Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

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.

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 Concise Health Risk Tracking Self-Report (CHRT-SR) assessment of suicidality in depressed outpatients: A psychometric evaluation.

BACKGROUND: The 12-item Concise Health Risk Tracking Self-Report (CHRT-SR12 ) is a brief, self-report measure that systematically assesses both suicidal thinking and associated thoughts that may indicate the propensity for suicidal acts. It can be used as a tool to both assess risk and guide treatment interventions targeting associated cognitions. METHODS: This report used acute treatment data from a clinically representative sample of outpatients with nonpsychotic major depressive disorder (N = 665) participating in the Combining Medications to Enhance Depression Outcomes trial, who received up to 12 weeks of escitalopram, escitalopram plus bupropion SR, or venlafaxine XR plus mirtazapine. Outcome assessors and patients were masked to treatment. RESULTS: Factor analysis of CHRT-SR12 confirmed that the 12 items have higher order structure with two subscales (Propensity, Suicidal Thoughts) and a total score. Internal consistencies were acceptable for both subscales and total score. All three scales were modestly correlated with overall depression severity (r = 0.54 to r = 0.21) and highly discriminating among patients grouped by suicide item ratings on three different depressive symptom ratings. The three scales also distinguished change over the acute phase treatment for those with different levels of baseline suicidal ideation (measured by 30-item Inventory of Depressive Symptomatology (item 18) and for those with change in suicidal ideation (baseline to last visit). CONCLUSIONS: The CHRT-SR12 has good to excellent psychometric properties and is sensitive to change in suicidal thinking and propensity toward suicidal behavior in outpatients with major depressive disorder. It allows for the monitoring of thoughts and feelings associated with increased suicidal risk as well as levels of thoughts about suicide.

A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial.

BACKGROUND: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials. METHODS: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission. RESULTS: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level. CONCLUSION: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders.

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.

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.

How video image size interacts with evidence strength, defendant emotion, and the defendant-victim relationship to alter perceptions of the defendant.

Courtroom video presentations can range from images on small screens installed in the jury box to images on courtroom video monitors or projection screens. Does video image size affect jurors' perceptions of information presented during trials? To investigate this we manipulated video image size as well as defendant emotion level presented during testimony (low, moderate), the defendant-victim relationship (spouses, strangers), and the strength of the evidence (weak, strong). Participants (N=263) read a case and trial summary, watched video of defendant testimony, and then answered a questionnaire. Larger screens generally accentuated what was presented (e.g., made stronger evidence seem stronger and weaker evidence seem weaker), acting mainly upon trial outcome variables (e.g., verdict). Non-trial outcomes (e.g., defendant credibility) were generally affected by defendant emotion level and the defendant-victim relationship. Researchers and attorneys presenting video images need to recognize that respondents may evaluate videotaped trial evidence differently as a function of how video evidence is presented.

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.

Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary porphyrins.

BACKGROUND: Recent studies suggest that children diagnosed with an autism spectrum disorder (ASD) have significantly increased levels of urinary porphyrins associated with mercury (Hg) toxicity, including pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin (cP), compared to typically developing controls. However, these initial studies were criticized because the controls were not age- and gender-matched to the children diagnosed with an ASD. METHODS: Urinary porphyrin biomarkers in a group of children (2-13 years of age) diagnosed with an ASD (n= 20) were compared to matched (age, gender, race, location, and year tested) group of typically developing controls (n= 20). RESULTS: Participants diagnosed with an ASD had significantly increased levels of 5cxP, prcP, and cP in comparison to controls. No significant differences were found in non-Hg associated urinary porphyrins (uroporphyrins, hexacarboxyporphyrin, and heptacarboxyporphyrin). There was a significantly increased odds ratio for an ASD diagnosis relative to controls among study participants with precoproporphyrin (odds ratio = 15.5, P < 0.01) and coproporphyrin (odds ratio = 15.5, P < 0.01) levels in the second through fourth quartiles in comparison to the first quartile. CONCLUSION: These results suggest that the levels of Hg-toxicity-associated porphyrins are higher in children with an ASD diagnosis than controls. Although the pattern seen (increased 5cxP, prcP, and cP) is characteristic of Hg toxicity, the influence of other factors, such as genetics and other metals cannot be completely ruled out.

Prospective trial of equine-assisted activities in autism spectrum disorder.

BACKGROUND: Anecdotal reports and some studies suggest that equine-assisted activities may be beneficial in autism spectrum disorders (ASD). OBJECTIVE: To examine the effects ofequine-assisted activities on overall severity of autism symptoms using the Childhood Autism Rating Scale (CARS) and the quality ofparent-child interactions using the Timberlawn Parent-Child Interaction Scale. In addition, this study examined changes in sensory processing, quality of life, and parental treatment satisfaction. DESIGN AND PARTICIPANTS: Children with ASD were evaluated at four time points: (1) before beginning a 3-to-6 month waiting period, (2) before starting the riding treatment, and (3) after 3 months and (4) 6 months of riding. Twenty-four participants completed the waiting list period and began the riding program, and 20 participants completed the entire 6 months of riding. Pretreatment was compared to posttreatment with each child acting as his or her own control. RESULTS: A reduction in the severity of autism symptoms occurred with the therapeutic riding treatment. There was no change in CARS scores during the pretreatment baseline period; however, there was a significant decrease after treatment at 3 months and 6 months of riding. The Timberlawn Parent-Child Interaction Scale showed a significant improvement in Mood and Tone at 3 months and 6 months of riding and a marginal improvement in the reduction of Negative Regard at 6 months of riding. The parent-rated quality of life measure showed improvement, including the pretreatment waiting period. All of the ratings in the Treatment Satisfaction Survey were between good and very good. CONCLUSION: These results suggest that children with ASD benefit from equine-assisted activities.

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.

A computerized decision support system for depression in primary care.

OBJECTIVE: In 2004, results from The Texas Medication Algorithm Project (TMAP) showed better clinical outcomes for patients whose physicians adhered to a paper-and-pencil algorithm compared to patients who received standard clinical treatment for major depressive disorder (MDD). However, implementation of and fidelity to the treatment algorithm among various providers was observed to be inadequate. A computerized decision support system (CDSS) for the implementation of the TMAP algorithm for depression has since been developed to improve fidelity and adherence to the algorithm. METHOD: This was a 2-group, parallel design, clinical trial (one patient group receiving MDD treatment from physicians using the CDSS and the other patient group receiving usual care) conducted at 2 separate primary care clinics in Texas from March 2005 through June 2006. Fifty-five patients with MDD (DSM-IV criteria) with no significant difference in disease characteristics were enrolled, 32 of whom were treated by physicians using CDSS and 23 were treated by physicians using usual care. The study's objective was to evaluate the feasibility and efficacy of implementing a CDSS to assist physicians acutely treating patients with MDD compared to usual care in primary care. Primary efficacy outcomes for depression symptom severity were based on the 17-item Hamilton Depression Rating Scale (HDRS(17)) evaluated by an independent rater. RESULTS: Patients treated by physicians employing CDSS had significantly greater symptom reduction, based on the HDRS(17), than patients treated with usual care (P < .001). CONCLUSIONS: The CDSS algorithm, utilizing measurement-based care, was superior to usual care for patients with MDD in primary care settings. Larger randomized controlled trials are needed to confirm these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00551083.

Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings.

BACKGROUND: Despite wide promotion, clinical practice guidelines have had limited effect in changing physician behavior. Effective implementation strategies to date have included: multifaceted interventions involving audit and feedback, local consensus processes, marketing; reminder systems, either manual or computerized; and interactive educational meetings. In addition, there is now growing evidence that contextual factors affecting implementation must be addressed such as organizational support (leadership procedures and resources) for the change and strategies to implement and maintain new systems. METHODS: To examine the feasibility and effectiveness of implementation of a computerized decision support system for depression (CDSS-D) in routine public mental health care in Texas, fifteen study clinicians (thirteen physicians and two advanced nurse practitioners) participated across five sites, accruing over 300 outpatient visits on 168 patients. RESULTS: Issues regarding computer literacy and hardware/software requirements were identified as initial barriers. Clinicians also reported concerns about negative impact on workflow and the potential need for duplication during the transition from paper to electronic systems of medical record keeping. CONCLUSION: The following narrative report based on observations obtained during the initial testing and use of a CDSS-D in clinical settings further emphasizes the importance of taking into account organizational factors when planning implementation of evidence-based guidelines or decision support within a system.

Toward a very brief quality of life enjoyment and Satisfaction Questionnaire.

OBJECTIVE: To develop and evaluate a new brief self-report measure of satisfaction/quality of life in depressed outpatients. METHODS: Using the Quality of Life Enjoyment and Satisfaction Questionnaire Short-Form (Q-LES-Q-SF) self-report from Step-1 (n = 2181) of the STAR*D trial, items were selected based on their magnitude of change with treatment and correlation with 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Psychometric analyses were conducted. Replication of scale performance was assessed with STAR*D Step-2 data (n = 250). RESULTS: The 7 items selected ("Mini-Q-LES-Q") rated satisfaction with work, household activities, social and family relations, leisure time activities, daily function and sense of well-being in the past week. This uni-dimensional scale captured 83-94% variance in Q-LES-Q-SF and had acceptable Item Response and Classical Test Theory characteristics. Baseline to exit percent changes in the Mini-Q-LES-Q and the QIDS-SR16 were significantly, modestly related (r = -0.552) (Step-1) and replicated (r = -0.562) (Step-2). The Mini-Q-LES-Q detected the expected improvement in satisfaction/quality of life in acute treatment, yet also identified residual deficits expected in many at acute-phase exit. LIMITATIONS: Population norms are yet undefined. Concurrent validity with detailed, well-validated scales that assess the seven Quality of Life domains incorporated in the Mini-Q-LES-Q remains unestablished. Sensitivity to symptom changes induced by psychotherapy or somatic therapies or sensitive to the effects of therapies aimed at enhancing quality of life enjoyment and function is unknown. CONCLUSION: The 7-item Mini-Q-LES-Q self-report measure satisfaction/quality of life has acceptable psychometric properties, reflects change with depressive symptom reduction, and detects residual deficits in this key clinical outcome.

Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial.

BACKGROUND: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could "accurately" identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. METHODS: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the "preferred" treatment. Remission rates were calculated for participants "accurately" treated based on the composite moderator (lucky) versus "inaccurately" treated (unlucky). FINDINGS: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. INTERPRETATION: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. FUNDING: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center.Trial Registration.Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

Anxiety and anhedonia in depression: Associations with neuroticism and cognitive control.

BACKGROUND: Despite the fact that higher levels of anxiety and anhedonia in Major Depressive Disorder (MDD) are linked to poorer treatment outcomes, mechanisms contributing to these clinical presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning may be critical processes involved in MDD and may help to explain symptoms of anxiety and anhedonia. METHODS: Using baseline data from patients with early-onset MDD (N = 296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, we conducted a path analysis to model relationships between neuroticism, cognitive control, and reward learning to levels of anxiety and anhedonia. RESULTS: Neuroticism was positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001). Cognitive control was negatively associated with anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with either anxiety or anhedonia. LIMITATIONS: Extraneous variables not included in the model may have even more influence in explaining symptoms of anxiety and anhedonia. Restricted range in these variables may have attenuated some of the hypothesized relationships. Most important, because this was a cross-sectional analysis in a currently depressed sample, we cannot draw any causal conclusions without experimental and longitudinal data. CONCLUSIONS: These cross-sectional findings suggest that neuroticism may contribute to anxiety and anhedonia in patients with early onset and either chronic or recurrent MDD, while enhanced cognitive control may protect against anxiety.

The Concise Health Risk Tracking-Self Report: Psychometrics within a placebo-controlled antidepressant trial among depressed outpatients.

BACKGROUND/AIMS: While substantial prior research has evaluated the psychometric properties of the 12-item Concise Health Risk Tracking-Self Report (CHRT-SR12), a measure of suicide propensity and suicidal thoughts, no prior research has investigated its factor structure, sensitivity to change over time, and other psychometric properties in a placebo-controlled trial of antidepressant medication, nor determined whether symptoms change throughout treatment. METHODS: Participants in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study ( n=278) provided data to evaluate the factor structure and sensitivity to change over time of the CHRT-SR12 through eight weeks of a clinical trial in which participants received either placebo or antidepressant medication (sertraline). RESULTS/OUTCOMES: Factor analysis confirmed two factors: propensity (comprised of first-order factors including pessimism, helplessness, social support, and despair) and suicidal thoughts. Internal consistency (α's ranged from 0.69-0.92) and external validity were both acceptable, with the total score and propensity factor scores significantly correlated with total scores and single-item suicidal-thoughts scores on the self-report Quick Inventory of Depressive Symptoms and the clinician-rated 17-item Hamilton Rating Scale for Depression. Through analyzing CHRT-SR12 changes over eight treatment weeks, the total score and both the factors decreased regardless of baseline suicidal thoughts. Change in clinician-rated suicidal thoughts was reflected by change in both the total score and propensity factor score. CONCLUSIONS/INTERPRETATION: These results confirm the reliability, validity, and applicability of the CHRT-SR12 to a placebo-controlled clinical trial of depressed outpatients receiving antidepressant medication.

Do baseline sub-threshold hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial.

Sub-threshold hypomanic symptoms are common in major depressive disorder. This study evaluated the prevalence, the clinical and sociodemographic correlates, and the overall and differential effects of the presence/absence of sub-threshold hypomanic symptoms at baseline on acute-phase treatment outcomes with bupropion-plus-escitalopram combination, escitalopram monotherapy, and venlafaxine-plus-mirtazapine combination. Combining medications to enhance depression outcomes (CO-MED) trial participants (n = 665) were designated as sub-threshold hypomanic symptoms present (Altman Self-Rating Mania Scale score (ASRM) ≥ 1) or absent (ASRM = 0) and compared on clinical and sociodemographic features and remission rates. Participants with sub-threshold hypomanic symptoms (n = 335/665, 50.4%) were more likely to be black and non-Hispanic, have comorbid medical and psychiatric disorders, experience longer index episodes, and report lower depression severity and psychosocial impairment. Intent-to-treat remission rates were lower overall (absent = 42.7%, present = 34.0%, p = 0.02), with escitalopram monotherapy (absent = 45.8%, present = 31.6%, p = 0.03), and with venlafaxine-XR-plus-mirtazapine combination (absent = 44.4%, present = 30.1%, p = 0.03) but not with bupropion-plus-escitalopram combination (absent = 37.7%, present = 40.0%, p = 0.73). Participants without sub-threshold hypomanic symptoms were more likely to remit than those with such symptoms overall [odds ratio (OR) = 1.49], with escitalopram monotherapy (OR = 1.71), and with venlafaxine-plus-mirtazapine combination (OR = 1.97) but not with bupropion-plus-escitalopram combination (OR = 0.96), even after controlling for baseline depression severity, psychosocial impairment, and number of comorbid psychiatric disorders. Sub-threshold hypomanic symptoms (found in about 50% of patients in this report) were associated with lower remission rates with escitalopram monotherapy and with venlafaxine-plus-mirtazapine combination but not with the bupropion-plus-escitalopram combination.

Psychometric properties of the concise health risk tracking (CHRT) in adolescents with suicidality.

BACKGROUND: Several self-report rating scales have been developed to assess suicidal ideation, yet few examine other factors related to increased suicidal risk, and even fewer have been validated in both adolescents and adults. We evaluate the 14-item Concise Health Risk Tracking - Self Report (CHRT-SR), a measure previously validated in adults, in a sample of adolescents at risk for suicide. METHOD: Data are from a retrospective chart review of adolescents treated in an intensive outpatient program for youth with severe suicidality. Teens completed the CHRT-SR and Quick Inventory of Depressive Symptomatology - Adolescents (QIDS-A) at baseline and discharge. The CHRT-SR was evaluated to determine the factor validity, internal consistency, construct validity, and sensitivity to change. RESULTS: Adolescents (n = 271) completed the CHRT-SR prior to treatment, and 231 completed the CHRT-SR at discharge. Three factors were identified with excellent model fit: Propensity, Impulsivity, and Suicidal Thoughts. Internal consistency reliability coefficients were good-to-excellent for the total score and all three factors at baseline (a = 0.774-0.915) and exit (a = 0.849-0.941). The total score and all three factors significantly correlated with overall depression severity and suicidal ideation as rated by teens and parent (p = .704-0.756, all p < .001). The CHRT-SR was sensitive to change, with moderate to large effect sizes (Cohen's d = 0.599-1.062). LIMITATIONS: Study limitations include generalizability, lack of a control group, and retrospective data from a sample of opportunity. CONCLUSIONS: The CHRT-SR is a reliable and valid measure for examining severity of suicidal thoughts and associated risk factors, and is sensitive to change following an intervention in adolescents.