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Purpose This report from VitalSign6 project describes treatment selection, follow-up rates and remission outcomes by initial depression severity using the PCP-FIRST model. Methods This retrospective analysis included 32,106 patients aged ≥12 years screened with the Patient Health Questionnaire 2-item (PHQ-2) from November 2016 to July 2019 across 37 primary care clinics. PHQ-2 positive-screen patients (PHQ-2 ≥ 3) received 9-item PHQ (PHQ-9) and 7-item Generalized Anxiety Disorder scales, clinician assessments, and evaluation for pharmacotherapy management with measurement-based care (MBC). Results Of PHQ-2 screened patients, 18.7% (5994/32,106) were positive and received a PHQ-9. Of 5994 patients with PHQ-9, 2571 received a clinical diagnosis of depression of whom, 333 had none-mild depression (PHQ-9 Conclusions Despite this being a real-world, usual care sample, remission outcomes exceed real world remission rate expectations of 6% in primary care.

Recent studies have suggested that mitochondrial dysfunction and dysregulated neuroinflammatory pathways are involved in the pathophysiology of major depressive disorder (MDD). Here, we aimed to assess the differences in markers of mitochondrial dynamics, mitophagy, general autophagy, and apoptosis in peripheral blood mononuclear cells (PBMCs) of MDD patients (n = 77) and healthy controls (HCs, n = 24). Moreover, we studied inflammation engagement as a moderator of mitochondria dysfunctions on the severity of depressive symptoms. We found increased levels of Mfn-2 (p

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

Background Adults with major depressive disorder (MDD) often experience reduced quality of life (QOL). Efficacious acute-phase treatments, including cognitive therapy (CT) or medication, decrease depressive symptoms and, to a lesser degree, increase QOL. We tested longer-term changes in QOL after response to acute-phase CT, including the potential effects of continuation treatment for depression and time-lagged relations between QOL and depressive symptoms. Methods Responders to acute-phase CT (N = 290) completed QOL and depressive symptom assessments repeatedly for 32 post-acute months. Higher-risk responders were randomized to 8 months of continuation treatment (CT, fluoxetine, or pill placebo) and then entered a 24-month follow-up. Lower-risk responders were only assessed for 32 months. Results On average, large gains in QOL made during acute-phase CT response were maintained for 32 months. Continuation CT or fluoxetine did not improve QOL relative to pill placebo. Controlling for residual depressive symptoms, higher QOL after acute-phase CT response was a protective factor against MDD relapse and recurrence. Higher QOL predicted subsequent reductions in depressive symptom severity, but depressive symptom severity did not predict subsequent changes in QOL. Limitations Generalization of results to other patient populations, treatments, and measures is uncertain. The clinical trial was not designed to test relations between QOL and depression. Replication is needed before clinical application of these results. Conclusions Gains in QOL made during response to acute-phase CT are relatively stable and may help protect against relapse/recurrence. Continuation CT or fluoxetine may not further improve QOL among acute-phase CT responders.

Major depressive disorder (MDD) is widely prevalent and one of the leading causes of disability. Treatment outcomes remain suboptimal with 1 in 3 patients with MDD responding inadequately to commonly used antidepressants. Pimavanserin, an atypical antipsychotic that modulates serotonergic neurotransmission by selectively binding to serotonin receptor (2A and 2C) subtypes and without dopaminergic activity, may have the potential as an adjunctive treatment for MDD. In a phase 2 trial (n=203), addition of pimavanserin, as compared to placebo, to stable treatment with antidepressants was associated with greater reduction in 17-item Hamilton Depression Rating Scale score [HAMD, least square means (95% confidence interval) of −1.7 (−0.03, −3.37), p=0.039]. Furthermore, treatment with pimavanserin was associated with significantly greater improvement in specific symptoms associated with depression such as impaired sexual function, anxiety, sleepiness, and irritability. However, the availability of pimavanserin for clinical care of patients with MDD remains uncertain. Top-line results of phase 3 studies (n=298) that were announced by the sponsor found similar reductions in HAMD (mean baseline-to-week-5 reduction of 9.0 and 8.1, p=0.296) and rates of adverse events (58.1% and 54.7%) with addition of pimavanserin and placebo respectively to stable treatment with antidepressants. Given the potential benefit for specific symptoms such as impaired sexual function, anxiety and sleep/wakefulness disturbances, future studies that enrich for these symptoms may be needed to clarify the utility of adjunctive pimavanserin in treatment of patients with MDD.

Background: Chronic Obstructive Pulmonary Disease (COPD) is chronic inflammatory condition that is known to be a prothrombotic state. Objective: To study the prothrombotic markers and coagulation profile in patients of Stable COPD and during its exacerbation and to compare these parameters in stable phase of disease and during exacerbation. Materials and Method: A cross sectional study in which 30 patients of COPD with exacerbation and 30 patients with stable COPD were recruited. Patients having acquired thrombotic risk factors like diabetes, hypertension, coronary artery disease, chronic kidney disease, chronic liver disease, malignancy & sepsis or any immunocompromised condition along with those who were on anticoagulant therapy, statins or antihypertensive medications were excluded from the study. Levels of prothrombotic markers (von Willebrand Factor antigen, D-dimer, fibrogen) and Caogulation profile (Prothrombin time and activated Partial Thromboplastin Time) were estimated in both the groups and repeated after stabilization of exacerbation phase also. There parameters were then statistically analyzed. Observation and Results: A generalized prothrombotic state was observed in exacerbation phase of COPD as compared to stable phase of COPD. Furthermore, all the parameters including fibrinogen, vWF, PT and aPTT showed persistent declining trend from exacerbation towards stabilization. Conclusion: COPD with acute exacerbation is a state of augmented prothrombotic state. On stabilization of acute exacerbation with treatment, coagulation profile came to a level lower than that of patients in stable phase of COPD. In exacerbation phase of COPD vWF values were significantly elevated than in stable phase. How to cite this article: Daga MK, Kumar N, Singh S, Mawari G, Mahapatra SJ, Jha Mk et al. Study of Prothrombotic Markers in COPD. J Adv Res Med 2020; 7(4): 1-6. DOI: https://doi.org/10.24321/2349.7181.202014

Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of mortality and loss of Disability-Adjusted Life-Years (DALYs) worldwide. It often is accompanied by the presence of various systemic comorbidities including osteoporosis which may have an impact on the course of the disease. Osteopenia and osteoporosis are the consequences of loss of Bone Mineral Density (BMD) and have been widely known major comorbidities in COPD patients. Female sex, age, and smoking are common pathogenic factors for both COPD and osteoporosis, other factors such as reduced daily physical activity, malnutrition, low body mass index, hypogonadism, vitamin D deficiency, chronic renal insufficiency, chronic hypoxemia, and drugs like corticosteroids, have been invoked to explain such a frequent association between them. Osteoporosis in COPD is however often undertreated. It has been shown in recent studies that both decreased Bone Mineral Density (BMD) and impaired bone quality contribute to bone fragility, causing fractures in COPD patients. Pulmonary function and activities of the daily life of COPD patients may be further deteriorated by osteoporosis-associated fractures. Calcium and vitamin D, hormone replacement when indicated, calcitonin, and bisphosphonate administration are few effective strategies to tackle bone loss and osteoporosis. Awareness about this high prevalence of osteoporosis in COPD patients is critically important and physicians should look for such fracture risks. Routine screening and early diagnosis of osteoporosis will enable physicians to provide the appropriate treatment to prevent fracture, which leads to improved quality of life as well as better long-term prognosis. How to cite this article:Daga MK, Kumar N, Raghu RV, Mawari G, Chand S, Aarthi J. Osteoporosis in Chronic Obstructive Pulmonary Disease: More than just a Comorbidity. J Adv Res Med 2020; 7(3): 7-12. DOI: https://doi.org/10.24321/2349.7181.202011

BACKGROUND Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study. METHODS Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Asberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (

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

Background Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). Methods To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1–3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs

The authors evaluated improvement in irritability with antidepressant treatment and its prognostic utility in treatment-seeking adult outpatients with major depressive disorder.Mixed-model analyses were used to assess changes in irritability (as measured with the five-item irritability domain of the Concise Associated Symptom Tracking [CAST-IRR] scale) from baseline to week 4 after controlling for depression severity (as measured with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C]) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (N=664). An interactive calculator for remission (QIDS-C score ≤5) and no meaningful benefit (30% reduction in QIDS-C score from baseline) at week 8 was developed with logistic regression analyses in the CO-MED trial using participants with complete data (N=431) and independently replicated in the Suicide Assessment and Methodology Study (SAMS) (N=163).In the CO-MED trial, irritability was significantly reduced (effect size=1.06) from baseline to week 4, and this reduction remained significant after adjusting for QIDS-C change (adjusted effect size=0.36). A one-standard-deviation greater reduction in CAST-IRR score from baseline to week 4 predicted a 1.73 times higher likelihood of remission and a 0.72 times lower likelihood of no meaningful benefit at week 8, independent of baseline QIDS-C and CAST-IRR scores and reduction in QIDS-C score from baseline to week 4. The model estimates for remission (area under the curve [AUC]=0.79) and no meaningful benefit (AUC=0.76) in the CO-MED trial were used to predict remission (AUC=0.80) and no meaningful benefit (AUC=0.84) in SAMS and to develop an interactive calculator.Irritability is an important symptom domain of major depressive disorder that is not fully reflected in depressive symptom severity measures. Early reductions in irritability, when combined with changes in depressive symptom severity, provide a robust estimate of likelihood of remission or no meaningful benefit in outpatients with major depression.

Background Day-to-day functioning is impaired in major depressive disorder. Yet there are no guidelines to systematically assess these functional changes. This report evaluates prognostic utility of changes in activity impairment to inform clinical decision-making at an individual level. Methods Mixed model analyses tested changes in activity impairment (sixth item of Work and Activity Impairment scale, rated 0–10) at mid-point (week 6) and end of step 1 (weeks 12–14) in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (n = 2697) after controlling for depression severity [Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR)]. Interactive calculators for end of step 1 remission (QIDS-SR ≤5) and no meaningful benefit (

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD). DataSources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. No language or publication year restrictions were used. Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD. Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST). Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate. Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect.

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 (VitalSign6; 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 VitalSign6. 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).

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.

This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS₁₇) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS₁₇ insomnia factor score and KSS score, correlation between the HDRS₁₇ insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6.At baseline, HDRS₁₇ insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P.05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo.Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function.ClinicalTrials.gov identifier: NCT03018340.

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

Irritability in pediatric samples is associated with higher rates of subsequent suicide-related outcomes. No study, to date, has evaluated the longitudinal association between irritability and suicidal ideation (SI) in adults with major depressive disorder (MDD). This report evaluated whether irritability is associated with SI at the same visit (i.e., concurrently) and whether early changes in irritability with antidepressant treatment predict subsequent levels of SI. Participants of Combining Medications to Enhance Depression Outcomes (CO-MED, n = 665), Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC, n = 296), and Suicide Assessment Methodology Study (SAMS, n = 266) were included. Repeated-measures mixed model analyses evaluated concurrent association throughout the trial between irritability (five-item irritability domain of Concise Associated Symptom Tracking scale) and SI (three-item suicidal thoughts factor of Concise Health Risk Tracking scale) after controlling for overall depression (excluding suicidality-related item), and predicted subsequent levels of SI (repeated observations from week-2-to-week-8) based on early (baseline-to-week-2) changes in irritability after controlling for early changes in overall depression. Higher irritability was associated with higher SI concurrently; estimates (standard error) were 0.18 (0.02, p

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

BACKGROUND: This report seeks to evaluate improvements in symptoms of irritability with sertraline (a selective serotonin reuptake inhibitor antidepressant) versus placebo. METHODS: Participants of Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study who were randomized to 8 weeks of treatment with either sertraline or placebo and completed 5-item irritability domain of Concise Associated Symptom Tracking scale (CASTIRR) at baseline were included (n=292). Repeated measures mixed model analysis with CAST-IRR as the outcome variable and treatment arm-by-time interaction as the independent variable of interest evaluated whether changes in irritability with treatment differed between sertraline and placebo arms. A separate analysis controlled for levels of overall depression severity (17-item Hamilton Depression Rating Scale). Covariates included age, sex, race, ethnicity, and site. RESULTS: There was a significant treatment arm-by-time interaction (F = 6.96, df = 6, 1418, p

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.

Background Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD. Methods CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events. Results During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin. Limitations : The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation. Conclusions Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results.

BACKGROUND Heterogeneity in major depressive disorder (MDD) is well recognized but not well understood. Core depressive features are reward and emotional symptoms, which reflect dysfunctions in the positive valence (PV) and negative valence (NV) systems, respectively. This study assessed whether PV and NV systems (based on selected symptoms) were associated with different clinical features, antidepressant response, and levels of immunomarkers in adults with MDD. METHODS These analyses used data from combining medications to enhance depression outcomes study (N = 665; n = 166 for immunomarkers). PV and NV symptom scores were extracted from the clinician-rated 30-item Inventory of Depressive Symptomatology. Correlational analyses were conducted. RESULTS PV and NV symptom scores were substantially associated with different clinical features. PV symptoms (impaired motivation, impaired energy, and anhedonia) were independently associated with female gender (p

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

Background Major depressive disorder (MDD) is often comorbid with metabolic diseases such as obesity, cardiovascular disease, and type 2 diabetes. A potential link between these disorders is adiponectin, an adipocyte-derived circulating hormone with insulin-sensitizing, anti-inflammatory, and neuroplasticity effects. Reductions in plasma levels of adiponectin have been reported in both humans with depression and in the chronic-defeat mouse model of depression. However, the predictive value of adiponectin for treatment response to depression has not been determined. Methods We investigated the potential predictive effect of baseline adiponectin levels in patients who provided plasma and were undergoing one of three pharmacological treatments (escitalopram monotherapy; escitalopram plus bupropion; and venlafaxine plus mirtazapine) in the Combining Medications to Enhance Depression Outcomes clinical trial (n = 160). Specifically, we assessed whether adiponectin moderates—that is, differentially predicts—treatment response among the treatment arms. Improvements with treatment were assessed using change in the clinician-rated 30-item Inventory of Depressive Symptomatology (IDS-C) from baseline through week 12. Moderator effects were tested using separate pairwise repeated measures mixed-effects models with a treatment-arm-by-adiponectin interaction. Results Baseline adiponectin levels moderated treatment outcome between two combination therapies. Specifically, low adiponectin predicted better response to escitalopram plus bupropion compared to venlafaxine plus mirtazapine, whereas high adiponectin predicted better response to venlafaxine plus mirtazapine compared to escitalopram plus bupropion (F = 4.84, p = 0.03). Adiponectin levels did not correlate with baseline depression severity (r = −0.03, p = 0.59). Conclusions Antidepressant selection for patients with MDD can be personalized using pre-treatment blood-based biomarkers, such as adiponectin, thereby improving treatment outcomes.

Quality problem Despite its global burden and prevalence, Major Depressive Disorder often goes undetected and untreated, and is particularly pervasive in the primary care setting. Initial assessment One in four Texans lack health insurance, and people with behavioral health disorders are disproportionately affected. It is possible to provide high-quality depression treatment in primary care settings with outcomes equal to those provided by specialty care. The Center for Depression Research and Clinical Care offered an opportunity to transform service delivery practices in underserved primary care practices to improve quality, health status, patient experience and coordination. Choice of solution A point-of-care, web-based, self-report based software program, VitalSign6, was developed to provide universal depression screening in primary care practices and assist providers in monitoring and treating patients' symptoms using principles of Measurement-Based Care. Implementation Implementation included a multi-faceted training program designed to build confidence and competence in participating clinics' medical providers and staff as well as ongoing performance improvement delivered by the VitalSign6 team. Evaluation Primary care providers (N = 11) were interviewed, using a semi-structured interview guide, with a focus on barriers and challenges to full integration, perceptions of the most/least valuable aspects of the program, and the program's impact on knowledge, attitudes and behaviors about depression screening and treatment. Lessons learned More efficient technology is needed to reduce time wasted, as is training to reduce stigma and correct misconceptions about antidepressant medications. Provider buy-in is essential. Conclusions Despite barriers, VitalSign6 increased knowledge, changed attitudes and enhanced providers' depression screening and treatment skills over time.

BackgroundMajor depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.MethodsWithin an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.ResultsFive pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).ConclusionsA subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

BACKGROUND: Currently, there are no valid clinical or biological markers to personalize the treatment of depression. Recent evidence suggests that body mass index (BMI) may guide the selection of antidepressant medications with different mechanisms of action. METHODS: Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants with BMI measurement (n=662) were categorized as normal- or underweight (

Background The habenula-pancreas axis regulates the stimulatory effects of nicotine on blood glucose levels and may participate in the emergence of type 2 diabetes in human tobacco smokers. This secondary analysis of young adults from the Human Connectome Project (HCP-YA) evaluated whether smoking status links the relationship between habenular volume and glycated hemoglobin (HbA1c), a marker of long-term glycemic control. Methods Habenula segmentation was performed using a fully-automated myelin content-based approach in HCP-YA participants and the results were inspected visually (n = 693; aged 22–37 years). A linear regression analysis was used with habenular volume as the dependent variable, the smoking-by-HbA1c interaction as the independent variable of interest, and age, gender, race, ethnicity, education, income, employment status, body mass index, and total gray matter volume as covariates. Results Habenula volume and HbA1c were similar in smokers and nonsmokers. There was a significant interaction effect (F(1, 673)= 5.03, p = 0.025) indicating that habenular volume was related to HbA1c in a manner that depended on smoking status. Among participants who were smokers (n = 120), higher HbA1c was associated with apparently larger habenular volume (β = 6.74, standard error=2.36, p = 0.005). No such association between habenular volume and HbA1c was noted among participants who were nonsmokers (n = 573). Discussion Blood glucose levels over an extended time period, reflected by HbA1c, were correlated with habenular volume in smokers, consistent with a relationship between the habenula and blood glucose homeostasis in smokers. Future studies are needed to evaluate how habenular function relates to glycemic control in smokers and nonsmokers.

Study Objectives:Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.Method:Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.Results:Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; PConclusions:These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

Uncertainty in selecting the appropriate antidepressant for each patient is a major challenge in treatment of major depressive disorder (MDD). No biologically driven markers are currently available to improve precision in treatment selection, thus leading to a trial-and-error process and prolonged morbidity for most patients. This study developed deep learning models that accurately predict treatment outcomes for sertraline, bupropion and placebo. Models were trained on data from the EMBARC study, in which 223 un-medicated subjects with MDD underwent pre-treatment reward task fMRI and received 8 weeks of treatment with sertraline, bupropion, or placebo. These models integrate fMRI and clinical measures and they explain up to 37% of the variance in ΔHAMD, classify remitters with NNT of 2.3-4.3, and classify responders with NNT of 3.2-4.9. Findings reveal new regions predictive of treatment outcome such as the hippocampus and paracentral lobule, while additional regions implicated in existing research are corroborated. Distinct models were identified for each treatment and provide substantial evidence of their potential to improve precision in treatment selection for MDD.

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

Background: Elevated S100 calcium binding protein B (S100B) levels in systemic circulation may induce neuroinflammation and reflect greater blood–brain barrier (BBB) dysfunction. Neuroinflammation in patients with major depressive disorder (MDD), in turn, may reduce likelihood of improvement with serotonergic antidepressants. Methods: Levels of S100B were measured in plasma samples obtained prior to initiation of treatment with bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine in participants of Combining Medications to Enhance Depression Outcomes trial (n = 153). Depression severity was measured with 16-item Quick Inventory of Depressive Symptomatology Self-Report and anhedonia was measured with 3 items of 30-item Inventory of Depressive Symptomatology. Differential changes in depression severity and anhedonia over acute-phase (baseline, weeks 1, 2, 4, 6, 8, 10, and 12) in the three treatment arms were tested with logS100B-by-treatment-arm interaction in mixed model analyses after controlling for age, gender, and body mass index. Results: There was a significant logS100B-by-treatment-arm interaction for anhedonia (F = 3.21, df = 2, 142, p = 0.04) but not for overall depression severity (F = 1.99, p = 0.14). Higher logS100B levels were associated with smaller reductions in anhedonia (effect size = 0.67, p = 0.047) in escitalopram monotherapy but not in the other two arms. Correlation coefficients of anhedonia severity averaged over acute-phase (including baseline) with baseline S100B levels were 0.57, −0.19, and 0.22 for escitalopram monotherapy, bupropion-plus-escitalopram and venlafaxine-plus-mirtazapine arms respectively. Conclusion: Higher baseline S100B levels in depressed patients resulted in poorer response to escitalopram monotherapy. Addition of bupropion, a dopaminergic antidepressant, partially mitigated this effect.

The authors aimed to evaluate psychometric properties of the Concise Associated Symptom Tracking (CAST) Scale and validate the clinical utility of measuring irritability by updating and replicating a previously published outcome calculator from the Combining Medications to Enhance Depression Outcomes (CO-MED) trial.Participants were 292 adults from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study who had completed the CAST scale at baseline. The scale's five-domain (irritability, anxiety, mania, insomnia, and panic) structure was evaluated with confirmatory factor analysis. Correlations with other clinical measures were used to confirm convergent and divergent validity. Logistic regression analyses from CO-MED were used to estimate individual outcomes in EMBARC.Cronbach's alpha for the CAST scale was 0.78. Model fit for the five-domain structure was adequate (goodness of fit index=0.93, comparative fit index=0.92, root mean square error of approximation=0.06). Scores on irritability, anxiety, panic, insomnia, and mania were correlated with scores on the Anger Attack Questionnaire irritability item (rMeasuring irritability may help predict clinical course. The CAST scale is a valid measure of depression-associated symptoms, including irritability.

Major depressive disorder (MDD) affects one in five adults during their lifetime. Patients with MDD and their clinicians have a multitude of options to select for management of this chronic and/or recurrent condition. Selection of treatment modalities may be guided by the severity of illness. Nonpharmacologic treatments such as psychotherapy or exercise may be considered for those with mild symptom severity, with pharmacologic treatment reserved for those with moderate or higher symptom severity. Severe or very severe depression may warrant the combination of both pharmacologic and psychotherapeutic treatments. In patients who fail to improve adequately with one or more first-line treatments, augmentation with second-generation antipsychotics should be considered. There currently are no objective markers to guide the selection of one first-line treatment over other. Exciting ongoing research in the field of depression may inform new methods to personalize treatment selection and potentially lead to the development of mechanistically novel antidepressants.

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.

Bipolar disorder is a chronic illness that affects 2%-4% of U.S. adults during their lifetime. The course of bipolar disorder is commonly characterized by prolonged periods of depression interspersed with manic-hypomanic episodes. Management of depression among patients with bipolar disorder is challenging because of the limited number of medications currently approved by the Food and Drug Administration, the high proportion of patients who do not respond to these medications, and the metabolic and other side effects associated with long-term use of these medications. In addition to reviewing the clinical options available to patients with bipolar depression and their treatment providers, this article presents an evidence-based management approach and discusses the off-label uses of currently available treatments and experimental therapeutics under development.

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.

OBJECTIVE Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.

Background Although normal Quality of Life (QoL) is the outcome desired by patients, it is unclear if QoL changes early in course of antidepressant treatments are independent of depression severity, and can predict subsequent remission. Methods The Quality of Life Inventory was obtained repeatedly in the Combining Medications to Enhance Depression Outcomes trial. Mixed model analyses assessed QoL change. Using population-based norms, participants were grouped as very low, low, or normal QoL at week 4, and association with remission was evaluated. Results Overall baseline to week 4 QoL improved significantly (p=0.0015) even after controlling for change in depression severity and baseline variables (gender, age, education, race, ethnicity, income, employment status, anxious features, depression onset before age 18, suicidal ideations, and treatment-arm). At week 4, participants with low and normal QoL had higher unadjusted odds ratio (OR) for remission at 3 months (low QoL OR=2.36, 95% confidence interval (CI)=1.25,4.44; normal QoL OR=2.59, 95% CI=1.53,4.39) and 7 months (low QoL OR=2.07, 95% CI=1.00,4.31; normal QoL OR=3.98, 95% CI=2.06,7.69) compared to those with very low QoL. Remission rates, adjusted for baseline variables, were higher only for participants with normal QoL (3 months OR=2.83, 95% CI=1.42,5.68; 7 months OR=6.10, 95% CI=2.40,15.63). Limitations Secondary analysis, short period of assessment for QoL change, remission instead of functional recovery as long-term outcome. Conclusion Quality of life improves early, independent of depression severity. Normal QoL at week 4 is associated with 2–6 times higher remission rates. Findings support QoL beyond symptomatic change as a potential mediator of remission.

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.

The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype on the molecular profile of DLPFC neural circuitry in the control brain, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks.

Objectives 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. Methods 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. Results 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. Conclusions 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.