Early Emergence of Rumination has no Association with Performance on a Non-affective Inhibitory Control Task.

Rumination is a vulnerability for depression and potentially linked to inhibitory control weaknesses. We aimed to replicate the association observed in adults between inhibitory control and rumination in adolescents, and to examine putative moderating roles of childhood maltreatment and perceived family cohesion in an adolescent sample at risk for depression due to familial/personal history. Ninety adolescents aged 11-17 (M = 14.6, SD = 1.8) completed self-report scales of rumination, maltreatment, and family cohesion, and performed a task assessing inhibitory control. Hierarchical regression models showed no significant relation between inhibitory control and moderator variables on rumination. However, adolescents who reported higher levels of maltreatment and who perceived lower family cohesion tended to indicate higher levels of rumination (BChilhood Maltreatment = 27.52, 95% CIs [5.63, 49.41], BFamily Cohesion = -0.40, 95% CIs [-0.65, -0.15]). These findings demonstrate an alternative understanding of factors that increase depression onset risk and recurrence in adolescents.

Relations of gray matter volume to dimensional measures of cognition and affect in mood disorders.

Understanding the relationship between brain measurements and behavioral performance is an important step in developing approaches for early identification of any psychiatric difficulties and interventions to modify these challenges. Conventional methods to identify associations between regional brain volume and behavioral measures are not optimized, either in scale, scope, or specificity. To find meaningful associations between brain and behavior with greater sensitivity and precision, we applied data-driven factor analytic models to identify and extract individual differences in latent cognitive functions embedded across several computerized cognitive tasks. Furthermore, we simultaneously utilized a keyword-based neuroimaging meta-analytic tool (i.e., NeuroSynth), restricted atlas-parcel matching, and factor-analytic models to narrow down the scope of search and to further aggregate gray matter volume (GMV) data into empirical clusters. We recruited an early adult community cross-sectional sample (Total n = 177, age 18-30) that consisted of individuals with no history of any mood disorder (healthy controls, n = 44), those with remitted major depressive disorder (rMDD, n = 104), and those with a diagnosis of bipolar disorder currently in euthymic state (eBP, n = 29). Study participants underwent structural magnetic resonance imaging (MRI) scans and separately completed behavioral testing using computerized measures. Factor-analyzing five computerized tasks used to assess aspects of cognitive and affective processing resulted in seven latent dimensions: (a) Emotional Memory, (b) Interference Resolution, (c) Reward Sensitivity, (d) Complex Inhibitory Control, (e) Facial Emotion Sensitivity, (f) Sustained attention, and (g)Simple Impulsivity/Response Style. These seven dimensions were then labeled with specific keywords which were used to create neuroanatomical maps using NeuroSynth. These masks were further subdivided into GMV clusters. Using regression, we identified GMV clusters that were predictive of individual differences across each of the aforementioned seven cognitive dimensions. We demonstrate that a dimensional approach consistent with core principles of RDoC can be utilized to identify structural variability predictive of critical dimensions of human behavior.

Increased sensitivity of insula to supraliminal faces in adults with histories of mood disorders and self-injury.

BACKGROUND: Mood disorders are associated with neurobiological disruptions in subliminal and supraliminal emotion processing. There may be additional variation based on sex and the presence of self-injurious thoughts and behaviors (SITBs). Examining individuals in remission allows us to understand trait-like emotion processing characteristics that persist in the absence of symptoms. This study investigates neural processing in response to supraliminal and subliminal emotional stimuli based upon mood disorder diagnosis, sex, and SITBs. METHODS: Seventy-five participants with a history of any mood disorder (AMD; 52 female) and 27 healthy controls (HC; 14 female) completed a fMRI task presenting subliminal and supraliminal facial stimuli. Within the AMD group, 20 had no history of SITBs, 26 had histories of suicidal ideation only, and 27 had histories of both SI and self-injurious behavior. We examined activation of salience network regions of interest including the amygdala, insula, and subgenual anterior cingulate cortex (sgACC) during the task. RESULTS: AMD showed greater insula activation in response to happy faces relative to sad faces, which was not seen in the HC group. Males exhibited lower insula activation in response to sad faces relative happy faces, a pattern not seen in females. Individuals with SITBs demonstrated a lack of sgACC blunting during supraliminal versus subliminal trials. CONCLUSIONS: We found different patterns of neural responses related to mood disorder status, sex, and SITBs. Findings highlight the importance of considering heterogeneity within diagnoses and examining neurobiological features in the context of remission.

Structural and Functional Neural Correlates of Treatment Response for Interpersonal Psychotherapy for Depressed Adolescents.

Precision medicine approaches hold tremendous promise to advance current clinical practice by providing information about which individuals will benefit from which treatments. This pilot study evaluated if baseline structure and function of the salience and emotion brain regions implicated in adolescent depression, specifically the amygdala and anterior cingulate cortex (ACC), predict response to Interpersonal Psychotherapy for Depressed Adolescents (IPT-A). Adolescents (n = 15; mean age = 14.5 (1.6); 80.0% female) diagnosed with a depressive disorder completed brain scans before the start of a 16 week trial of IPT-A. Clinical measures assessing depressive symptoms were completed before, during, and after a trial of therapy. Results show that at baseline, greater ACC activation in the context of an emotion-matching task and greater amygdala-ACC resting-state functional connectivity was related to greater improvement in depression symptoms. There was minimal evidence that brain structure predicted changes in depressive symptoms. The present study is the first to evaluate neural predictors of IPT-A response. While the results are preliminary, these findings suggest some avenues for future research to pursue in the hopes that more will benefit from treatment.

Self-Injury in Adolescence Is Associated with Greater Behavioral Risk Avoidance, Not Risk-Taking.

Strategies to link impulsivity and self-injurious behaviors (SIBs) show highly variable results, and may differ depending on the impulsivity measure used. To better understand this lack of consistency, we investigated correlations between self-report and behavioral impulsivity, inhibitory control, SIBs, and rumination. We included participants aged 13-17 years with either current or remitted psychopathology who have (n = 31) and who do not have (n = 14) a history of SIBs. Participants completed self-report measures of impulsivity, the Rumination Responsiveness Scale (RRS), and two behavioral measures of impulsivity: the Balloon Analogue Risk Task (BART) and Parametric Go/No-Go (PGNG). Lifetime SIBs were positively associated with self-reported impulsivity, specifically positive and negative urgency. However, individuals with greater lifetime SIBs demonstrated greater risk aversion (lower impulsivity) as measured by the BART, whereas there was no relation between lifetime SIBs and PGNG performance. There was no relation between rumination and behavioral impulsivity, although greater rumination was associated with higher negative urgency. Future research examining the role of SIBs in the context of active versus remitted psychopathology is warranted. Because most adolescents were remitted from major depressive disorder at the time of study, follow-up studies can determine if lower risk-taking may aid individuals with more prior SIBs to achieve and maintain a remitted state.

Effect of SSRIs on Resting-State Functional Brain Networks in Adolescents with Major Depressive Disorder.

Investigation of brain changes in functional connectivity and functional network topology from receiving 8-week selective serotonin reuptake inhibitor (SSRI) treatments is conducted in 12 unmedicated adolescents with major depressive disorder (MDD) by using wavelet-filtered resting-state functional magnetic resonance imaging (fMRI). Changes are observed in frontal-limbic, temporal, and default mode networks. In particular, topological analysis shows, at the global scale and in the 0.12-0.25 Hz band, that the normalized clustering coefficient and smallworldness of brain networks decreased after treatment. Regional changes in clustering coefficient and efficiency were observed in the bilateral caudal middle frontal gyrus, rostral middle frontal gyrus, superior temporal gyrus, left pars triangularis, putamen, and right superior frontal gyrus. Furthermore, changes of nodal centrality and changes of connectivity associated with these frontal and temporal regions confirm the global topological alternations. Moreover, frequency dependence is observed from FDR-controlled subnetworks for the limbic-cortical connectivity change. In the high-frequency band, the altered connections involve mostly frontal regions, while the altered connections in the low-frequency bands spread to parietal and temporal areas. Due to the limitation of small sample sizes and lack of placebo control, these preliminary findings require confirmation with future work using larger samples. Confirmation of biomarkers associated with treatment could suggest potential avenues for clinical applications such as tracking treatment response and neurobiologically informed treatment optimization.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

Corrigendum: White Matter Microstructure in Adolescents and Young Adults With Non-Suicidal Self-Injury.

[This corrects the article DOI: 10.3389/fpsyt.2019.01019.].

Neurocircuitry associated with symptom dimensions at baseline and with change in borderline personality disorder.

Borderline personality disorder (BPD) is a serious illness associated with chronic suffering and self-injurious behavior. Parsing the relationships between specific symptom domains and their underlying biological mechanisms may help us further understand the neural circuits implicated in these symptoms and how they might be amenable to change with treatment. This study examines the association between symptom dimensions (Affective Disturbance, Cognitive Disturbance, Disturbed Relationships, and Impulsivity) and amygdala resting-state functional connectivity (RSFC) in a sample of adults with BPD (n = 18). We also explored the relationships between change in symptom dimensions and change in amygdala RSFC in a subset of this sample (n = 13) following 8 weeks of quetiapine or placebo. At baseline, higher impulsivity was associated with increased positive RSFC between right amygdala and left hippocampus. There were no significant differences in neural change between treatment groups. Improvement in cognitive disturbance was associated with increased positive RSFC between left amygdala and temporal fusiform and parahippocampal gyri. Improvement in disturbed relationships was associated with increased negative RSFC between right amygdala and frontal pole. These results support that specific dimensions of BPD are associated with specific neural connectivity patterns at baseline and with change, which may represent neural treatment targets.

White Matter Microstructure in Adolescents and Young Adults With Non-Suicidal Self-Injury.

Background: Non-suicidal self-injury (NSSI) is a growing public health concern that commonly begins in adolescence, and can persist into young adulthood. A promising approach for advancing our understanding of NSSI in youth is to examine white matter microstructure using diffusion magnetic resonance imaging (dMRI). Method: The present study examined whole-brain group differences in structural connectivity (as measured by generalized fractional anisotropy [GFA]) between 28 female adolescents and young adults ages 13-21 years with NSSI and 22 age-matched healthy controls (HC). We also explored the association between clinical characteristics including NSSI severity and duration, impulsivity, emotion regulation and personality traits within the NSSI group and GFA of the uncinate fasciculus and cingulum. Results: Compared to the HC group, participants with NSSI had lower GFA in several white matter tracts, including the uncinate fasciculus, cingulum, bilateral superior and inferior longitudinal fasciculi, anterior thalamic radiation, callosal body, and corticospinal tract. When controlling for depressive symptoms, the NSSI group showed an association between NSSI duration (time since initiating NSSI behavior) and lower GFA in the left cingulum. Higher levels of attentional impulsivity were related to lower GFA in the left uncinate fasciculus within the NSSI group. Conclusions: We found evidence suggesting widespread white matter microstructure deficits in adolescents and young adults with NSSI versus HC. We also report inverse associations between white matter integrity and clinical characteristics (duration of NSSI and attentional impulsivity). These white matter microstructural deficits may represent a possible neurobiologically-based vulnerability to developing maladaptive coping mechanisms, such as NSSI. Additionally, results suggest that this white matter disorganization may either worsen with prolonged engagement in NSSI or predict persistent NSSI; thereby highlighting the importance of early intervention targeting this behavior.

Increases in orbitofrontal cortex thickness following antidepressant treatment are associated with changes in resting state autonomic function in adolescents with major depression - Preliminary findings from a pilot study.

In adults with major depressive disorder (MDD), effective treatment has been associated with increases in both heart rate variability (HRV) and cortical thickness. However, the impact of treatment on these indices has not yet been examined in adolescents. Cortical thickness and HRV were measured in twelve adolescents with MDD before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). We examined treatment-related changes in depression symptoms, HRV, heart rate (HR), and cortical thickness, and analyzed correlations among these change indices. At follow-up, patients showed significantly decreased depression severity, increased HRV and increased thickness of the left medial orbitofrontal cortex (OFC). Clinical improvement was associated with increased HRV and decreased HR. Increased HRV was associated with increased cortical thickness of left lateral OFC and superior frontal cortex. Due to the small sample size, results represent preliminary findings that need replication. Further, in the absence of a placebo arm, we cannot confirm that the observed effects are due solely to medication. These preliminary findings suggest that SSRI treatment in adolescents impacts both cortical thickness and autonomic functioning. Confirmation of these findings would support OFC thickness and HRV as neurobiological mediators of treatment outcome.

Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study.

BACKGROUND: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors. METHODS: Adolescents, 12-18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children's Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS). RESULTS: Thirteen participants (mean age 16.9 years, range 14.5-18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response. CONCLUSIONS: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose-response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.

Brain structural thickness and resting state autonomic function in adolescents with major depression.

Major depressive disorder (MDD) has been associated with abnormalities in cortical thickness and autonomic function. Adolescence is a time notable for brain development and MDD onset. In healthy adolescents, greater resting state vagal activity (RVA) is associated with lower cortical thickness. The relationship between brain structural thickness and RVA in adolescents with MDD has not previously been studied. This secondary analysis drew on a sample of 37 non-depressed controls and 53 adolescents with MDD. Resting state heart rate and two indices of RVA (HF-HRV and RMSSD) were recorded during a neuroimaging session. Cortical thickness within fronto-limbic regions of interest was measured using Freesurfer analysis of T1-weighted high-resolution structural images. Self-reports of depression severity showed a significant interaction with cortical thickness of the right insula in predicting RMSSD [t = 2.22, P=0.030, ß = 5.44; model fit of the interaction term as indicated by the 'Bayes Factor' (BF): 7.58] and HF-HRV (t = 2.09, P=0.041, ß = 4.72; BF: 7.94). Clinician ratings of depression severity showed further interactions. Findings underscore the important relationships between RVA and cortical development, suggesting two possible explanations: (i) in adolescent MDD, greater fronto-limbic thickness is compensatory for deficits in autonomic regulation or (ii) increased autonomic arousal results in delayed fronto-limbic maturation. Longitudinal research is necessary to further clarify the nature of the relationship between autonomic functioning and cortical development.

Neural and neuroendocrine predictors of pharmacological treatment response in adolescents with depression: A preliminary study.

OBJECTIVE: Typically, about 30 to 50% of adolescents with depression fail to respond to evidence-based treatments, including antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). Efforts for identifying predictors and moderators of treatment response are needed to begin to address critical questions relevant to personalized care in adolescent depression. In this pilot study, we aim to identify biological predictors of response to antidepressant treatment. METHOD: We used a multiple levels of analysis approach to evaluate threat system functioning (fronto-limbic system and the associated hormonal cascade) to determine if key biological indexes at baseline could predict improvement in depressive symptoms after eight weeks of antidepressant treatment in adolescents with depression. RESULTS: Neural predictors of favorable treatment response included lower amygdala connectivity with left supplementary motor area and with right precentral gyrus, and greater amygdala connectivity with right central opercular cortex and Heschl's gyrus connectivity during rest. During an emotion task, neural predictors of treatment response were greater activation of the bilateral anterior cingulate cortex and left medial frontal gyrus. Additionally, different patterns of salivary cortisol obtained in the context of a modified Trier Social Stress Test were associated with those whose depressive symptoms remitted as compared to those whose symptoms persisted. CONCLUSIONS: This approach shows significant promise for identifying predictors of treatment response in adolescents with depression. Future work is needed that incorporates sufficiently powered, randomized control trials to provide the basis by which both predictors and moderators of treatment response are identified. The hope is that this work will inform the development of methods that can guide clinician decision-making in assigning beneficial treatments for adolescents who are suffering from depression.

N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study.

BACKGROUND: Nonsuicidal self-injury (NSSI) is common in adolescents and young adults, and few evidence-based treatments are available for this significant problem. N-acetylcysteine (NAC) is a widely available nutritional supplement that has been studied in some psychiatric disorders relevant to NSSI including mood and addictive disorders. This pilot study tested the use of NAC as a potential treatment for NSSI in youth. METHODS: Thirty-five female adolescents and young adults with NSSI aged 13-21 years were enrolled in this study that had an open-label, single-arm study design. All participants were given oral NAC as follows: 600 mg twice daily (weeks 1-2), 1200 mg twice daily (weeks 3-4), and 1800 mg twice daily (weeks 5-8). Patients were seen every 2 weeks throughout the trial, at which time youth reported the frequency of NSSI episodes. Levels of depression, impulsivity, and global psychopathology were measured at baseline and at the end of the trial using the Beck Depression Inventory-II (BDI-II), Barratt Impulsivity Scale, and Symptoms Checklist-90 (SCL-90). RESULTS: About two-thirds of the enrolled female youth completed the trial (24/35). NAC was generally well tolerated in this sample. NAC treatment was associated with a significant decrease in NSSI frequency at visit 6 and visit 8 compared to baseline. We also found that depression scores and global psychopathology scores (but not impulsivity scores) decreased after NAC treatment. Decrease in NSSI was not correlated with decrease in BDI-II or SCL-90 scores, suggesting these might be independent effects. CONCLUSION: We provide preliminary evidence that NAC may have promise as a potential treatment option for adolescents with NSSI. The current results require follow-up with a randomized, placebo-controlled trial to confirm efficacy.

Multi-modal neuroimaging of adolescents with non-suicidal self-injury: Amygdala functional connectivity.

BACKGROUND: Non-suicidal self-injury (NSSI) is a significant mental health problem among adolescents. Research is needed to clarify the neurobiology of NSSI and identify candidate neurobiological targets for interventions. Based on prior research implicating heightened negative affect and amygdala hyperactivity in NSSI, we pursued a systems approach to characterize amygdala functional connectivity networks during rest (resting-state functional connectivity [RSFC)]) and a task (task functional connectivity [TFC]) in adolescents with NSSI. METHOD: We examined amygdala networks in female adolescents with NSSI and healthy controls (n = 45) using resting-state fMRI and a negative emotion face-matching fMRI task designed to activate the amygdala. Connectivity analyses included amygdala RSFC, amygdala TFC, and psychophysiological interactions (PPI) between amygdala connectivity and task conditions. RESULTS: Compared to healthy controls, adolescents with NSSI showed atypical amygdala-frontal connectivity during rest and task; greater amygdala RSFC in supplementary motor area (SMA) and dorsal anterior cingulate; and differential amygdala-occipital connectivity between rest and task. After correcting for depression symptoms, amygdala-SMA RSFC abnormalities, among others, remained significant. LIMITATIONS: This study's limitations include its cross-sectional design and its absence of a psychiatric control group. CONCLUSIONS: Using a multi-modal approach, we identified widespread amygdala circuitry anomalies in adolescents with NSSI. While deficits in amygdala-frontal connectivity (driven by depression symptoms) replicates prior work in depression, hyperconnectivity between amygdala and SMA (independent of depression symptoms) has not been previously reported. This circuit may represent an important mechanism underlying the link between negative affect and habitual behaviors. These abnormalities may represent intervention targets for adolescents with NSSI.

Neural Correlates of Antidepressant Treatment Response in Adolescents with Major Depressive Disorder.

OBJECTIVE: The neural changes underlying response to antidepressant treatment in adolescents are unknown. Identification of neural change correlates of treatment response could (1) aid in understanding mechanisms of depression and its treatment and (2) serve as target biomarkers for future research. METHOD: Using functional magnetic resonance imaging, we examined changes in brain activation and functional connectivity in 13 unmedicated adolescents with major depressive disorder (MDD) before and after receiving treatment with a selective serotonin reuptake inhibitor medication for 8 weeks. Specifically, we examined brain activation during a negative emotion task and resting-state functional connectivity (RSFC), focusing on the amygdala to capture networks relevant to negative emotion. We conducted whole-brain analyses to identify how symptom improvement was related to change in brain activation during a negative emotion task or amygdala RSFC. RESULTS: After treatment, clinical improvement was associated with decreased task activation in rostral and subgenual anterior cingulate cortex and increased activation in bilateral insula, bilateral middle frontal cortices, right parahippocampus, and left cerebellum. Analysis of change in amygdala RSFC showed that treatment response was associated with increased amygdala RSFC with right frontal cortex, but decreased amygdala RSFC with right precuneus and right posterior cingulate cortex. CONCLUSION: The findings represent a foothold for advancing understanding of pathophysiology of MDD in adolescents by revealing the critical neural circuitry changes that underlie a positive response to a standard treatment. Although preliminary, the present study provides a research platform for future work needed to confirm these biomarkers at a larger scale before using them in future target engagement studies of novel treatments.

Conceptualizing the neurobiology of non-suicidal self-injury from the perspective of the Research Domain Criteria Project.

Non-suicidal self-injury (NSSI) commonly starts in adolescence and is associated with an array of negative outcomes. Neurobiological research investigating NSSI is in its early stages and most studies have examined this behavior within the context of specific diagnoses. However, the Research Domain Criteria (RDoC) initiative encourages researchers to examine brain-behavior relationships across diagnoses. This review on the neurobiology associated with NSSI is organized using the domains proposed by RDoC: Negative Valence, Positive Valence, Cognitive, Social Processes, and Arousal/Regulatory Systems. Evidence of neurobiological anomalies is found in each of these domains. We also propose future research directions, especially in regard to human development. Future NSSI studies should address this behavior independent of diagnosis, examine relevant constructs across multiple units of analysis, and assess how systems change across development and course of illness. These advances will be essential for guiding neurobiologically informed intervention and prevention strategies to target NSSI. In doing so, we may prevent the associated negative outcomes across the lifespan.

Multilevel assessment of the neurobiological threat system in depressed adolescents: interplay between the limbic system and hypothalamic-pituitary-adrenal axis.

Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12-19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.