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.

Integration of Measurement-Based Care for Youth Depression and Suicidality Using VitalSign6.

Depression and suicidality are prevalent in youth and are associated with a range of negative outcomes. The current study aimed to evaluate a measurement-based care (MBC) software (VitalSign6) tool to improve the screening and treatment of depression and suicidality in youth aged 8-17 years within a rural, underserved population. To assess for depression and suicidality, the Patient Health Questionnaire-2 was administered as an initial screen, and the Patient Health Questionnaire-9 Modified for Adolescents (PHQ-9-A) was administered if the initial screen was positive. Data were collected at medical clinics over one year, and descriptive statistics and t-tests or Wilcoxon-Mann-Whitney tests were conducted. A total of 1,984 youth were initially screened (mean age of 13 years; 51.6% female); 24.2% screened positive for depression, and 14.9% endorsed suicidality. Of those who screened positive, the mean PHQ-9-A score was 12.8; 66.9% had PHQ-9-A scores in the moderate to severe range, and 44.2% endorsed suicidality. Almost half of the youth who screened positive for depression had at least one follow-up assessment, and about one quarter achieved remission 4 months after initial screening. Adolescents (12-17 years) had higher PHQ-9-A scores, higher suicidality, and more follow-up assessments than younger youth (8-11 years). Younger youth had higher rates of remission. The widespread use of MBC was feasible in this setting. It is important to utilize MBC to identify and treat youth with depression and suicidality and to do so in younger populations to improve their trajectory over time; VitalSign6 is one tool to help achieve these goals.

The clinical presentation of major depressive disorder in youth with co-occurring obsessive-compulsive disorder.

BACKGROUND: Major depressive disorder (MDD) is common in youth and among the most frequent comorbid disorders in pediatric obsessive-compulsive disorder (OCD), but it is unclear whether the presence of OCD affects the symptom presentation of MDD in youth. METHODS: A sample of youth with OCD and MDD (n = 124) and a sample of youth with MDD but no OCD (n = 673) completed the Patient Health Questionnaire for Adolescents (PHQ-A). The overall and symptom-level presentation of MDD were examined using group comparisons and network analysis. RESULTS: Youth with MDD and OCD, compared to those with MDD and no OCD, had more severe MDD (Cohen's d = 0.39) and more reported moderate to severe depression (75 % vs 61 %). When accounting for demographic variables and the overall severity of MDD, those with comorbid OCD reported lower levels of anhedonia and more severe difficulties with psychomotor retardation/agitation. No significant differences in the interconnections among symptoms emerged. LIMITATIONS: Data were cross-sectional and self-reported, gold standard diagnostic tools were not used to assess OCD, and the sample size for the group with MDD and OCD was relatively small yielding low statistical power for network analysis. CONCLUSIONS: Youth with MDD and OCD have more severe MDD than those with MDD and no OCD and they experience more psychomotor issues and less anhedonia, which may relate to the behavioral activation characteristic of OCD.

Psychometric properties of the GAD-7 and PROMIS-Anxiety-4a among youth with depression and suicidality: Results from the Texas youth depression and suicide research network.

There is a tremendous need for brief, valid, and free assessments of anxiety in child mental healthcare. The goal of this study was to determine the psychometric properties of two such measures, the GAD-7 and PROMIS-Anxiety-4a, in 1000 children, adolescents, and young adults (8-20 years-old) with depression and/or suicidality. The GAD-7, the PROMIS-Anxiety-4a, and other validated assessments of anxiety, physical functioning, and psychiatric diagnoses were completed. Confirmatory factor analyses showed an acceptable fit for a single factor in both measures via all indices but the RMSEA. They demonstrated measurement invariance across pre-adolescents (8-12 years-old) and adolescents and emerging adults (13-20 years-old), though scalar invariance was not observed for the GAD-7. Both measures showed strong convergent validity, GAD-7: r = 0.68; PROMIS-Anxiety-4a: r = 0.75, divergent validity with a measure of physical function, GAD-7: r = -0.24; PROMIS-Anxiety-4a: r = -0.28, good internal consistency, ω = 0.89 for both, and high test-retest reliability, GAD-7: r = 0.69; PROMIS-Anxiety-4a: r = 0.71. Both measures also showed acceptable sensitivity and specificity in detecting the presence of any anxiety disorder, GAD-7 cut-off score of 10: AUC = 0.75; PROMIS-Anxiety-4a cutoff score of 12: AUC = 0.79. The GAD-7 correlated similarly with the Screen for Child Anxiety Related Disorders total score and generalized anxiety subscale, and also showed similar diagnostic sensitivity and specificity when used to detect the presence of any anxiety disorder vs. generalized anxiety disorder specifically. Results suggest that both of these brief, publicly available instruments are valid and reliable assessments of anxiety among youth in treatment for depression and/or suicidality.

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.

Linking trauma to mental health in the statewide Texas Youth Depression and Suicide Research Network (TX-YDSRN).

Rates of youth depression and suicide are rising worldwide and represent public health crises. The present study examined the relationship between trauma history and symptoms of depression, suicidal ideation, and anxiety among suicidal and depressed youth. A diverse group of 1000 8-20-year-olds enrolled in the statewide Texas Youth Depression and Suicide Research Network (TX-YDSRN) reported their trauma history (Traumatic Events Screening Inventory for Children) and symptoms of depression (Patient Health Questionnaire for adolescents; PHQ-A), anxiety (Generalized Anxiety Disorder scale; GAD-7), and suicidality (Concise Health Risk Tracking scale; CHRT-SR). Nearly half of the sample reported exposure to multiple categories of traumatic experiences. Number of trauma exposure categories significantly predicted PHQ-A and GAD-7 scores. Exposure to interpersonal trauma and to sexual trauma were significantly associated with PHQ-A, GAD-7, and CHRT-SR scores. The number of trauma exposure categories was associated with increased levels of anxiety and depression; however, only exposure to interpersonal or sexual trauma was associated with more suicidality. Clinicians should assess trauma exposure in patients seeking psychiatric care, especially for interpersonal and sexual trauma, which may be predictive of increased risk for suicidality in depressed youth. Future work should disentangle the effects of specific trauma types from multiple trauma exposure.

Data-driven subgrouping of youths with depression reveals that resilience is associated with higher physical functioning despite high symptom burden in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) measure, which assesses past week status of seven domains (physical function mobility, anxiety, depressive symptoms, fatigue, peer relationships, pain interference, and pain intensity), represents a new paradigm using patient-reported outcomes. We used a data-driven approach with PROMIS to identify subgroups of youths receiving depression treatment. METHODS: Youths (n = 721) enrolled in the Texas Youth Depression and Suicide Research Network who completed the PROMIS were analyzed. Latent class analyses (LCAs) identified subgroups and compared their baseline clinical/sociodemographic features. RESULTS: Compared to population norms, our sample had worse than average physical function, anxiety, depression, fatigue, and pain interference. Using LCA, four subgroups were identified: 1) lower symptom severity and higher physical functioning (14.6 %); 2) higher symptom burden, higher pain interference/intensity, and lower physical functioning (52.7 %); 3) higher symptom burden, higher pain interference/intensity, but with higher physical functioning (9.2 %); and 4) higher symptom burden, but lower physical functioning and pain interference/intensity (23.6 %). Group 3 demonstrated higher resilience than Group 2. In contrast, Group 2 had higher anxiety than Group 4. LIMITATIONS: Individuals may have different symptom profiles due to the observational nature of the study. Replication of these subgroups may be difficult, as future samples may differ in these characteristics. Further work may demonstrate the stability of these groups. CONCLUSIONS: A data-driven analysis identified a small but significant subgroup with high physical functioning despite high symptom burden and pain, and this group reported higher resilience. Resilience-enhancing interventions may help improve functional outcomes in depressed youth.

Suicidal thoughts and behaviors in youth seeking mental health treatment in Texas: Youth Depression and Suicide Network research registry.

INTRODUCTION: Suicidality in youth is a serious public health problem. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) was initiated in 2020 to create a research registry for youth with depression and/or suicidality in Texas. This report presents baseline clinical/demographic characteristics of the first 1000 participants, focusing on suicidal thoughts and behaviors. METHODS: The registry includes 8-20-year-old youth receiving treatment for depression, or who screen positive for depression and/or suicidal ideation/behavior. Baseline data include diagnosis, depression/anxiety severity, suicidal ideation/behavior, trauma history, and measures of resilience. RESULTS: We present baseline data on the first 1000 participants. Most (79.6%) of the sample had a primary depressive disorder. The sample had moderate to severe depression (Patient Health Questionnaire for Adolescents, PHQ-A; 12.9 ± 6.4) and anxiety (Generalized Anxiety Disorder, GAD-7; 11.3 ± 5.9). Nearly half reported ≥1 lifetime suicide attempts and 90% reported lifetime or current suicidal ideation. Participants with past/current suicidality (attempts and/or ideation) had greater illness severity (depression, anxiety, and suicidal thoughts/behaviors), lower resilience, and higher rates of trauma exposure than those without suicidality. CONCLUSIONS: Baseline data indicate moderate levels of depression, anxiety, and suicidality and their correlates in this cohort. Future reports will determine trajectories of outcomes and predictors, moderators, and social determinants related to these outcomes.

Texas Youth Depression and Suicide Research Network (TX-YDSRN) research registry and learning healthcare network: Rationale, design, and baseline characteristics.

BACKGROUND: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants. METHODS: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality symptoms, associated comorbidities, treatment history, services used, and social determinants of health. Subsequent assessments occur every two months for 24 months. RESULTS: Among 1000 participants, 68.7 % were 12-17 years, 24.6 % were ≥ 18 years, and 6.7 % were < 12. Overall, 36.8 % were non-Hispanic Caucasian, 73.4 % were female, and 79.9 % had a primary depressive disorder. Nearly half of the sample reported ≥1 suicide attempt, with rates similar in youth 12-17 years old (49.9 %) and those 18 years and older (45.5 %); 29.9 % of children <12 reported at least one suicide attempt. Depression and anxiety scores were in the moderate-severe range for all age groups (Patient Health Questionnaire for Adolescents [PHQ-A]: 12.9 ± 6.4; Generalized Anxiety Disorder [GAD-7]: 11.3 ± 5.9). LIMITATIONS: The sample includes youth who are receiving depression care at enrollment and may not be representative of non-diagnosed, non-treatment seeking youth. CONCLUSIONS: The TX-YDSRN is one of the largest prospective longitudinal cohort registries designed to develop predictive models for outcome trajectories based on disorder heterogeneity, social determinants of health, and treatment availability.

Obsessive-compulsive disorder in youth and young adults with depression: Clinical characteristics of comorbid presentations.

Obsessive-compulsive disorder (OCD), anxiety disorders, and depressive disorders are highly comorbid, and each contribute to significant functional impairment for affected youth. Comorbid anxiety disorders in depressed youth have been associated with greater depressive symptom severity and impairment, but the impact of comorbid OCD in this population remains unclear. Accordingly, the present study examined the differential clinical characteristics of youth with depression and comorbid OCD relative to age/gender matched depressed youth with no such comorbidity and to those with depression and a comorbid (non-OCD) anxiety disorder. A sample of 797 youth and young adults ages 8-20 years who met diagnostic criteria for depression alone, depression with co-occurring OCD or any anxiety disorder were included in the present study. Rates of comorbid anxiety and OCD were very high (60.5% and 15.5%, respectively). Relative to youth with only depression, depressed youth with comorbid OCD or anxiety had greater severity of depression, suicidality, and overall impairment in social, physical, and emotional functioning. These results highlight the contribution of OCD or anxiety comorbidity in more complex clinical presentations for depressed youth.

Leveraging the Science of Teamwork to Sustain Handoff Improvements in Cardiovascular Surgery.

BACKGROUND: Improving the reliability of handoffs and care transitions is an important goal for many health care organizations. Increasing evidence shows that human-centered design and improved teamwork can lead to sustainable care transition improvements and better patient outcomes. This study was conducted within a cardiovascular service line at an academic medical center that performs more than 600 surgical procedures annually. A handoff process previously implemented at the center was poorly adopted. This work aimed to improve cardiovascular handoffs by applying human factors and the science of teamwork. METHODS: The study's quality improvement method used Plan-Do-Study-Act cycles and participatory design and ergonomics to develop, implement, and assess a new handoff process and bundle. Trained observers analyzed video-recorded and live handoffs to assess teamwork, leadership, communication, coordination, cooperation, and sustainability of unit-defined handoff best practices. The intervention included a teamwork-focused redesign process and handoff bundle with supporting cognitive aids and assessment metrics. RESULTS: The study assessed 153 handoffs in multiple phases over 3 years (2016-2019). Quantitative and qualitative assessments of clinician (teamwork) and implementation outcomes were performed. Compared with the baseline, the observed handoffs demonstrated improved team leadership (p < 0.0001), communication (p < 0.0001), coordination (p = 0.0018), and cooperation (p = 0.007) following the deployment of the handoff bundle. Sustained improvements in fidelity to unit-defined handoff best practices continued 2.3 years post-deployment of the handoff bundle. CONCLUSION: Participatory design and ergonomics, combined with implementation and safety science principles, can provide an evidence-based approach for sustaining complex sociotechnical change and making handoffs more reliable.

Leveraging the microbiome to understand clinical heterogeneity in depression: findings from the T-RAD study.

Alterations in the gut microbiome have been linked to a variety of mental illnesses including anxiety and depression. This study utilized advanced bioinformatics tools that integrated both the compositional and community nature of gut microbiota to investigate how gut microbiota influence clinical symptoms in a sample of participants with depression. Gut microbiota of 179 participants with major depressive disorder (MDD) in the Texas Resilience Against Depression (T-RAD) study were analyzed by 16S rRNA gene sequencing of stool samples. Severity of anxiety, depression, and anhedonia symptoms were assessed with General Anxiety Disorder - 7 item scale, Patient Health 9-item Questionnaire, and Dimensional Anhedonia Rating Scale, respectively. Using weighted correlation network analysis, a data-driven approach, three co-occurrence networks of bacterial taxa were identified. One of these co-occurrence networks was significantly associated with clinical features including depression and anxiety. The hub taxa associated with this co-occurrence module -one Ruminococcaceae family taxon, one Clostridiales vadinBB60 group family taxon, and one Christencenellaceae family taxon- were connected to several additional butyrate-producing bacteria suggesting that deficits in butyrate production may contribute to clinical symptoms. Therefore, by considering the community nature of the gut microbiome in a real world clinical sample, this study identified a gut microbial co-occurrence network that was significantly associated with clinical anxiety in a cohort of depressed individuals.

Psychometric properties of Concise Associated Symptom Tracking (CAST) scale in youths and young adults: Findings from the Texas youth depression and suicide research network (TX-YDSRN).

Symptoms of irritability, anxiety, panic, and insomnia are common in patients with depression, and their worsening after antidepressant treatment initiation is associated with poorer long-term outcomes. The Concise Associated Symptom Tracking (CAST) scale was developed to measure these symptoms in adults with major depressive disorder (MDD). Here, we evaluate the psychometric properties of CAST in an ongoing community-based observational study involving children, adolescents, and young adults. Individuals from the ongoing Texas Youth Depression and Suicide Research Network (TX-YDSRN; N = 952) with CAST data available were included. Fit statistics [Goodness of Fit Index (GFI), Comparative Fit Index (CFI), and Root Mean Square Error of Approximation (RMSEA)] from confirmatory factor analyses were used to evaluate the five- and four-domain structure of CAST. Item response theory (IRT) analyses were also used. Individuals were grouped based on age (in years) as youths (8-17) and young adults (18-20). Correlations with other clinical measures were used to inform construct validity. Four-domain (irritability, anxiety, panic, and insomnia) 12-item structure of CAST (CAST-12) was optimal for youths (N = 709, GFI = 0.906, CFI = 0.919, RMSEA = 0.095) and young adults (N = 243, GFI = 0.921, CFI = 0.938, RMSEA = 0.0797) with Cronbach's alpha of 0.87 and 0.88, respectively. Slope of each item exceeded 1.0 on IRT analyses suggesting adequate discrimination for each item. Scores on irritability, anxiety, panic, and insomnia were significantly correlated with similar items on other scales. Together these findings suggest that CAST-12 is a valid self-report measure of irritability, anxiety, insomnia, and panic in youths and young adults.

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.

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.

Data driven clusters derived from resting state functional connectivity: Findings from the EMBARC study.

BACKGROUND: To address the clinical heterogeneity of Major Depressive Disorder (MDD), this investigation determined whether resting state functional magnetic resonance imaging (fMRI) could be deployed to identify circuit based homogeneous subgroups, and whether subgroups identified show differential treatment outcomes. METHODS: Pretreatment resting state fMRIs obtained from 278 outpatients with nonpsychotic MDD from Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression Study were used to create data-driven subgroups using CLICK clustering. These subgroups were then compared using baseline clinical data, as well as baseline-to-week 8 changes in depression severity measured using the 17-item Hamilton Rating Scale for Depression (HAMD17) and response/remission rates by treatment group. RESULTS: Three subgroups were identified. Cluster-1 was characterized by overallhyperconnectivity coupled with profound hypoconnectivity between the supramarginal gyrus (executive control network; ECN) and the superior frontal cortex (dorsal attention network; DAN). Cluster-2 was characterized by overall hypoconnectivity coupled with hyperconnectivity between supramarginal gyrus (ECN) and superior frontal cortex (DAN). Cluster-3 showed hypoconnectivity, especially profound between the angular cortex (default mode network; DMN) and middle frontal cortex (ECN). While baseline clinical measures did not differentiate the three clusters, Cluster-3 had the remission rate (51.6%) compared to Cluster-1 and Cluster-2 (32.7% and 31.9%) when treated with sertraline. LIMITATIONS: Due to the exploratory nature of these analyses, there were no adjustments for multiple comparisons. CONCLUSIONS: Baseline functional connectivity can be used to subgroup patients with MDD that differ in acute phase treatment outcomes. Measures of connectivity may address the heterogeneity of MDD.

BLENDS: Augmentation of Functional Magnetic Resonance Images for Machine Learning Using Anatomically Constrained Warping.

Introduction: Data augmentation improves the accuracy of deep learning models when training data are scarce by synthesizing additional samples. This work addresses the lack of validated augmentation methods specific for synthesizing anatomically realistic four-dimensional (4D) (three-dimensional [3D] + time) images for neuroimaging, such as functional magnetic resonance imaging (fMRI), by proposing a new augmentation method. Methods: The proposed method, Brain Library Enrichment through Nonlinear Deformation Synthesis (BLENDS), generates new nonlinear warp fields by combining intersubject coregistration maps, computed using symmetric normalization, through spatial blending. These new warp fields can be applied to existing 4D fMRI to create new augmented images. BLENDS was tested on two neuroimaging problems using de-identified data sets: (1) the prediction of antidepressant response from task-based fMRI (original data set n = 163), and (2) the prediction of Parkinson's disease (PD) symptom trajectory from baseline resting-state fMRI regional homogeneity (original data set n = 43). Results: BLENDS readily generates hundreds of new fMRI from existing images, with unique anatomical variations from the source images, that significantly improve prediction performance. For antidepressant response prediction, augmenting each original image once (2 × the original training data) significantly increased prediction R2 from 0.055 to 0.098 (p<1e-6), whereas at 10 × augmentation R2 increased to 0.103. For the prediction of PD trajectory, 10 × augmentation R2 increased from -0.044 to 0.472 (p<1e-6). Conclusions: Augmentation of fMRI through nonlinear transformations with BLENDS significantly improved the performance of deep learning models on clinically relevant predictive tasks. This method will help neuroimaging researchers overcome data set size limitations and achieve more accurate predictive models.

Accelerated Brain Aging in Adults With Major Depressive Disorder Predicts Poorer Outcome With Sertraline: Findings From the EMBARC Study.

BACKGROUND: Major depressive disorder (MDD) may be associated with accelerated brain aging (higher brain age than chronological age). This report evaluated whether brain age is a clinically useful biomarker by checking its test-retest reliability using magnetic resonance imaging scans acquired 1 week apart and by evaluating the association of accelerated brain aging with symptom severity and antidepressant treatment outcomes. METHODS: Brain age was estimated in participants of the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study using T1-weighted structural magnetic resonance imaging (MDD n = 290; female n = 192; healthy control participants n = 39; female n = 24). Intraclass correlation coefficient was used for baseline-to-week-1 test-retest reliability. Association of baseline Δ brain age (brain age minus chronological age) with Hamilton Depression Rating Scale-17 and Concise Health Risk Tracking Self-Report domains (impulsivity, suicide propensity [measures: pessimism, helplessness, perceived lack of social support, and despair], and suicidal thoughts) were assessed at baseline (linear regression) and during 8-week-long treatment with either sertraline or placebo (repeated-measures mixed models). RESULTS: Mean ± SD baseline chronological age, brain age, and Δ brain age were 37.1 ± 13.3, 40.6 ± 13.1, and 3.1 ± 6.1 years in MDD and 37.1 ± 14.7, 38.4 ± 12.9, and 0.6 ± 5.5 years in healthy control groups, respectively. Test-retest reliability was high (intraclass correlation coefficient = 0.98-1.00). Higher baseline Δ brain age in the MDD group was associated with higher baseline impulsivity and suicide propensity and predicted smaller baseline-to-week-8 reductions in Hamilton Depression Rating Scale-17, impulsivity, and suicide propensity with sertraline but not with placebo. CONCLUSIONS: Brain age is a reliable and potentially clinically useful biomarker that can prognosticate antidepressant treatment outcomes.

Accelerated brain aging in individuals with diabetes: Association with poor glycemic control and increased all-cause mortality.

BACKGROUND: Diabetes has been linked to accelerated brain aging, i.e., neuroimaging-predicted age of brain is higher than chronological age. This report evaluated whether accelerated brain aging in diabetes is associated with higher levels of glycated hemoglobin (HbA1c) and increased mortality. METHODS: Brain age in Dallas Heart Study (n = 1949) was estimated using T1-weighted magnetic resonance imaging (MRI) scans and a previously-published Gaussian Processes Regression model. Accelerated brain aging (adjusted Δ brain age) was computed as follows: (brain age adjusted for chronological age)-minus-(chronological age). Mortality data until 12/31/2016 were obtained from the National Death Index. Associations of adjusted Δ brain age with diabetes in full sample and with HbA1c in individuals with diabetes were evaluated. Proportion of association between diabetes and all-cause mortality that was accounted for by adjusted Δ brain age were evaluated with mediation analyses. Covariates included Framingham 10-year risk score, race/ethnicity, income, body mass index, and history of myocardial infarction. RESULTS: Diabetes was associated with] higher adjusted Δ brain age [estimate= 1.79; 95% confidence interval (CI): 0.889, 2.68]. Among those with diabetes, higher HbA1c (log-base-2-transformed) was associated with higher adjusted Δ brain age (estimate=3.88; 95% CI: 1.47, 6.30). Over a median follow-up of 97.5 months, 24/246 (9.8%) with diabetes and 63/1703 (3.7%) without diabetes died. Adjusted Δ brain age accounted for 65.3 (95% CI: 39.3, 100.0)% of the association between diabetes and all-cause mortality. CONCLUSION: Accelerated brain aging may be related to poor glycemic control in diabetes and partly account for the association between diabetes and all-cause mortality.

Immune characterization of suicidal behavior in female adolescents.

Background: To address the need to identify potential markers of suicide behavior for adolescents (ages 12-18 years), mass cytometry was used to explore the cellular mechanisms that may underpin immune dysregulation in adolescents with recent suicidal behavior. Methods: Peripheral blood mononuclear cell (PBMC) samples from 10 female adolescents with a recent suicide attempt and 4 healthy female adolescents were used. A panel of 30 antibodies was analyzed using mass cytometry. We used two complementary approaches to 1) identify the cell types that significantly differed between the two groups, and 2) explore differences in the expression profile of markers on the surface of these cells. Mass cytometry data were investigated using (Center for Disease Control, 2021) Opt-SNE for dimension reduced (Curtin and Heron, 2019), FlowSOM for clustering, and (Bridge et al., 2006) EgdeR and SAM for statistical analyses. Results: Opt-SNE (a data driven clustering analysis) identified 15 clusters of distinct cell types. From these 15 clusters, cluster 5 (classical monocytes) had statistically lower abundance in suicidal adolescents as compared to healthy controls, whereas cluster 7 (gamma-delta T cells) had statistically higher abundance in suicidal adolescents compared to healthy control. Furthermore, across the 15 cell types, chemokine receptors, CXCR3 (cluster 5) and CXCR5 (clusters 4, 5, 7, and 9), had an elevated expression profile in those with a recent suicide attempt versus healthy controls. Conclusion: This report demonstrates the utility of high dimensional cell phenotyping in psychiatric disorders and provides preliminary evidence for distinct immune dysfunctions in adolescents with recent suicide attempts as compared to healthy controls.