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Background: Profiling patients on a proposed 'immunometabolic depression' (IMD) dimension, described as a cluster of atypical depressive symptoms related to energy regulation and immunometabolic dysregulations, may optimise personalised treatment., Aims: To test the hypothesis that baseline IMD features predict poorer treatment outcomes with antidepressants., Method: Data on 2551 individuals with depression across the iSPOT-D ( n = 967), CO-MED ( n = 665), GENDEP ( n = 773) and EMBARC ( n = 146) clinical trials were used. Predictors included baseline severity of atypical energy-related symptoms (AES), body mass index (BMI) and C-reactive protein levels (CRP, three trials only) separately and aggregated into an IMD index. Mixed models on the primary outcome (change in depressive symptom severity) and logistic regressions on secondary outcomes (response and remission) were conducted for the individual trial data-sets and pooled using random-effects meta-analyses., Results: Although AES severity and BMI did not predict changes in depressive symptom severity, higher baseline CRP predicted smaller reductions in depressive symptoms ( n = 376, β pooled = 0.06, P = 0.049, 95% CI 0.0001-0.12, I 2 = 3.61%); this was also found for an IMD index combining these features ( n = 372, β pooled = 0.12, s.e. = 0.12, P = 0.031, 95% CI 0.01-0.22, I 2 = 23.91%), with a higher - but still small - effect size compared with CRP. Confining analyses to selective serotonin reuptake inhibitor users indicated larger effects of CRP (β pooled = 0.16) and the IMD index (β pooled = 0.20). Baseline IMD features, both separately and combined, did not predict response or remission., Conclusions: Depressive symptoms of people with more IMD features improved less when treated with antidepressants. However, clinical relevance is limited owing to small effect sizes in inconsistent associations. Whether these patients would benefit more from treatments targeting immunometabolic pathways remains to be investigated.

Deaths due to suicide are one of the leading causes of mortality among youths and young adults. Active suicidal ideation (SI) is considered one of the strongest risk factors for suicide. Here, we evaluated the neurocircuitry of SI in a sample of youths and young adults (aged 10-26 years) with current or past diagnosis of either major depression or bipolar disorder who were enrolled in Texas Resilience Against Depression Study (T-RAD), and had neuroimaging and SI (assessed with the 3-item Suicidal Thoughts factor of Concise Health Risk Tracking self-report scale) data available (n = 72, 53 females). Resting-state functional connectivity (FC) was computed amongst 121 cortical and subcortical regions of interest resulting in 7260 FC pairs. Mean (SD) age and SI levels of participants were 19.6 years (4.01) and 1.48 (2.36) respectively. In univariate analyses, 34 out of the 7260 FC pairs were correlated with SI (p < .005). Stronger connectivity of default mode network (DMN) with striatum was associated with higher SI. Conversely, higher SI was associated with weaker connectivity of limbic network with hippocampus, DMN, dorsal attention network, and executive control network. In multivariate analyses, these 34 FC pairs together had an average correlation of 0.54 after five-fold cross-validation. In conclusion, SI was associated with distinct patterns of resting-state functional connectivity among youths and young adults with regions in DMN and the ventral striatum as key nodes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The aim of this report was to evaluate the psychometric properties of the Pain Frequency, Intensity, and Burden Scale (P-FIBS), a brief measure of pain, as well as the association of pain with irritability and depression and how these symptoms relate to functional impairments., Methods: Participants of 2 randomized controlled trials (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care [EMBARC; n = 251 with DSM-IV diagnosis of major depressive disorder; study duration: August 2011-December 2015] and STimulant Reduction Intervention Using Dosed Exercise [STRIDE; n = 302 with DSM-IV diagnosis of stimulant abuse or dependence; study-duration: July 2010-February 2013]) and treatment-seeking patients in primary care clinics from an ongoing quality-improvement project (VitalSign 6 ; n = 4,370; project duration: August 2014-July 2019) were included. Psychometric properties of the P-FIBS were evaluated with confirmatory factor and item response theory analyses in EMBARC and VitalSign 6 . The approach of Baron and Kenny was used to assess whether irritability accounted for the effect of pain on depression., Results: Cronbach α (0.84-0.89) and model fits for single-factor structure of P-FIBS were acceptable. Pain was positively correlated with irritability (r = 0.22-0.29) and depression (r = 0.10-0.33). Irritability accounted for 40.7%-65.5% of the effect of pain on depression. Higher irritability and depression were associated with poorer social functioning, quality of life, and productivity in work- and non-work-related activities. Pain was associated with non-work-related activity impairments even after controlling for irritability and depression., Conclusions: The P-FIBS is a brief and reliable measure of pain. Irritability is associated with pain and accounts for a large proportion of the effect of pain on depression. Symptoms of pain, irritability, and depression are associated with functional impairments., Trial Registration: ClinicalTrials.gov identifiers: NCT01407094 (EMBARC), NCT01141608 (STRIDE)., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD., Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures., Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events., Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.

Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).

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., Competing Interests: Declaration of competing interest Dr. Trivedi has received funding from Agency for Healthcare Research and Quality (AHRQ), Cyberonics Inc., National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Johnson & Johnson. He has also served as an advisor or consultant for Abbott Laboratories Inc., Akzo (Organon Pharmaceuticals Inc.), Allergan Sales LLC, Alkermes, Arcadia Pharmaceuticals Inc., AstraZeneca, Axon Advisors, Brintellix, Bristol-Myers Squibb Company, Cephalon Inc., Cerecor, Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals Inc., Forest Pharmaceuticals, GlaxoSmithKline, Global Medical Education Inc., Health Research Associates, Johnson & Johnson, Lundbeck, MedAvante, Medscape, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America Inc., MSI Methylation Sciences Inc., Nestle Health Science-PamLab Inc., Naurex, Neuronetics, One Carbon Therapeutics Ltd., Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals Inc., Pfizer Inc., PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories. Dr. Jha has received contract research funding from Acadia Pharmaceutical and Janssen Research. Dr. Trombello currently owns stock in Merck and Gilead Sciences. Dr. Hughes has served as Youth Aware of Mental Health (YAM) trainer, consulting for Mental Health in Mind International. Dr. Hughes also receives royalties from Guilford Press. Dr. Greer has received contract research support from Janssen Research and Development, grant funding from NARSAD, and consultant/honoraria for Lundbeck and Takeda. Drs. Chin Fatt, Cooper, Mason, Toll, Gadad, Czysz, Minhajuddin, Fuller, Carmody, Ms. Sethuram, Mrs. Mayes have no disclosures to report., (Copyright © 2019. Published by Elsevier Ltd.)

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., (© 2019 Annals of Family Medicine, Inc.)

Depression is a common problem in patients with cardiovascular disease (CVD) and is associated with increased mortality, excess disability, greater health care expenditures, and reduced quality of life. Depression is present in 1 of 5 patients with coronary artery disease, peripheral artery disease, and heart failure. Depression complicates the optimal management of CVD by worsening cardiovascular risk factors and decreasing adherence to healthy lifestyles and evidence-based medical therapies. As such, standardized screening pathways for depression in patients with CVD offer the potential for early identification and optimal management of depression to improve health outcomes. Unfortunately, the burden of depression in patients with CVD is under-recognized; as a result, screening and management strategies targeting depression have been poorly implemented in patients with CVD. In this review, the authors discuss a practical approach for the screening and management of depression in patients with CVD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The standard of care for antidepressant treatment in major depressive disorder (MDD) is a trial-and-error approach. Patients often have to undergo multiple medication trials for weeks to months before finding an effective treatment. Clinical factors such as severity of baseline symptoms and the presence of specific individual (anhedonia or insomnia) or cluster (atypical, melancholic, or anxious) of symptoms are commonly used without any evidence of their utility in selecting among currently available antidepressants. Genomic and proteomic biomarker have gained recent attention for their potential in informing antidepressant medication selection. In this report, we have reviewed some of the major pharmacogenomics studies along with individual genetic and proteomic biomarker of antidepressant response. Additionally, we have reviewed the blood-based protein biomarkers that can inform selection of one antidepressant over another. Among all currently available biomarkers, C-reactive protein (CRP) appears to be the most promising and pragmatic choice. Low CRP (<1 mg/L) in patients with MDD predicts better response to escitalopram while higher levels are associated with better response to noradrenergic/dopaminergic antidepressants. Future studies are needed to demonstrate the superiority of a CRP-based treatment assignment over high-quality measurement-based care in real-world clinical practices.

Background: Platelet derived growth factor is integral to maintenance of blood brain barrier, increases in response to blood brain barrier disruption, and may reflect neuroinflammation. Based on previous reports of better outcomes with dopaminergic antidepressants in depressed patients with elevated inflammatory biomarkers, we hypothesize that elevated peripheral platelet derived growth factor levels can serve as a powerful biomarker for selecting dopaminergic antidepressants., Methods: Platelet derived growth factor, basic fibroblast growth factor, and granulocyte colony stimulating factor were measured as part of Bioplex Pro human cytokine 27-plex kit in participants of the Combining Medications to Enhance Depression Outcomes trial who provided baseline plasma (n=166) and were treated with either bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine. Differential changes in overall symptom severity and anhedonia as well as side effects were tested with a treatment-arm-by-biomarker interaction in mixed model analyses. Effect of biomarkers with significant interaction was calculated in subsequent analyses stratified by treatment arm., Results: There was a significant treatment-arm-by-platelet derived growth factor interaction for depression severity (P=.03) and anhedonia (P=.008) but not for side effects (P=.44). Higher baseline platelet derived growth factor level was associated with greater reduction in depression severity (effect size=0.71, P=.015) and anhedonia (effect size=0.66, P=.02) in the bupropion- selective serotonin reuptake inhibitor but not the other two treatment arms. There was no significant treatment-arm-by-biomarker interaction for both depression severity and side effects with the other two biomarkers., Conclusion: As compared with selective serotonin reuptake inhibitor monotherapy or venlafaxine-plus-mirtazapine, bupropion-plus-escitalopram selectively improves anhedonia, which in turn results in improved overall depression severity in depressed patients with elevated platelet derived growth factor levels., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

The goal of this study was to evaluate the relationship between early change in psychosocial function independent of depression severity and longer-term symptomatic remission. Participants of Combining Medications to Enhance Depression Outcomes trial were randomly selected for model selection (n = 334) and validation (n = 331). Changes in psychosocial function (Work and Social Adjustment Scale, WSAS) from baseline to week 6 were assessed and two data-driven sub-groups of WSAS change were identified in the randomly selected model selection half. Results of analyses to predict symptomatic remission at 3 and 7 months were validated for these sub-groups in the second half (validation sample). From baseline to week 6, psychosocial function improved significantly even after adjusting for depression severity at each visit and select baseline variables (age, gender, race, ethnicity, education, income, employment, depression onset before age 18, anxious features, and suicidal ideation), treatment-arm, and WSAS score. The WSAS change patterns identified two (early improvement and gradual change) subgroups. After adjusting for baseline variables and remission status at week 6, participants with early improvement in the second half (validation sample) had greater remission rates than those with gradual change at both 3 (3.3 times) and 7 months (2.3 times) following acute treatment initiation. In conclusion, early improvement in psychosocial function provides a clinically meaningful prediction of longer-term symptomatic remission, independent of depression symptom severity., Competing Interests: Drs. Jha, Minhajuddin, and Carmody report no financial relationships with commercial interests. Dr. Greer has received research funding from NARSAD and honoraria and/or consultant fees from H. Lundbeck A/S and Takeda Pharmaceuticals International, Inc. Dr. Rush has received consulting fees from the American Psychiatric Association, Brain Resource Ltd, H. Cyberonics, Eli Lilly, Emmes Corp, Lundbeck A/S, Medavante, Inc; National Institute of Drug Abuse; Santium Inc.; Takeda USA and the University of Colorado; speaking fees from the University of California at San Diego, Hershey Penn State Medical Center, the American Society for Clinical Psychopharmacology; the New York State Psychiatric Institute; Stanford Medical School; royalties from Guilford Publications and the University of Texas Southwestern Medical Center; and research support from Duke-National University of Singapore. Dr. Madhukar H. Trivedi is or has been an advisor/consultant and received fees from: Alkermes Inc., Allergan, AstraZeneca, Brintellix, BMS, Cerecor, Eli Lilly & Company, Forest, Health Research Associates, Johnson & Johnson, Lundbeck, Medscape, MSI Methylation Sciences Inc., Merck, Naurex Inc., Nestle Health Science – Pamlab Inc., One Carbon Therapeutics, Otsuka America Pharmaceuticals Inc., PamLab, Pfizer Inc., Roche, SHIRE Development, Takeda Pharmaceuticals Inc. In addition, he has received grants/research support from: Agency for Healthcare Research and Quality (AHRQ), National Institute of Mental Health (NIMH), Johnson and Johnson, National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and National Institute on Drug Abuse (NIDA). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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.

The efficacy of antidepressant treatment for depression is controversial due to the only modest superiority demonstrated over placebo. However, neurobiological heterogeneity within depression may limit overall antidepressant efficacy. We sought to identify a neurobiological phenotype responsive to antidepressant treatment by testing pretreatment brain activation during response to, and regulation of, emotional conflict as a moderator of the clinical benefit of the antidepressant sertraline versus placebo. Using neuroimaging data from a large randomized controlled trial, we found widespread moderation of clinical benefits by brain activity during regulation of emotional conflict, in which greater downregulation of conflict-responsive regions predicted better sertraline outcomes. Treatment-predictive machine learning using brain metrics outperformed a model trained on clinical and demographic variables. Our findings demonstrate that antidepressant response is predicted by brain activity underlying a key self-regulatory emotional capacity. Leveraging brain-based measures in psychiatry will forge a path toward better treatment personalization, refined mechanistic insights and improved outcomes.

The burden of major depressive disorder is compounded by a limited understanding of its risk factors, the limited efficacy of treatments, and the lack of precision approaches to guide treatment selection. The Texas Resilience Against Depression (T-RAD) study was designed to explore the etiology of depression by collecting comprehensive socio-demographic, clinical, behavioral, neurophysiological/neuroimaging, and biological data from depressed individuals (D2K) and youth at risk for depression (RAD). This report details the baseline sociodemographic, clinical, and functional features from the initial cohort (D2K N = 1040, RAD N = 365). Of the total T-RAD sample, n = 1078 (76.73 %) attended ≥2 in-person visits, and n = 845 (60.14 %) attended ≥4 in-person visits. Most D2K (84.82 %) had a primary diagnosis of any depressive disorder, with a bipolar disorder diagnosis being prevalent (13.49 %). RAD participants (75.89 %) did not have a psychiatric diagnosis, but other non-depressive diagnoses were present. D2K participants had 9-item Patient Health Questionnaire scores at or near the moderate range (10.58 ± 6.42 > 24 yrs.; 9.73 ± 6.12 10–24 yrs). RAD participants were in the non-depressed range (2.19 ± 2.65). While the age ranges in D2K and RAD differ, the potential to conduct analyses that compare at-risk and depressed youth is a strength of the study. The opportunity to examine the trajectory of depressive symptoms in the D2K cohort over the lifespan is unique. As a longitudinal study, missing data were common. T-RAD will allow data to be collected from multiple modalities on a clinically well-characterized sample. These data will drive important discoveries on diagnosis, treatment, and prevention of depression. • Heterogeneity in symptoms and treatment response hinders treatment of depression. • Longitudinal clinical and biological data are needed for Precision Psychiatry. • Texas Resilience Against Depression is a naturalistic observational cohort study. • The study is gathering longitudinal data in depressed adults and at-risk youth. • Data collected include self-report measures, EEG, MRI, blood, and stool samples. [ABSTRACT FROM AUTHOR]

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

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

Objective: To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time.Methods: This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models.Results: Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups.Limitations: TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes.Conclusions: These post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability.Trial Registration: ClinicalTrials.gov identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2). [ABSTRACT FROM AUTHOR]

Background: This report evaluated whether irritability in adults with stimulant use disorder is associated with suicidal ideation (SI) at the same visit (i.e., concurrently) and whether early changes in irritability predict subsequent levels of SI.Methods: Adults with stimulant use disorder (n=302) from nine residential addiction treatment programs were included. Participants were randomized to augmentation of usual care with dosed exercise or health education intervention. Irritability, SI, and depression were measured every week with 5-item irritability domain of Concise Associated Symptom Tracking scale, 3-item suicidal thoughts factor of Concise Health Risk Tracking scale, and 16-item Quick Inventory of Depressive Symptomatology Clinician-Rated version (excluding the suicide-related item) respectively during acute-(baseline-to-week-12) and continuation-(week-12-to-week-36) phase. Covariates included age, sex, race, ethnicity, treatment arm, type of substance(s) used, and comorbid psychiatric and medical disorders.Results: Higher irritability was associated with higher SI concurrently both in the acute-phase: r=0.28 (p<0.0001) and in the continuation-phase: r=0.33 (p<0.0001). Irritability was associated with concurrent SI after controlling for depression [acute-phase: β=0.17 (p<0.0001); continuation-phase: β=0.18 (p<0.0001)]. Greater baseline-to-week-2 reductions in irritability predicted lower levels of SI from week-2-to-week-12 (β=-0.11, p=0.003) and from week-12-to-week-36 (β=-0.22, p<0.0001) after controlling for baseline levels of depression and SI and baseline-to-week-2 changes in depression and SI.Limitations: Secondary analyses, self-report measures of irritability and SI, limited generalizability.Conclusions: Irritability is associated with SI concurrently, and greater reductions in irritability earlier in treatment are associated with lower levels of subsequent SI. Therefore, targeting irritability may reduce suicidality in adults with stimulant use disorder. [ABSTRACT FROM AUTHOR]

Objective: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.Methods: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.Results: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.Conclusions: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted. [ABSTRACT FROM AUTHOR]

Abstract Peripheral inflammation is associated with poor response to antidepressant treatments. However, whether sex differentially affects this association remains unknown. Participants of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) with baseline plasma samples were included in this study (n = 220; male n = 75, female n = 145). Depression severity [Hamilton Rating Scale for Depression 17-item (HAMD-17)] was measured at baseline and weeks- 1, 2, 3, 4, 6, and 8. Plasma c-reactive protein (CRP) was measured with commercially-available ELISA kits at baseline, week-1, and week-8. Sex difference in prediction of baseline-to-week-8 HAMD-17 change by baseline CRP was tested with sex-by-baseline-CRP-by-time interaction in mixed model analysis. Additionally, changes in CRP from baseline-to-week-8 CRP and its association with HAMD-17 changes over that period were also evaluated. Covariates included body mass index, site, smoking status, and age. There was a significant sex difference in association of baseline-to-week-8 HAMD-17 reduction with baseline CRP (p = 0.033). Higher baseline CRP was associated with lower baseline-to-week-8 HAMD-17 reduction in females (p < 0.0001) but not in males (p = 0.632). Additionally, CRP was significantly reduced (p = 0.041, effect size = 0.254) from baseline-to-week-8, but there were no sex differences in this reduction (p = 0.249). Baseline-to-week-8 changes in HAMD-17 and CRP were not significantly associated either overall (p = 0.348) or based on sex (p = 0.370). In a large study of depressed outpatients, we replicated previous findings that elevated baseline CRP levels are associated with worse antidepressant treatment outcomes. However, this effect was limited only to females. These findings emphasize the importance of studying sex differences in biological mechanisms linking inflammation and depression. Highlights • Higher baseline CRP predicts worse acute-phase antidepressant outcomes. • This association is limited to female patients with major depressive disorder. • Reduction in CRP with antidepressant treatment did not differ on the basis of sex. • Baseline-to-week-8 changes in depression and CRP were not significantly correlated. [ABSTRACT FROM AUTHOR]

Objective Among individual depressive symptoms, anhedonia has been reliably associated with activation of the innate immune response. However, it is unclear whether this association extends to T cell cytokines and if gender differentially affects this association. Method Concentrations of T (IL-17, T-helper (Th) 1- and Th2-) and non-T cell cytokines were measured in plasma using the Bioplex Pro™ human cytokine multiplex kit in Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants who provided plasma at baseline (n = 166). Anhedonia was measured with three items of the clinician-rated Inventory of Depressive Symptomatology and depression severity (minus anhedonia item) was measured with Quick Inventory of Depression Severity Self-Report version (modified-QIDS-SR). Separate generalized linear models for anhedonia and modified-QIDS-SR as dependent variables were conducted with IL-17, Th1-, Th2-, and non-T cell- cytokines as primary independent variables and gender, body mass index (BMI), and age as covariates. Exploratory analyses included gender-by-biomarker interactions. Results Higher levels of IL-17 (p = 0.032), Th1- (p = 0.002), Th2-(p = 0.001) and non-T-(p = 0.009) cell markers were associated with greater severity of anhedonia controlling for BMI, age, and gender. Gender also had a significant main effect on anhedonia, however, there was a significant gender by immune marker interaction only for IL-17 (p = 0.050). Anhedonia severity increased with higher IL-17 in males (r = 0.42, p = 0.003) but not in females (r = 0.09, p = 0.336). Only non-T cell markers were associated with the modified-QIDS-SR, and there were no significant gender-specific associations with this variable. Conclusions T and non-T cell-related inflammatory markers were associated with greater severity of anhedonia, while gender moderated the association of IL-17 with anhedonia in patients with major depressive disorder. [ABSTRACT FROM AUTHOR]

The article discusses a mental health screening, assessment and navigation protocol referred to as MH-SCAN being implemented by the University of Texas (UT) Southwestern Medical Center Moncrief Cancer Institute for cancer patients experiencing depression and other mental health issues. Topics include the difficulties of routine mental health screening among oncology patients, the standard of cancer care included in the project, and the creation of a team to address patients' suicidal ideation.

Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to determine whether a unique analytic approach - as a proof of concept - could identify individual depressed outpatients (using 30 baseline clinical and demographic variables) who are very likely (75% certain) to not benefit (NB) or to remit (R), accepting that without sufficient certainty, no prediction (NP) would be made. Methods: Patients from the Combining Medications to Enhance Depression Outcomes trial treated with escitalopram (S-CIT) + placebo (n=212) or S-CIT + bupropion-SR (n=206) were analyzed separately to assess replicability. For each treatment, the elastic net was used to identify subsets of predictive baseline measures for R and NB, separately. Two different equations that estimate the likelihood of remission and no benefit were developed for each patient. The ratio of these two numbers characterized likely outcomes for each patient. Results: The two treatment cells had comparable rates of remission (40%) and no benefit (22%). In S-CIT + bupropion-SR, 11 were predicted NB of which 82% were correct; 26 were predicted R - 85% correct (169 had NP). For S-CIT + placebo, 13 were predicted NB - 69% correct; 44 were predicted R - 75% correct (155 were NP). Overall, 94/418 (22%) patients were identified with a meaningful degree of certainty (69%-85% correct). Different variable sets with some overlap were predictive of remission and no benefit within and across treatments, despite comparable outcomes. Conclusion: In two separate analyses with two different treatments, this analytic approach - which is also applicable to pretreatment laboratory tests - identified a meaningful proportion (over 20%) of depressed patients for whom a treatment outcome was predicted with sufficient certainty that the clinician can elect to strongly recommend for or choose to avoid a particular treatment. Different persons seem to be remitting or not benefiting with these two different treatments. [ABSTRACT FROM AUTHOR]

Objective Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed. Method Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n = 51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n = 55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants. Results The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1 mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient = −0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient = 0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1 mg/L and Bupropion-SSRI for ≥1 mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker. Conclusions Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder. Clinicaltrials.gov identifier: NCT00590863 [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) significantly impacts performance of both work- and nonwork-related routine daily activities. We have shown that work productivity is significantly impaired in employed MDD patients, but the extent of impairments in nonworkrelated routine activities and its association with antidepressant treatment outcomes has not been established. Materials and methods: Activity impairment was measured using the sixth item of Work Productivity and Activity Impairment Scale in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n=665). Published norms were used to define activity impairment levels. The relationship between activity impairment and baseline sociodemographic and clinical characteristics was evaluated along with changes in activity impairment and its relationship with other clinical outcomes such as symptom severity, function, and side effect burden. Remission status at 3 and 7 months was predicted based on week 6 activity impairment level. Results: Higher psychosocial and cognitive impairments and greater number of comorbid medical conditions were associated with greater activity impairment at baseline. Proportion of participants with severe activity impairment declined from 47.6% at baseline to 18.7% at 3 months, while mean activity impairment decreased from 57.1 at baseline to 32.8 at 3 months. During course of treatment, levels of activity impairment correlated most strongly with psychosocial function among measures of symptom severity, function, quality of life, and side effect burden. No or minimal activity impairment at week 6 was associated with two to three times higher rates of remission at 3 and 7 months as compared to moderate or severe activity impairment levels even after controlling for remission status at week 6 and select baseline variables. Conclusion: Depressed patients have high levels of nonwork-related activity impairment at baseline that improves significantly with treatment and independently predicts long-term clinical outcomes. Brief systematic assessment of activity impairment during the course of antidepressant treatment can help inform clinical decision-making. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Evaluate whether early improvement in irritability predicts improvement in depression severity in a naturalistic sample of adolescents undergoing pharmacologic treatment for major depressive disorder. Adolescents (N = 161) aged 13–18 years with a moderate to severe depressive episode were enrolled. Outcome measures included the Children's Depression Rating Scale-Revised (CDRS-R), Quick Inventory of Depressive Symptomatology (QIDS - A 17), and Clinical Global Impression scale (CGI). Paired t -tests were used to estimate the change in irritability items from baseline to week-4, and Cohen's d effect sizes were computed. Separate linear regression analyses with CDRS-R, QIDS-A 17 , and CGI at week-8 as the dependent variables and baseline levels of irritability and baseline-to-week-4 changes in irritability as independent variables of interest were conducted. These analyses were repeated after controlling for overall depression severity (minus the irritability item) at baseline and baseline to week-4 change. Greater baseline to week-4 reduction in irritability was associated with lower levels of CDRS-R, QIDS-A 17 , and CGI at week-8. These findings were significant for QIDS-A 17 and CGI even after controlling for baseline-to-week-4 changes in other depressive symptoms. The single item evaluation of irritability reduced assessment reliability in the absence of validated measures of irritability. Early reduction in irritability is strongly associated with better outcomes in depressed youths, regardless of baseline depression severity. Further research is needed to quantify the burden of irritability, explore it as a tool for measurement-based care, and to develop targeted treatments for irritability. • Irritability decreases in treated youths with MDD regardless of baseline depression. • Early reduction in irritability predicted depression severity after 8 weeks. • Early reduction in irritability was a predictor of overall improvement of disease. [ABSTRACT FROM AUTHOR]

Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk of suicide. Next step treatment options for patients with TRD, include switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another (non-antidepressant) medication. It is unclear which of these treatment approaches should be applied to a given patient, and in what order. Due to this ambiguity, comparing antidepressants and augmentation agents on the basis of their efficacy, tolerability, and speed of symptom relief would be beneficial for clinicians. To accomplish this, a systematic search was conducted following PRISMA guidelines. Only randomized controlled trials were included in this qualitative synthesis, resulting in 66 articles. This review identified several effective pharmaco-therapeutic strategies that are currently available for patients with TRD. Ketamine and esketamine appear to be effective for the treatment of TRD. Augmentation with certain second generation antipsychotics, such as quetiapine or aripiprazole is likewise effective, and may be preferred over switching to antidepressant monotherapy. While the combination of olanzapine and fluoxetine was one of the first pharmacotherapy approved for TRD, and its use may be limited by metabolic side-effects. Other effective strategies include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants including bupropion, tricyclics, or mirtazapine. There is insufficient research to demonstrate the efficacy of ziprasidone or levothyroxine (T4). A shared decision-making approach is recommended to guide treatment selection to address each patient's individual needs. [ABSTRACT FROM AUTHOR]

• Interleukin 4 (IL-4) levels are lower in adolescents and young adults with depression and suicidality. • Other inflammation-related markers didn't differ in those with recent suicidality vs. healthy controls and those at-risk. • IL-4 levels were negatively correlated with self-reported depression severity. • Lower IL-4 levels were associated with higher autoantibody levels in an unrelated sample of depressed outpatients. 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). 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). 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]. 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. [ABSTRACT FROM AUTHOR]

Major depressive disorder affects one in five adults in the United States. While practice guidelines recommend universal screening for depression in primary care settings, clinical outcomes suffer in the absence of optimal models to manage those who screen positive for depression. The current practice of employing additional mental health professionals perpetuates the assumption that primary care providers (PCP) cannot effectively manage depression, which is not feasible, due to the added costs and shortage of mental health professionals. We have extended our previous work, which demonstrated similar treatment outcomes for depression in primary care and psychiatric settings, using measurement-based care (MBC) by developing a model, called Primary Care First (PCP-First), that empowers PCPs to effectively manage depression in their patients. This model incorporates health information technology tools, through an electronic health records (EHR) integrated web-application and facilitates the following five components: (1) Screening (2) diagnosis (3) treatment selection (4) treatment implementation and (5) treatment revision. We have implemented this model as part of a quality improvement project, called VitalSign6, and will measure its success using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework. In this report, we provide the background and rationale of the PCP-First model and the operationalization of VitalSign6 project. [ABSTRACT FROM AUTHOR]

Highlights • A unidimensional self-report (the Mini-Q-LES-Q) was constructed using 7 items selected from the 14-item Quality of Life, Enjoyment and Satisfaction Scale (short form) (Q-LES-Q SF) while capturing 83–94% of the variance in the Q-LES-Q-SF. • The Mini-Q-LES-Q has excellent psychometric properties, detects improvements in quality of life-satisfaction with acute-phase antidepressant medication treatment, as well as residual quality of life-satisfaction deficiencies even when depressive symptom control is optimal. • The Mini-Q-LES-Q, which captures over 80% of the variance of the 14-item version, may help clinicians decide when and whether to target this important clinical domain. Abstract 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-SR 16). 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-SR 16 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. [ABSTRACT FROM AUTHOR]

Introduction: Insomnia is prevalent in adults with major depressive disorder (MDD) and is a key diagnostic criterion of MDD; however, little is understood about the burden of insomnia symptom severity in MDD. We evaluated the relationship between insomnia symptom severity and the clinical, economic, and patient‐centric burden among community‐dwelling individuals with MDD. Methods: Respondents with diagnosed depression who reported insomnia symptoms in the past 12 months (N = 4402) were identified from the 2019 United States National Health and Wellness Survey. Multivariable analyses assessed the association of Insomnia Severity Index (ISI) with health‐related outcomes while controlling for sociodemographic and health characteristics. Further analyses also controlled for depression severity (9‐item Patient Health Questionnaire). Results: Mean ISI score was 14.3 ± 5.6. Higher ISI was associated with greater depression severity (r =.51, p <.001). After adjustments, a one‐standard deviation (5.6‐point) increase in ISI score was significantly associated with higher depression (rate ratio [RR] = 1.36), anxiety (RR = 1.33) and daytime sleepiness (RR = 1.16) levels, more healthcare provider (RR = 1.13) and emergency room visits (RR = 1.31), hospitalizations (RR = 1.21), work productivity and activity impairment (RRs = 1.27 and 1.23, respectively), and poorer mental and physical health‐related quality of life (β = −3.853 and −1.999, respectively) (p <.001). These findings remained statistically significant when controlling for concurrent depression severity. Conclusion: In adults with MDD, greater insomnia symptom severity is associated with worse health‐related outcomes, which suggests the importance of addressing insomnia symptoms as a clinical target for treating MDD. [ABSTRACT FROM AUTHOR]

Although insomnia is a common core symptom of major depressive disorder (MDD), the burden of moderate-to-severe insomnia symptoms in patients with MDD is not well-understood. This study quantified the clinical, patient-centric, and economic burden of adults with MDD with moderate-to-severe insomnia symptoms (MDDIS) compared to adults with MDD with no-to-mild insomnia symptoms (other-MDD) and adults without MDD. Data from 2019 US National Health and Wellness Survey identified adults self-reporting physician-diagnosed depression, stratified by insomnia status (MDDIS: Insomnia Severity Index [ISI] score ≥15; other-MDD: ISI score <15), and adults not reporting depression (non-MDD). Other-MDD and non-MDD were matched 2:1 to MDDIS on age/sex/race. Matched bivariate analyses examined differences in health-related outcomes by depression-insomnia status. Of 74,994 survey respondents, 2045 (2.7%) were classified as MDDIS, 8220 (11.0%) as other-MDD, and 59,859 (79.8%) as non-MDD. MDDIS respondents (vs other-MDD and non-MDD) reported greater depression severity, anxiety severity, daytime sleepiness, activity impairment, direct costs, and costs due to work productivity impairments, and lower mental and physical functioning (all P < 0.05). Depression diagnosis was not based on clinical/diagnostic interview; causal relationships cannot be determined due to the cross-sectional design. Among US adults with MDD, presence of moderate-to-severe insomnia symptoms is associated with additional burden and notable impairments across several health outcomes versus those with MDD but no-to-minimal insomnia symptoms and general population without MDD. This study highlights the burden of MDDIS and the need for better identification and management of moderate-to-severe insomnia symptoms in adults with MDD. • This study quantifies the burden of MDD with moderate-to-severe insomnia (MDDIS) • Higher depressive, anxiety, and daytime sleepiness symptoms in adults with MDDIS • Higher direct costs and work productivity impairment costs in adults with MDDIS • Lower mental and physical functioning in adults with MDDIS • Burden of MDDIS was significant even when controlling for other depressive symptoms [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional magnetic resonance imaging, clinical assessments, and demographics. Participants in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study (n = 222) underwent reward processing task-based functional magnetic resonance imaging at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline nonresponders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Depression Rating Scale was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. The predictive model for sertraline achieved R 2 of 48% (95% CI, 33%–61%; p < 10−3) in predicting the change in Hamilton Depression Rating Scale and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R 2 of 28% (95% CI, 15%–42%; p < 10−3) and NNT of 2.95 in predicting response. The bupropion model achieved R 2 of 34% (95% CI, 10%–59%, p < 10−3) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers. [ABSTRACT FROM AUTHOR]

The current study aimed to characterize the multifaceted nature of anxiety in patients with major depression by evaluating distinct anxiety factors. We then related these derived anxiety factors to performance on a Flanker Task of cognitive control, in order to further validate these factors. Data were collected from 195 patients with nonpsychotic chronic or recurrent major depression or dysthymic disorder. At baseline, participants completed self-report measures of anxiety, depression, and other related symptoms (mania, suicidality) and clinicians administered a structured diagnostic interview and the Hamilton Rating Scale for Depression, including anxiety/somatization items. Four discrete factors (State Anxiety, Panic, Neuroticism/Worry, and Restlessness/Agitation) emerged, with high degrees of internal consistency. Discriminant and convergent validity analyses also yielded findings in the expected direction. Furthermore, the neuroticism/worry factor was associated with Flanker Task interference, such that individuals higher on neuroticism/worry responded more incorrectly (yet faster) to incongruent vs. congruent trials whereas individuals higher on the fear/panic factor responded more slowly, with no accuracy effect, to the Flanker Task stimuli. These results parse anxiety into four distinct factors that encompass physiological, psychological, and cognitive components of anxiety. While state anxiety, panic and neuroticism/worry are related to existing measures of anxiety, the Restlessness/Agitation factor appears to be a unique measure of general anxious arousal. Furthermore, two factors were independently validated through the Flanker Task. These results suggest that these anxiety domains have distinct behavioral profiles and could have differential responses to distinct treatments. [ABSTRACT FROM AUTHOR]

• Half of a sample with chronic and/or recurrent MDD suffered childhood maltreatment (CMT). • Persons with CMT had higher rates of panic/phobic, cognitive and anhedonia than those without CMT. • A history of CMT was associated with earlier MDD onset, more severe MDD, and worse functioning. • Previous CMT was linked to more suicidality, worse quality of life, and more psychiatric comorbidities. • Clinical presentation was worse in participants who reported multiple types of CMT. This study examined: 1) the prevalence of childhood maltreatment (CMT) in individuals with chronic and/or recurrent depression, 2) the association between CMT and depressive symptoms, 3) the link between CMT and worse clinical presentation of depression, 4) the effects of accumulation of different types of CMT, and 5) the relationship between the age at CMT and depression. We analyzed the baseline data of 663 individuals from the CO-MED study. CMT was determined by a brief self-reported questionnaire assessing sexual abuse, emotional abuse, physical abuse, and neglect. Correlational analyses were conducted. Half of the sample (n = 331) reported CMT. Those with CMT had higher rates of panic/phobic, cognitive and anhedonic symptoms than those without CMT. All individual types of maltreatment were associated with a poorer clinical presentation including: 1) earlier MDD onset; 2) more severe MDD, 3) more suiccidality, 4) worse quality of life, and functioning, and 5) more psychiatric comorbidities. Clinical presentation was worse in participants who reported multiple types of CMT. In chronic and/or recurrent depression, CMT is common, usually of multiple types and is associated with a worse clinical presentation in MDD. The combination of multiple types of CMT is associated with more impairment. [ABSTRACT FROM AUTHOR]