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.

The Stimulant Selective Severity Assessment: A replication and exploratory extension of the Cocaine Selective Severity Assessment.

BACKGROUND: Cocaine and methamphetamine have similar withdrawal symptoms and many individuals concurrently use both substances; however, no measures concurrently assess withdrawal from multiple stimulants. OBJECTIVES: This study's aim was to explore the Stimulant Selective Severity Assessment (SSSA), a modified version of the Cocaine Selective Severity Assessment (CSSA), in a sample of stimulant users to determine if it can assess withdrawal symptoms in users of one or more stimulants. METHODS: Baseline data were analyzed from the STimulant Reduction Intervention using Dosed Exercise trial, a multisite randomized clinical trial that evaluated exercise versus health education on drug use outcomes in individuals with stimulant use disorders. Data were analyzed for internal consistency, construct validity, and scale dimensionality. RESULTS: Internal consistency for the full sample was good (α = 0.81; N = 302), with similar alphas in Cocaine (0.81; n = 177) and Cocaine/Other Stimulant (0.82; n = 92) groups, but with much lower alpha for the group without cocaine use (Other Stimulant, i.e., primarily methamphetamine, α = 0.66; n = 32). Support for construct validity was evidenced by significant positive correlations (r = 0.17 to 0.67) with measures of stimulant craving, depressive symptoms, and pain. Four factors were revealed. Conclusions/Importance: The Stimulant Selective Severity Assessment is a new measure that can be used to assess withdrawal symptoms in users of cocaine or cocaine plus methamphetamine, but it should not be administered to users of methamphetamine only.

Interleukin 17 selectively predicts better outcomes with bupropion-SSRI combination: Novel T cell biomarker for antidepressant medication selection.

BACKGROUND: Interleukin 17 (IL-17) is produced by highly inflammatory Th17 cells and has been implicated in pathophysiology of depression. IL-17 putatively disrupts the blood brain barrier and affects dopamine synthesis whereas dopamine has been shown to decrease Th17 cell-mediated immune response. Nevertheless, whether IL-17 can predict differential treatment outcome with antidepressants modulating dopaminergic transmission is unknown. METHODS: IL-17 and other T cell and non-T cell markers (Th1, Th2 and non-T cell markers) were measured with the Bioplex Pro™ human cytokine 27-plex kit in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants who provided baseline plasma and were treated with either bupropion plus escitalopram (bupropion-SSRI), escitalopram plus placebo (SSRI monotherapy), or venlafaxine plus mirtazapine (n=166). Differential changes in symptom severity and side-effects based on levels of IL-17 and other T and non-T cell markers were tested using a treatment-arm-by-biomarker interaction in separate repeated measures mixed model analyses. Subsequent analyses stratified by treatment arm were conducted for those markers with a significant interaction. RESULTS: There was a significant treatment-arm-by-IL-17 interaction for depression severity (p=0.037) but not for side-effects (p=0.28). Higher baseline IL-17 level was associated with greater reduction in depression severity (effect size=0.78, p=0.008) in the bupropion-SSRI but not the other two treatment arms. Other T and non-T cell markers were not associated with differential treatment outcomes. CONCLUSION: Higher baseline levels of IL-17 are selectively associated with greater symptomatic reduction in depressed patients treated with bupropion-SSRI combination.

Prediction of treatment outcomes to exercise in patients with nonremitted major depressive disorder.

BACKGROUND: Only one-third of patients with major depressive disorder (MDD) achieve remission with initial treatment. Consequently, current clinical practice relies on a "trial-and-error" approach to identify an effective treatment for each patient. The purpose of this report was to determine whether we could identify a set of clinical and biological parameters with potential clinical utility for prescription of exercise for treatment of MDD in a secondary analysis of the Treatment with Exercise Augmentation in Depression (TREAD) trial. METHODS: Participants with nonremitted MDD were randomized to one of two exercise doses for 12 weeks. Participants were categorized as "remitters" (≤12 on the IDS-C), nonresponders (<30% drop in IDS-C), or neither. The least absolute shrinkage and selection operator (LASSO) and random forests were used to evaluate 30 variables as predictors of both remission and nonresponse. Predictors were used to model treatment outcomes using logistic regression. RESULTS: Of the 122 participants, 36 were categorized as remitters (29.5%), 56 as nonresponders (45.9%), and 30 as neither (24.6%). Predictors of remission were higher levels of brain-derived neurotrophic factor (BDNF) and IL-1B, greater depressive symptom severity, and higher postexercise positive affect. Predictors of treatment nonresponse were low cardiorespiratory fitness, lower levels of IL-6 and BDNF, and lower postexercise positive affect. Models including these predictors resulted in predictive values greater than 70% (true predicted remitters/all predicted remitters) with specificities greater than 25% (true predicted remitters/all remitters). CONCLUSIONS: Results indicate feasibility in identifying patients who will either remit or not respond to exercise as a treatment for MDD utilizing a clinical decision model that incorporates multiple patient characteristics.

IMPROVEMENTS IN PSYCHOSOCIAL FUNCTIONING AND HEALTH-RELATED QUALITY OF LIFE FOLLOWING EXERCISE AUGMENTATION IN PATIENTS WITH TREATMENT RESPONSE BUT NONREMITTED MAJOR DEPRESSIVE DISORDER: RESULTS FROM THE TREAD STUDY.

BACKGROUND: Functional impairments often remain despite symptomatic improvement with antidepressant treatment, supporting the need for novel treatment approaches. The present study examined the extent to which exercise augmentation improved several domains of psychosocial functioning and quality of life (QoL) among depressed participants. METHODS: Data were collected from 122 partial responders to antidepressant medication. Participants were randomized to either high- (16 kcal/kg of weight/week [KKW]) or low-dose (4-KKW) exercise. Participants completed a combination of supervised and home-based exercise for 12 weeks. The Short-Form Health Survey, Work and Social Adjustment Scale, Social Adjustment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Satisfaction with Life Scale were collected at 6 and 12 weeks. Participants with data for at least one of the two follow-up time points (n = 106) were analyzed using a linear mixed model to assess change from baseline within groups and the difference between groups for each psychosocial outcome measure. All analyses controlled for covariates, including baseline depressive symptomatology. RESULTS: Participants experienced significant improvements in functioning across tested domains, and generally fell within a healthy range of functioning on all measures at Weeks 6 and 12. Although no differences were found between exercise groups, improvements were observed across a variety of psychosocial and QoL domains, even in the low-dose exercise group. CONCLUSIONS: These findings support exercise augmentation of antidepressant treatment as a viable intervention for treatment-resistant depression to improve function in addition to symptoms.

Baseline medical comorbidities in adults randomized in the STRIDE trial for psychostimulant use disorders.

BACKGROUND AND OBJECTIVES: Rates of medical illnesses may be higher among individuals with substance use disorders, complicating their care. This study aimed to expand the understanding of other medical conditions in treatment-seeking adults with stimulant use disorder (SUD) using data from Stimulant Reduction Intervention using Dose Exercise (STRIDE), a randomized, multisite trial investigating exercise augmentation of treatment as usual. METHODS: Utilizing STRIDE baseline data, we examined demographic and clinical characteristics based on the number of self-reported diagnosed medical conditions among participants meeting eligibility criteria (passing medical screening exam and maximal exercise test, non-opioid dependent, no concomitant beta blocker, or opioid replacement therapy). RESULTS: The majority (59%) of study participants (N = 302, mean age all participants = 39 years) did not report any history of other medical problems. Those with two or more conditions were older (mean age 46 years), reported more pain and worse physical functioning, and more psychiatric disorders (average 1.44). Hypertension was more common among participants with cocaine use disorders only (present in 16%) and liver disease was more common in those with cocaine plus other stimulant use disorders (present in 7%). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: In this sample, patients with SUD were in surprisingly good health. A subpopulation had an overall higher burden of illness with worsened physical and psychiatric functioning. Provision of coordinated care may optimize treatment outcomes for patients based on medical comorbidity burden as well as type of drug abused, although these conclusions should be considered preliminary as they are based on self-reported data.

Men and women from the STRIDE clinical trial: An assessment of stimulant abstinence symptom severity at residential treatment entry.

BACKGROUND AND OBJECTIVES: Gender-specific factors associated with stimulant abstinence severity were examined in a stimulant abusing or dependent residential treatment sample (N = 302). METHOD: Bivariate statistics tested gender differences in stimulant abstinence symptoms, measured by participant-reported experiences of early withdrawal. Multivariate linear regression examined gender and other predictors of stimulant abstinence symptom severity. RESULTS: Women compared to men reported greater stimulant abstinence symptom severity. Anxiety disorders and individual anxiety-related abstinence symptoms accounted for this difference. African American race/ethnicity was predictive of lower stimulant abstinence severity. DISCUSSION AND CONCLUSIONS: Women were more sensitive to anxiety-related stimulant withdrawal symptoms. SCIENTIFIC SIGNIFICANCE: Clinics that address anxiety-related abstinence symptoms, which more commonly occur in women, may improve treatment outcome.

Depressive Symptoms and Associated Clinical Characteristics in Outpatients Seeking Community-Based Treatment for Alcohol and Drug Problems.

BACKGROUND: Comorbid psychiatric and substance use disorders are common and associated with poorer treatment engagement, retention, and outcomes. This study examines the presence of depressive symptoms and the demographic and clinical correlates in a diverse sample of substance abuse treatment seekers to better characterize patients with co-occurring depressive symptoms and substance use disorders and understand potential treatment needs. METHODS: Baseline data from a randomized clinical effectiveness trial of a computer-assisted, Web-delivered psychosocial intervention were analyzed. Participants (N = 507) were recruited from 10 geographically diverse outpatient drug treatment programs. Assessments included the self-report Patient Health Questionnaire, and measures of coping strategies, social functioning, physical health status, and substance use. RESULTS: One fifth (21%; n = 106) of the sample screened positive for depression; those screening positive for depression were significantly more likely to screen positive for anxiety (66.9%) and posttraumatic stress disorder (PTSD; 42.9%). After controlling for anxiety and PTSD symptoms, presence of depressive symptoms remained significantly associated with fewer coping strategies (P = .001), greater impairment in social adjustment (P < .001), and poorer health status (P < .001), but not to days of drug use in the last 90 days (P = .14). CONCLUSIONS: Depression is a clinically significant problem among substance abusers, and, in this study, patients who screened positive for depression were more likely to have co-occurring symptoms of anxiety and PTSD. Additionally, the presence of depressive symptoms was associated with fewer coping strategies and poorer social adjustment. Coping skills are a significant predictor of addiction outcomes, and it may be especially important to screen for and enhance coping among depressed patients. Evidence-based interventions that target coping skills and global functioning among substance abusers with depressive symptoms may be important adjuncts to usual treatment.

Comorbidities and race/ethnicity among adults with stimulant use disorders in residential treatment.

Comorbid physical and mental health problems are associated with poorer substance abuse treatment outcomes; however, little is known about these conditions among stimulant abusers at treatment entry. This study compared racial and ethnic groups on baseline measures of drug use patterns, comorbid physical and mental health disorders, quality of life, and daily functioning among cocaine and stimulant abusing/dependent patients. Baseline data from a multi-site randomized clinical trial of vigorous exercise as a treatment strategy for a diverse population of stimulant abusers (N=290) were analyzed. Significant differences between groups were found on drug use characteristics, stimulant use disorders, and comorbid mental and physical health conditions. Findings highlight the importance of integrating health and mental health services into substance abuse treatment and could help identify potential areas for intervention to improve treatment outcomes for racial and ethnic minority groups.

Research staff training in a multisite randomized clinical trial: Methods and recommendations from the Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial.

BACKGROUND: Descriptions of and recommendations for meeting the challenges of training research staff for multisite studies are limited despite the recognized importance of training on trial outcomes. The STRIDE (STimulant Reduction Intervention using Dosed Exercise) study is a multisite randomized clinical trial that was conducted at nine addiction treatment programs across the United States within the National Drug Abuse Treatment Clinical Trials Network (CTN) and evaluated the addition of exercise to addiction treatment as usual (TAU), compared to health education added to TAU, for individuals with stimulant abuse or dependence. Research staff administered a variety of measures that required a range of interviewing, technical, and clinical skills. PURPOSE: In order to address the absence of information on how research staff are trained for multisite clinical studies, the current manuscript describes the conceptual process of training and certifying research assistants for STRIDE. METHODS: Training was conducted using a three-stage process to allow staff sufficient time for distributive learning, practice, and calibration leading up to implementation of this complex study. RESULTS: Training was successfully implemented with staff across nine sites. Staff demonstrated evidence of study and procedural knowledge via quizzes and skill demonstration on six measures requiring certification. Overall, while the majority of staff had little to no experience in the six measures, all research assistants demonstrated ability to correctly and reliably administer the measures throughout the study. CONCLUSIONS: Practical recommendations are provided for training research staff and are particularly applicable to the challenges encountered with large, multisite trials.

The Fibromyalgia Pain Experience: A Scoping Review of the Preclinical Evidence for Replication and Treatment of the Affective and Cognitive Pain Dimensions.

Fibromyalgia is a chronic, widespread pain disorder that is strongly represented across the affective and cognitive dimensions of pain, given that the underlying pathophysiology of the disorder is yet to be identified. These affective and cognitive deficits are crucial to understanding and treating the fibromyalgia pain experience as a whole but replicating this multidimensionality on a preclinical level is challenging. To understand the underlying mechanisms, animal models are used. In this scoping review, we evaluate the current primary animal models of fibromyalgia regarding their translational relevance within the affective and cognitive pain realms, as well as summarize treatments that have been identified preclinically for attenuating these deficits.

PlanoUp!: A pilot program for the identification and treatment of depression for youth in low-income secondary schools.

Rates of depression in youth are continuing to increase at a steady rate, yet these youth often do not receive mental health services (Bertha & Balázs, 2013; Thomas et al., 2011). Schools are an ideal setting to connect youth to mental health services; however, many barriers exist with respect to schools having adequate resources and access to the appropriate levels of services (Duong et al., 2021; Owens & Peltier, 2002). Schools may collaborate with local community providers with available resources to address these gaps. The current article describes the pilot of a school-based mental health promotion program intended to reduce depression in youth by promoting access to care through referrals to community providers. Data were collected, via self-report measures, every 3 months for 12 months from students from three middle and high schools in North Texas. The students (N = 88) enrolled in this program experienced significant reductions in their depression symptoms at the end of 12 months. This program highlights the importance of school-community partnerships to promote access to care to address mental health concerns. The results from our pilot study demonstrate the feasibility and the potential of school-based programs in improving the mental health of youth in schools through community partnership. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

A primary care first (PCP-first) model to screen and treat depression: A VitalSign6 report from a second cohort of 32,106 patients.

PURPOSE: This report from VitalSign6 project describes treatment selection, follow-up rates and remission outcomes by initial depression severity using the PCP-FIRST model. METHODS: This retrospective analysis included 32,106 patients aged ≥12 years screened with the Patient Health Questionnaire 2-item (PHQ-2) from November 2016 to July 2019 across 37 primary care clinics. PHQ-2 positive-screen patients (PHQ-2 ≥ 3) received 9-item PHQ (PHQ-9) and 7-item Generalized Anxiety Disorder scales, clinician assessments, and evaluation for pharmacotherapy management with measurement-based care (MBC). RESULTS: Of PHQ-2 screened patients, 18.7% (5994/32,106) were positive and received a PHQ-9. Of 5994 patients with PHQ-9, 2571 received a clinical diagnosis of depression of whom, 333 had none-mild depression (PHQ-9 < 10) and 2238 had moderate-severe depression (PHQ-9 ≥ 10). Of the 333 patients with none-mild depression and 2238 patients with moderate-severe depression, 266 and 1929 had at least 18 weeks of data available. Of these, 54.9% (146/266) with none-mild depression and 69.1% (1332/1929) with moderate-severe depression were started on pharmacotherapy. Of the 1478 patients with clinical diagnosis of depression, initiated on pharmacotherapy, 1046 returned for ≥1 follow-up and 616 returned for ≥3 follow-ups over 18 weeks. Of the 1046 patients with ≥1 follow-up visit within 18 weeks, remission rates for patients with mild depression, moderate-severe depression, and overall were 55.6% (66/99), 30% (282/941), and 32.4% (338/1040) respectively. CONCLUSIONS: Despite this being a real-world, usual care sample, remission outcomes exceed real world remission rate expectations of 6% in primary care.

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.

Determining the primary endpoint for a stimulant abuse trial: lessons learned from STRIDE (CTN 0037).

BACKGROUND: No consensus is available for identifying the best primary outcome for substance use disorder trials, making interpretation across trials difficult. Abstinence is the most desirable treatment outcome although a wide variety of other endpoints have been used. OBJECTIVES: This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common endpoint across trials will facilitate comparisons of treatment efficacy. METHODS: Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity, and tests of clinical meaningfulness. CONCLUSION: We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back interview conducted three times a week with recall aided by a take-home Substance Use Diary. To improve the accuracy of the self-reported drug use, the results of qualitative urine drug screens will be used in conjunction with the Time Line Follow Back results. SCIENTIFIC SIGNIFICANCE: There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended candidate endpoint be considered. However, the study design and goals ultimately must guide the final decision.

Dorsolateral Prefrontal Cortex and Subcallosal Cingulate Connectivity Show Preferential Antidepressant Response in Major Depressive Disorder.

BACKGROUND: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. METHODS: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. RESULTS: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). CONCLUSIONS: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.

Identifying and responding to trial implementation challenges during multisite clinical trials.

INTRODUCTION: The National Drug Abuse Treatment Clinical Trials Network (CTN) was initiated by the National Institute on Drug Abuse (NIDA) in 2000 with the aim of improving substance use treatment and reducing the time between the discovery of effective treatments and their implementation into clinical practice. While initial trials were conducted almost exclusively in specialty addiction treatment settings, the CTN began evolving strategically in 2010 to conduct research in general medical settings, including healthcare systems, primary care settings, emergency departments, and pharmacies, to broaden impact. The advantages of a research network like the CTN is not only the collective content expertise that investigators contribute to the network, but the collective experience gained by conducting studies in the network and then applying those lessons to future studies. OBJECTIVE: To summarize trial implementation challenges encountered, and the process by which solutions were identified and implemented, within one of the last early-phase CTN Stage II behavioral intervention studies conducted in a specialty addiction treatment setting. METHOD AND RESULTS: We describe the implementation of the CTN-0037 STimulant Reduction Intervention using Dosed Exercise (STRIDE) trial. Issues encountered during study implementation are categorized into four major areas, described in terms useful to future study teams: 1) study team infrastructure challenges, 2) participant- and site- level challenges, 3) intervention-related challenges, and 4) longitudinal study design challenges. Potential consequences of identified problems and the solutions developed to manage these problems are discussed within the context of these four areas. We propose how to extend these implementation lessons and apply them in other healthcare settings to expand the CTN. CONCLUSIONS: Effective study management allows for flexible, collaborative solutions to expected and unexpected obstacles to study success. Implementation strategies derived from the first 15 to 20 years of CTN studies are a result of working with providers and participants, and the ongoing collaboration among CTN investigators and network staff. Timely identification and response to problems during study implementation are critical to the success of a trial, regardless of its design. We believe a collaborative approach to identifying and responding to study implementation challenges will increase the likelihood of successful adoption of relevant, efficacious interventions. As the CTN continues to expand, the wealth of successful trial implementation strategies developed during the first 20 years of the CTN need to be applied and adapted to studies in broader network settings, and considered in conjunction with more formalized implementation science processes that are currently available.

Dysfunctional adaptive immune response in adolescents and young adults with suicide behavior.

BACKGROUND: Immune system dysfunction has been implicated in the pathophysiology of suicide behavior. Here, we conducted an exploratory analysis of immune profile differences of three groups of adolescents and young adults (ages 10-25 years): healthy controls (n = 39), at risk of major depressive disorder (MDD; at-risk, n = 33), and MDD with recent suicide behavior/ ideation (suicide behavior, n = 37). METHODS: Plasma samples were assayed for chemokines and cytokines using Bio-Plex Pro Human Chemokine 40-plex assay. Log-transformed cytokine and chemokine levels were compared after controlling for age, gender, body mass index, race, ethnicity, and C-reactive protein (CRP) levels. In post-hoc analyses to understand the effect of dysregulated immune markers identified in this exploratory analysis, their association with autoantibodies was tested in an unrelated sample (n = 166). RESULTS: Only levels of interleukin 4 (IL-4) differed significantly among the three groups [false discovery rate (FDR) adjusted p = 0.0007]. Participants with suicide behavior had lower IL-4 [median = 16.8 pg/ml, interquartile range (IQR) = 7.9] levels than healthy controls (median = 29.1 pg/ml, IQR = 16.1, effect size [ES] = 1.30) and those at-risk (median = 24.4 pg/ml, IQR = 16.3, ES = 1.03). IL-4 levels were negatively correlated with depression severity (r= -0.38, p = 0.024). In an unrelated sample of outpatients with MDD, levels of IL-4 were negatively correlated (all FDR p < 0.05) with several autoantibodies [54/117 in total and 12/18 against innate immune markers]. CONCLUSIONS: Adolescent and young adult patients with recent suicide behavior exhibit lower IL-4 levels. One biological consequence of reduced IL-4 levels may be increased risk of autoimmunity.

Effect of Intrinsic Patterns of Functional Brain Connectivity in Moderating Antidepressant Treatment Response in Major Depression.

OBJECTIVE: Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo. METHODS: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest-based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms. RESULTS: Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity. CONCLUSIONS: This study identified specific functional network-based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder.