Reward Behavior Disengagement, a Neuroeconomic Model-Based Objective Measure of Reward Pathology in Depression: Findings from the EMBARC Trial.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

Suicide risk assessment and suicide risk management protocol for the Texas Youth Depression and Suicide Research Network.

Introduction: Suicide prevention research is a national priority, and national guidance includes the development of suicide risk management protocols (SRMPs) for the assessment and management of suicidal ideation and behavior in research trials. Few published studies describe how researchers develop and implement SRMPs or articulate what constitutes an acceptable and effective SRMP. Methods: The Texas Youth Depression and Suicide Research Network (TX-YDSRN) was developed with the goal of evaluating screening and measurement-based care in Texas youth with depression or suicidality (i.e., suicidal ideation and/or suicidal behavior). The SRMP was developed for TX-YDSRN through a collaborative, iterative process, consistent with a Learning Healthcare System model. Results: The final SMRP included training, educational resources for research staff, educational resources for research participants, risk assessment and management strategies, and clinical and research oversight. Conclusion: The TX-YDSRN SRMP is one methodology for addressing youth participant suicide risk. The development and testing of standard methodologies with a focus on participant safety is an important next step to further the field of suicide prevention research.

Psychometrics of the Concise Health Risk Tracking Self-Report (CHRT-SR16) Assessment of Suicidality in a Sample of Adults with Moderate to Severe Methamphetamine Use Disorder: Findings from the ADAPT-2 Randomized Trial.

Background: The co-occurrence of suicidality and substance use disorders has been well established, but rating scales to examine suicidal behavior and risk are sparse among participants with substance use disorders. We examined the psychometric properties of the 16-item Concise Health Risk Tracking Scale - Self Report (CHRT-SR16) to measure suicidality among adults with moderate-to-severe methamphetamine use disorder. Methods: Participants (n = 403) with moderate-to-severe methamphetamine use disorder completed the CHRT-SR16 as part of a randomized, double-blind, placebo-controlled pharmacotherapy trial. The CHRT-SR16 factor structure was assessed using confirmatory factor analysis (CFA). Internal consistency was estimated with coefficients alpha (α) and omega (ω), test-retest reliability with intraclass correlation coefficient (ICC) and standard error of measurement, and convergent validity using Spearman's ρ rank order correlation coefficient test between CHRT-SR16 factors and the Patient Health Questionnaire (PHQ-9). The analyses utilized baseline and week 1 data (for test-retest reliability only). Results: CFA revealed a seven-factor model of Pessimism, Helplessness, Social Support, Despair, Impulsivity, Irritability, and Suicidal Thoughts as the best-fitting model. The CHRT-SR16 also exhibited strong internal consistency (α = 0.89; ω = 0.89), test-retest reliability (ICC = 0.78) and convergent validity with the PHQ-9 total score (ρ = 0.62). Conclusion: The CHRT-SR16 showed strong psychometric properties in a sample of participants with primary methamphetamine use disorder. Clinicaltrialsgov Identifier: NCT03078075.

Psychometric properties of the Treatment Effectiveness Assessment in methamphetamine use disorder.

INTRODUCTION: The ability for people living with stimulant use disorder to live meaningful lives requires not only abstinence from addictive substances, but also healthy engagement with their community, lifestyle practices, and overall health. The Treatment Effectiveness Assessment (TEA) assesses components of recovery consisting of four functional domains: substance use, health, lifestyle, and community. This secondary data analysis of 403 participants with severe methamphetamine use disorder tested the reliability and validity of the TEA. METHODS: Participants were enrolled in the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for methamphetamine use disorder. The study used total TEA and domain scores at baseline to assess factor structure and internal consistency, as well as construct validity related to substance cravings (visual analog scale [VAS]), quality of life (quality-of-life assessment [QoL]), mental health (Patient Health Questionnaire-9 [PHQ-9], Concise Health Risk Tracking Scale Self-Report [CHRT-SR16]), and social support (CHRT-SR16). RESULTS: Individual TEA items showed moderate to large correlations with each other (r = 0.27-0.51; p < .001), and strong correlations to the total score (r = 0.69-0.78; p < .001). Internal consistency was strong (coefficient α = 0.73 [0.68-0.77]; coefficient ω = 0.73 [0.69-0.78]). Construct validity was acceptable, with the strongest correlation between the TEA Health item and the general health status item on the QoL (r = 0.53, p < .001). CONCLUSIONS: TEA has acceptable levels of reliability and validity supporting prior similar findings in a sample of participants with moderate to severe methamphetamine use disorder. Results from this study provide support for its use in assessing clinically meaningful changes beyond simply reduced substance use.

Adaption of tele-behavioral activation to increase physical activity in depression: Protocol for iterative development and evaluation.

Background: Poor treatment outcomes, disease recurrence, and medical co-morbidities contribute to the significant burden caused by depressive disorders. Increasing physical activity in persons with depression has the potential to improve both depression treatment outcomes and physical health. However, evidence for physical activity interventions that can be delivered as part of depression treatment remains limited. This study will examine a Behavioral Activation teletherapy intervention adapted to include a specific focus on increasing physical activity. Methods: The two-phase study will include a preliminary pilot study (n = 15) to evaluate and refine the manualized intervention using a mixed-methods approach followed by a single-arm study to evaluate feasibility and preliminary efficacy of the adapted BA teletherapy. Participants will be adults, age 18-64, with moderate to severe depressive symptoms (defined as a PHQ-9 score ≥10) and who currently engage in 90 min or less of moderate-to-vigorous physical activity. Individuals will be excluded if they have a current or past manic or hypomanic episode, psychosis, schizophrenia or schizophreniform disorder, or active suicidal ideation, or if not medically-cleared to exercise. The BA intervention will consist of 8 weekly sessions, followed by 2 bi-weekly booster sessions. Feasibility outcomes will include metrics of screening, enrollment, intervention adherence and fidelity, and participant retention. Intervention preliminary efficacy will be evaluated through assessment of changes in depressive symptoms and moderate-to-vigorous physical activity. Conclusion: Data from this trial will be used to support the conduct of a randomized controlled trial to evaluate the efficacy of the adapted BA intervention.

Neural substrates of emotional conflict with anxiety in major depressive disorder: Findings from the Establishing Moderators and biosignatures of Antidepressant Response in Clinical Care (EMBARC) randomized controlled trial.

BACKGROUND: The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict. METHODS: A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors. RESULTS: During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor. CONCLUSIONS: Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli.

Burnout During the COVID-19 Pandemic: Descriptive and Predictive Data from a Survey of Psychologists at a Single Academic Medical Center.

OBJECTIVE: Burnout in academic medicine has been widely studied, but most work has been conducted among physicians. Psychologists in academic medicine have unique burnout factors. Therefore, investigating the prevalence and predictors of burnout among psychologists in academic medicine during the COVID-19 pandemic represents an important addition to the literature. METHODS: Sixty-two psychologists responded to burnout-related items in a larger, 40-item Psychiatry Department climate survey conducted from October to November 2020. Five items from the MINI-Z survey were administered to examine control over workload and sufficiency of documentation time as predictors of both continuous and dichotomously defined burnout. Linear and logistic regression was employed with years as a faculty member entered as a covariate. RESULTS: Slightly less than half (48.4%) of respondents met dichotomous criteria for burnout. Faculty with fewer years of experience scored higher on their level of continuous burnout. Both control over workload and sufficiency of time for documentation were independent predictors of continuous burnout, but only control over workload remained a statistically significant predictor in a simultaneous model. Control over workload was a significant predictor in dichotomous models but did not remain so once sufficiency of documentation time was also added. CONCLUSION: Burnout prevalence among psychologists was comparable to rates among physicians at other institutions, even when examined during the COVID-19 pandemic. Academic medicine administrators and organizational leaders should consider policies and programming to increase control over workload, especially among junior psychologist faculty.

Psychometric properties of the Generalized Anxiety Disorder 7-item scale in youth: Screening in a primary care sample.

BACKGROUND: Anxiety disorders in youth are frequently underdiagnosed and untreated, partly due to a lack of screening in primary care. The Generalized Anxiety Disorder 7-item (GAD-7) scale is a brief self-report measure designed to screen for anxiety in primary care settings. However, little is known about the psychometrics of this scale with adolescents. METHODS: Participants included 579 youth age 11 to 17 years who received screening for depression in a primary care setting through a web-based application, VitalSign6, over a 4-year period. Psychometric analyses were completed based on classical test theory (CTT) and item response theory (IRT). RESULTS: Using CTT and IRT methods, the GAD-7 has a unidimensional structure with good psychometric properties. In addition, the IRT analysis demonstrates that items 1 and 2 are strongly associated with the total score, and thus are good choices as a 2-item screening tool. Convergent validity was demonstrated, with high correlations between the GAD-7 and other measures of anxiety, and discriminant validity was also demonstrated, with low correlations to measures of other psychological states. CONCLUSIONS: This psychometric evaluation of the GAD-7 provides support for the utility of this measure with adolescents. The GAD-2 is a good estimate of GAD-7 total score.

Preliminary Evidence for Sociotropy and Autonomy in Relation to Antidepressant Treatment Outcome.

Sociotropy and autonomy are cognitive-personality styles that have been hypothesized to confer vulnerability to different presentations of major depressive disorder (MDD), which may respond differentially to treatment. Specifically, the profile of low sociotropy and high autonomy is hypothesized to indicate a positive response to antidepressant medication. The current study examines sociotropy and autonomy in relation to sertraline treatment response in individuals with MDD. As part of an ancillary study to the larger Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) project, individuals with MDD participated in an 8-week trial of sertraline and completed a self-report questionnaire of sociotropy and autonomy. Discriminant function analyses were used to examine whether sociotropy and autonomy scores could distinguish antidepressant treatment responders (determined by a 50% or greater reduction in depressive symptoms) from non-responders. The sociotropy scale successfully discriminated sertraline treatment responders from non-responders. Further, lower sociotropy was associated with greater improvements in depressive symptomology following sertraline treatment. The current findings suggest individuals with MDD characterized by low sociotropy are more likely to benefit from sertraline. Given the promising results of the Sociotropy-Autonomy Scale in discriminating treatment responders from non-responders, the low resources necessary for administration, and the ease of translation into routine clinical care, the scale warrants further research attention.

Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder.

OBJECTIVE: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. METHODS: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). RESULTS: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. CONCLUSION: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.

Diagnosis and Management of Depression in Patients With Kidney Disease.

Depression disproportionately affects patients with kidney disease, including those with nondialysis chronic kidney disease, end-stage kidney disease requiring dialysis, and kidney transplant recipients. Patients across the spectrum of kidney disease should be screened for depression every 6 to 12 months using self-report questionnaires, followed by an interview with a clinician to confirm the presence of sadness or anhedonia when depressive symptoms are identified. Pharmacologic treatment with selective serotonin reuptake inhibitors has not consistently shown benefit compared with placebo and may be associated with serious adverse outcomes including cardiovascular events, bleeding, and fractures. However, based on the availability of alternative therapies, a watchful trial with close monitoring for therapeutic and adverse effects is reasonable. Several clinical trials have suggested that cognitive behavioral therapy and physical activity improve depressive symptoms when compared with a control group. Given the low risk associated with these therapies, they should be recommended to patients who have access and are amenable to such interventions. Future trials are needed to study therapeutic options for depression in nondialysis chronic kidney disease, peritoneal dialysis, or kidney transplant recipients, as well as alternative pharmacologic therapy and combination therapies. Given improvement in depressive symptoms with placebo in existing trials, inclusion of a control group is paramount.

Anger attacks are associated with persistently elevated irritability in MDD: findings from the EMBARC study.

BACKGROUND: This report tests the association of self-reported symptoms of irritability with overt behavior of anger attacks (uncharacteristic sudden bouts of anger that are disproportionate to situation and associated with autonomic activation). METHODS: Participants of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care study who completed Massachusetts General Hospital Anger Attacks questionnaire were included (n = 293). At each visit, the 17-item Hamilton Depression Rating Scale and the 16-item Concise Associated Symptom Tracking scale were used to measure depression, anxiety, and irritability. In those with anger attacks present v. those without anger attacks, separate t tests and mixed model analyses compared afore-mentioned symptoms at baseline and changes with treatment respectively. As anger attacks may occur without aggressive behaviors, analyses were repeated based only on the presence of aggressive behaviors. RESULTS: At baseline, those with anger attacks (n = 109) v. those without anger attacks (n = 184) had similar levels of depression but higher levels of irritability [effect size (d) = 0.80] and anxiety (d = 0.32). With acute-phase treatment, participants with anger attacks experienced a greater reduction in irritability (p < 0.001) but not in depression (p = 0.813) or anxiety (p = 0.771) as compared to those without anger attacks. Yet, irritability levels at week-8 were higher in those with anger attacks (d = 0.32) than those without anger attacks. Similar results were found in participants with aggressive behaviors. CONCLUSIONS: The presence of anger attacks in outpatients with major depressive disorder may identify a sub-group of patients with persistently elevated irritability.

The risk of depression among racially diverse people living with HIV: the impact of HIV viral suppression.

Understanding the correlates of depression in HIV patients can help identify groups whose members are at increased risk for depression. We conducted a cross-sectional retrospective study among racially diverse, indigent patients living with HIV (PLWH) who were obtaining care in an urban safety-net hospital system and had completed a Patient Health Questionnaire-9 (PHQ-9) in 2014 or 2015. We collected demographics, HIV risk factors, HIV viral loads, CD4 counts, missed visits, and emergency department (ED) visits. Data from the Substance Abuse and Mental Illness Symptoms Screener (SAMISS) were abstracted. Missing data on substance use and CD4 cell counts were imputed to examine the odds of depression (PHQ-9 ≥ 10) by multivariable analysis for a complete case and sensitivity analysis. Stratified analysis by HIV viral suppression (VS) was used to determine the odds of depression among subgroups. Of the 5126 HIV patients (70.8% male,56.3% Black, 44.6% MSM, 6.0% IDU), 1271 (24.8%) experienced depression (PHQ ≥ 10). In a multivariable logistic model female gender, White race, injection drug use (IDU) or men who have sex with men (MSM) as an HIV risk factor, making ≥1 ED visit, having missed any HIV visit, having AIDS, and having a positive drug screen by SAMISS increased the odds for depression. Those who had achieved HIV VS or received efavirenz had lower odds of depression. Even among those with AIDS, those failing to achieve VS were at increased odds for depression, whereas those achieving VS were not. Moderate to severe depression is prevalent among PLWH. Among those with AIDS, HIV VS modifies the odds of depression.

Two Trajectories of Depressive Symptom Reduction Throughout Behavioral Activation Teletherapy Among Underserved, Ethnically Diverse, Primary Care Patients: A VitalSign6 Report.

While prior research has investigated trajectories of depressive symptom change throughout psychotherapy, such work has not been conducted exclusively among underserved patients receiving brief Behavioral Activation (BA) teletherapy, intervention modifications that should reduce barriers to therapy initiation and engagement. The current project used cluster analysis to determine discrete groups of symptom change among patients receiving an 8-session BA teletherapy intervention, and analyzed whether demographic and clinical characteristics were associated with group membership. Data from 105 patients referred from charity primary care clinics and receiving at least two therapy sessions were analyzed. Patients were predominantly female and Latina. The 9-item Patient Health Questionnaire (PHQ-9) was the outcome. Two categories were determined: a larger group (N = 61) demonstrating initially less severe symptoms and experiencing a gradual recovery, and a smaller group beginning with more severe symptoms, and experiencing a steeper recovery. In both groups, a majority of participants experienced at least a 5-point drop in depressive symptoms, while in the latter group, a majority of patients achieved depressive symptom remission (PHQ-9 < 5). Monolingual Spanish speakers were more likely to be in the former group, but no other demographic or clinical characteristics were associated with group membership. In both groups, a majority of the symptom reduction occurred by sessions 4-6. Therefore, two categories of depressive symptom change, slow responders and rapid responders, occur among patients receiving a brief BA teletherapy intervention. No demographic differences aside from primary language, nor any clinical characteristics, distinguish group membership, suggesting similar patterns of symptom reduction among a primarily underserved sample.

Positive and negative valence systems in major depression have distinct clinical features, response to antidepressants, and relationships with immunomarkers.

BACKGROUND: Heterogeneity in major depressive disorder (MDD) is well recognized but not well understood. Core depressive features are reward and emotional symptoms, which reflect dysfunctions in the positive valence (PV) and negative valence (NV) systems, respectively. This study assessed whether PV and NV systems (based on selected symptoms) were associated with different clinical features, antidepressant response, and levels of immunomarkers in adults with MDD. METHODS: These analyses used data from combining medications to enhance depression outcomes study (N = 665; n = 166 for immunomarkers). PV and NV symptom scores were extracted from the clinician-rated 30-item Inventory of Depressive Symptomatology. Correlational analyses were conducted. RESULTS: PV and NV symptom scores were substantially associated with different clinical features. PV symptoms (impaired motivation, impaired energy, and anhedonia) were independently associated with female gender (p < .001), older age (p = .012), and higher cognitive and physical impairment (p < .001) according to the 7-item Cognitive and Physical Functioning Questionnaire. Conversely, NV symptoms (anxiety and interpersonal sensitivity) were independently associated with younger age (p = .013), more anxious comorbidities (p = .001 for generalized anxiety disorder and p = .002 for social phobia) and other commonly associated noncriterion symptoms (p < .001). Overall, PV symptoms were more responsive to antidepressants than NV symptoms (p < .0001; Cohen's d = .455). A PV symptom score was positively correlated with the concentration of three proinflammatory and one anti-inflammatory factor. In contrast, an NV symptom score was negatively associated with only one proinflammatory immunomarker. CONCLUSIONS: PV and NV system functions appear to be reflected in selected clinical symptoms that differentially relate to other clinical features, treatment outcomes, and immunological function.

An electroencephalographic signature predicts antidepressant response in major depression.

Antidepressants are widely prescribed, but their efficacy relative to placebo is modest, in part because the clinical diagnosis of major depression encompasses biologically heterogeneous conditions. Here, we sought to identify a neurobiological signature of response to antidepressant treatment as compared to placebo. We designed a latent-space machine-learning algorithm tailored for resting-state electroencephalography (EEG) and applied it to data from the largest imaging-coupled, placebo-controlled antidepressant study (n = 309). Symptom improvement was robustly predicted in a manner both specific for the antidepressant sertraline (versus placebo) and generalizable across different study sites and EEG equipment. This sertraline-predictive EEG signature generalized to two depression samples, wherein it reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation treatment outcome. Furthermore, we found that the sertraline resting-state EEG signature indexed prefrontal neural responsivity, as measured by concurrent transcranial magnetic stimulation and EEG. Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression.

Comprehensive phenotyping of depression disease trajectory and risk: Rationale and design of Texas Resilience Against Depression study (T-RAD).

Depression has a chronic and recurrent course often with early onset and is the leading cause of disability worldwide. In contrast to diagnoses for other conditions which rely on precise medical tests, the diagnosis of depression still focuses exclusively on symptom reports. As a result, heterogeneous patient groups are included under broad categories. Furthermore, in the absence of companion diagnostic tests, choosing specific treatments for patients remains imprecise with only one-third of patients entering remission with initial treatment, with others requiring multiple intervention steps to achieve remission. In addition to improving treatment outcomes, disease prevention is essential to reduce overall disease burden. Adolescence is a critical window where complex emotional, social, familial, and biological shifts may predispose to lifelong depression. Thus, personalized medicine, integrating individual variability in genes, brain function, and clinical phenotypes, can offer a comprehensive approach to provide precise diagnosis, novel drug development, optimal treatment assignment, and prevention of illness and its associated burden. Texas Resilience Against Depression study (T-RAD) encompasses two natural history, longitudinal (10 + years), prospective studies (D2K and RAD), each enrolling 2500 participants. The D2K study follows participants (ages 10 years and older) who have a current or past diagnosis of depression or bipolar disorder. The RAD study follows participants aged 10-24 years who are at risk for depression but not yet suffering from the disease. The T-RAD study will help to uncover the socio-demographic, lifestyle, clinical, psychological, and neurobiological factors that contribute to mood disorder onset, recurrence, progression, and differential treatment response.

Cortical Connectivity Moderators of Antidepressant vs Placebo Treatment Response in Major Depressive Disorder: Secondary Analysis of a Randomized Clinical Trial.

Importance: Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice. Objective: To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment. Design, Setting, and Participants: In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019. Interventions: Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks. Main Outcomes and Measures: Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit. Results: Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points. Conclusions and Relevance: These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT01407094.

A Structured Approach to Detecting and Treating Depression in Primary Care: VitalSign6 Project.

PURPOSE: This report describes outcomes of an ongoing quality-improvement project (VitalSign6) in a large US metropolitan area to improve recognition, treatment, and outcomes of depressed patients in 16 primary care clinics (6 charity clinics, 6 federally qualified health care centers, 2 private clinics serving low-income populations, and 2 private clinics serving patients with either Medicare or private insurance). METHODS: Inclusion in this retrospective analysis was restricted to the first 25,000 patients (aged ≥12 years) screened with the 2-item Patient Health Questionnaire (PHQ-2) in the aforementioned quality-improvement project. Further evaluations with self-reports and clinician assessments were recorded for those with positive screen (PHQ-2 >2). Data collected from August 2014 though November 2016 were available at 3 levels: (1) initial PHQ-2 (n = 25,000), (2) positive screen (n = 4,325), and (3) clinician-diagnosed depressive disorder with 18 or more weeks of enrollment (n = 2,160). RESULTS: Overall, 17.3% (4,325/25,000) of patients screened positive for depression. Of positive screens, 56.1% (2,426/4,325) had clinician-diagnosed depressive disorder. Of those enrolled for 18 or more weeks, 64.8% were started on measurement-based pharmacotherapy and 8.9% referred externally. Of the 1,400 patients started on pharmacotherapy, 45.5%, 30.2%, 12.6%, and 11.6% had 0, 1, 2, and 3 or more follow-up visits, respectively. Remission rates were 20.3% (86/423), 31.6% (56/177), and 41.7% (68/163) for those with 1, 2, and 3 or more follow-up visits, respectively. Baseline characteristics associated with higher attrition were: non-white, positive drug-abuse screen, lower depression/anxiety symptom severity, and younger age. CONCLUSION: Although remission rates are high in those with 3 or more follow-up visits after routine screening and treatment of depression, attrition from care is a significant issue adversely affecting outcomes.