and relapse, hyperconnectivities may increase relapse risk or represent compensatory mechanisms.

Dysfunctional Attitudes Scale Perfectionism: A Predictor and Partial Mediator of Acute Treatment Outcome among Clinically Depressed Adolescents

The effect of perfectionism on acute treatment outcomes was explored in a randomized controlled trial of 439 clinically depressed adolescents (12–17 years of age) enrolled in the Treatment for Adolescents with Depression Study (TADS) who received cognitive behavior therapy (CBT), fluoxetine, a combination of CBT and FLX, or pill placebo. Measures included the Childrens Depression Rating Scale–Revised, the Suicidal Ideation Questionnaire–Grades 7–9, and the perfectionism subscale from the Dysfunctional Attitudes Scale (DAS). Predictor results indicate that adolescents with higher versus lower DAS perfectionism scores at baseline, regardless of treatment, continued to demonstrate elevated depression scores across the acute treatment period. In the case of suicidality, DAS perfectionism impeded improvement. Treatment outcomes were partially mediated by the change in DAS perfectionism across the 12-week period.

Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders

BackgroundChildhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP).ResultsCompared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age.ConclusionsOur findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.

Onset of Alcohol or Substance Use Disorders Following Treatment for Adolescent Depression.

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.

Treating Depression and Oppositional Behavior in Adolescents

Adolescents with depression and high levels of oppositionality often are particularly difficult to treat. Few studies, however, have examined treatment outcomes among youth with both externalizing and internalizing problems. This study examines the effect of fluoxetine, cognitive behavior therapy (CBT), the combination of fluoxetine and CBT, and placebo on co-occurring oppositionality within a sample of depressed adolescents. All treatments resulted in decreased oppositionality at 12 weeks. Adolescents receiving fluoxetine, either alone or in combination with CBT, experienced greater reductions in oppositionality than adolescents not receiving antidepressant medication. These results suggest that treatments designed to alleviate depression can reduce oppositionality among youth with a primary diagnosis of depression.

Current Neural and Behavioral Dimensional Constructs across Mood Disorders.

Our understanding of the underlying neurobiology for mood disorders is still limited. We present an integrated model for conceptualizing and understanding mood disorders drawing upon a broad literature. This integrated model of emotion processing and regulation incorporates the linguistic constructs of the Research Domain Criteria (RDoC) initiative. In particular, we focus on the positive valence domain/circuit (PVC), highlighting recent reward research and the negative valence domain/circuit (NVC), highlighting rumination. Furthermore, we also illustrate the Cognitive Control and Problem Solving (CCaPS) circuit, which is heavily involved in emotion regulation, as well as the default mode network (DMN) and interactions between circuits. We conclude by proposing methods for addressing challenges in the developmental study of mood disorders, including using high-risk design that incorporates risk for many disorders.

Ethnic differences among adolescents beginning treatment for depression.

This study examines ethnic/racial differences at the start of treatment among participants in the Treatment for Adolescents with Depression Study (TADS). African American and Latino youth were compared to Caucasian youth on symptom presentation and cognitive variables associated with depression. Contrary to hypothesis, there were no significant differences in symptom presentation as measured by the interview-based items of the Childrens Depression Rating Scale--Revised (CDRS-R). However, African American and Latino youth were both rated as demonstrating more severe symptoms on the observational items of the CDRS-R compared to Caucasian youth. In terms of cognitive variables associated with depression, African Americans reported fewer negative cognitive biases compared to Caucasians, but cognitive biases were significantly correlated with depression severity across ethnic groups.