The metabolome-wide signature of major depressive disorder.

Major Depressive Disorder (MDD) is a common, frequently chronic condition characterized by substantial molecular alterations and pathway dysregulations. Single metabolite and targeted metabolomics platforms have revealed several metabolic alterations in depression, including energy metabolism, neurotransmission, and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulations in depression and reveal previously untargeted mechanisms. Here, we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline, which were repeated in 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology Self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at 6-year follow-up. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Adding body mass index and lipid-lowering medication to the models changed results only marginally. Among the overlapping metabolites, 34 were confirmed in internal replication analyses using 6-year follow-up data. Downregulated metabolites were enriched with long-chain monounsaturated (P = 6.7e-07) and saturated (P = 3.2e-05) fatty acids; upregulated metabolites were enriched with lysophospholipids (P = 3.4e-4). Mendelian randomization analyses using genetic instruments for metabolites (N = 14,000) and MDD (N = 800,000) showed that genetically predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.

Bupropion and Naltrexone in Methamphetamine Use Disorder.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

Features of immunometabolic depression as predictors of antidepressant treatment outcomes: pooled analysis of four clinical trials.

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, ßpooled = 0.06, P = 0.049, 95% CI 0.0001-0.12, I2 = 3.61%); this was also found for an IMD index combining these features (n = 372, ßpooled = 0.12, s.e. = 0.12, P = 0.031, 95% CI 0.01-0.22, I2= 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 (ßpooled = 0.16) and the IMD index (ßpooled = 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.

Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Metabolomic and inflammatory signatures of symptom dimensions in major depression.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. METHODS: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. RESULTS: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. CONCLUSION: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression.

OBJECTIVE: To use the Clinical Global Impression-Severity (CGI-S) scale to estimate clinically meaningful and clinically substantial changes as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Sheehan Disability Scale (SDS), and the Patient Health Questionnaire-9 (PHQ-9) in patients with treatment-resistant depression (TRD). METHODS: Pooled data were derived from two 4-week, randomized, active-controlled studies evaluating esketamine nasal spray (ESK) plus oral antidepressant (OAD) or OAD plus placebo nasal spray (PBO) in adults with TRD (N = 565). CGI-S, MADRS, SDS, and PHQ-9 scores were obtained at baseline and over 4 weeks of treatment. In this post hoc analysis, change scores on the MADRS, SDS, and PHQ-9 that corresponded to a clinically meaningful (1-point) or clinically substantial (2-point) change on the CGI-S scale were identified. RESULTS: Clinically meaningful changes in CGI-S scores after 28 days corresponded to 6-, 4-, and 3-point changes from baseline on the MADRS, SDS, and PHQ-9, respectively. Similarly, a 2-point CGI-S score change (clinically substantial change) corresponded to a 12-, 8-, and 6-point change on the MADRS, SDS, and PHQ-9, respectively. The proportion of patients showing substantial clinical improvement in the ESK plus OAD group versus the OAD plus PBO group after 28 days of treatment favored ESK plus OAD: 69.0% vs 55.3% (MADRS), 64.5% vs 48.9% (SDS), and 77.1% vs 64.7% (PHQ-9). CONCLUSION: We provide a basis for identifying clinically meaningful and clinically substantial changes as assessed with commonly used outcome measures for depression to facilitate the translation of clinical trial results into clinical practice.

Vagus Nerve Stimulation in Patients Receiving Maintenance Therapy With Electroconvulsive Therapy: A Series of 10 Cases.

OBJECTIVES: Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS: This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS: One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS: Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.

Can psychological features predict antidepressant response to rTMS? A Discovery-Replication approach.

BACKGROUND: Few studies focused on the relationship between psychological measures, major depressive disorder (MDD) and repetitive transcranial magnetic stimulation (rTMS) response. This study investigated several psychological measures as potential predictors for rTMS treatment response. Additionally, this study employed two approaches to evaluate the robustness of our findings by implementing immediate replication and full-sample exploration with strict p-thresholding. METHODS: This study is an open-label, multi-site study with a total of 196 MDD patients. The sample was subdivided in a Discovery (60% of total sample, n = 119) and Replication sample (40% of total sample, n = 77). Patients were treated with right low frequency (1 Hz) or left high frequency (10 Hz) rTMS at the dorsolateral prefrontal cortex. Clinical variables [Beck Depression Inventory (BDI), Neuroticism, Extraversion, Openness Five-Factor Inventory, and Depression, Anxiety, and Stress Scale, and BDI subscales] were obtained at baseline, post-treatment, and at follow-up. Predictors were analyzed in terms of statistical association, robustness (independent replication), as well as for their clinical relevance [positive predictive value (PPV) and negative predictive value (NPV)]. RESULTS: Univariate analyses revealed that non-responders had higher baseline anhedonia scores. Anhedonia scores at baseline correlated negatively with total BDI percentage change over time. This finding was replicated. However, anhedonia scores showed to be marginally predictive of rTMS response, and neither PPV nor NPV reached the levels of clinical relevance. CONCLUSIONS: This study suggests that non-responders to rTMS treatment have higher baseline anhedonia scores. However, anhedonia was only marginally predictive of rTMS response. Since all other psychological measures did not show predictive value, it is concluded that psychological measures cannot be used as clinically relevant predictors to rTMS response in MDD.

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

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

Fixed-dose gabapentin augmentation in the treatment of alcohol withdrawal syndrome: a retrospective, open-label study.

Background: Lorazepam use in the treatment of alcohol withdrawal syndrome (AWS) is not without risk.Objective: This study compares AWS outcomes using a standard, symptom-triggered lorazepam dosing protocol (control group) and symptom-triggered lorazepam dosing augmented with a gabapentin loading dose and taper (GABA group).Methods: Consecutive, non-randomized adults (n = 982; 64.0% male) undergoing treatment for AWS were included in this retrospective, open-label study. Symptom-triggered lorazepam dosing was informed by scores on the Clinical Institute Withdrawal Assessment-Alcohol, revised (CIWA-Ar). Gabapentin augmentation utilized an initial loading dose (900 mg) and a three-day taper. Outcomes included average symptom severity per treatment hour and average lorazepam dose per treatment hour. Average time in the protocol by group, stratified by highest CIWA-Ar score, was examined as a secondary outcome. A priori group differences were controlled statistically.Results: GABA patients were older and exhibited somewhat more severe withdrawal symptoms than controls. After controlling for confounders, gabapentin augmentation did not significantly lower average lorazepam dosing per treatment hour or withdrawal symptom severity per treatment hour. Compared to controls, overall withdrawal symptoms diminished somewhat more rapidly for GABA patients experiencing low or moderate-level withdrawal symptoms; however, severe withdrawal symptoms remitted more slowly in the GABA group. Results should be interpreted in light of the uncontrolled nature of group assignment and other confounders.Conclusions: Compared to symptom-triggered lorazepam dosing alone, gabapentin augmentation did not produce better outcomes during treatment of acute AWS. These results do not support the use of scheduled gabapentin as an augmentation to benzodiazepines during inpatient treatment of AWS.

Prediction of Acute-Phase Treatment Outcomes by Adding a Single-Item Measure of Activity Impairment to Symptom Measurement: Development and Validation of an Interactive Calculator from the STAR*D and CO-MED Trials.

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 (<30% QIDS-SR reduction from baseline) were developed for participants with complete data (n = 1476) and independently replicated in the Combining Medications to Enhance Depression Outcomes trial (n = 399). RESULTS: Activity impairment improved independently with acute-phase treatment in STAR*D (F = 7.27; df = 2,2625; P < .001). Baseline to mid-point activity impairment change significantly predicted remission (P < .001, model area under the curve = 0.823) and no meaningful benefit (P < .001, area under the curve = 0.821) in the STAR*D trial. Adding activity impairment variables to depression severity measures correctly reclassified 28.4% and 15.8% remitters and nonremitters (net reclassification improvement analysis, P < .001), and 11.4% and 16.8% of those with no meaningful benefit and meaningful benefit (net reclassification improvement analysis, P < .001). The STAR*D trial model estimates accurately predicted remission (area under the curve = 0.80) and no meaningful benefit (area under the curve = 0.82) in the Combining Medications to Enhance Depression Outcomes trial and was used to develop an interactive calculator. CONCLUSION: A single-item self-report measure of activity impairment changes independently with antidepressant treatment. Baseline to week 6 changes in activity impairment and depression severity can be combined to predict acute-phase remission and no meaningful benefit at an individual level.

Fatigue in Nondialysis Chronic Kidney Disease: Correlates and Association with Kidney Outcomes.

BACKGROUND: Fatigue, although common and associated with outcomes in dialysis-dependent chronic kidney disease (CKD), has not been studied in nondialysis chronic kidney disease (CKD-ND) patients. METHODS: In this longitudinal cohort of 266 outpatients with CKD-ND stages 2-5, we measured self-reported fatigue on 3 scales-Quick Inventory of Depression Symptomatology-Self Report (QIDS-SR16), Beck Depression Inventory-I (BDI-I), and short form 12 health survey (SF-12) questionnaires and evaluated the prespecified composite of progression to dialysis initiation, death, or hospitalization after 12 months. Logistic and linear regression assessed characteristics associated with fatigue. Survival analysis measured associations of fatigue with outcomes. RESULTS: Mean age was 64.4 ± 12.0 years, and mean estimated glomerular filtration rate (eGFR) was 31.6 ± 16.7 mL/min/1.73 m2. Fatigue was common, with 69.2% reporting fatigue on QIDS-SR16 and 77.7% on BDI-I. Unemployment, comorbidities, use of antidepressant medications, and lower hemoglobin correlated with fatigue. There were 126 outcome events. Participants that reported any versus no fatigue on QIDS-SR16 were more likely to reach the composite, hazard ratio (HR) 1.70 (95% CI 1.11-2.59), which persisted after adjusting for demographics, comorbidities, substance abuse, hemoglobin, albumin, eGFR, and calcium-phosphorus product, HR 1.63 (1.05-2.55). Fatigue severity by the SF-12 was also associated with outcomes independent of demographics, comorbidities, and substance abuse, HR per unit increase 1.18 (1.03-1.35). No association was observed with fatigue on the BDI-I. CONCLUSION: Fatigue affected about 2/3 of CKD-ND patients and associated with unemployment, comorbidities, antidepressant medication use, and anemia. Fatigue measured by the QIDS-SR16 and SF-12 independently predicted outcomes in CKD patients. Eliciting the presence of fatigue may be a clinically significant prognostic assessment in CKD patients.

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

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

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

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

Algorithms For Treatment of Major Depressive Disorder: Efficacy and Cost-Effectiveness.

In spite of multiple new treatment options, chronic and treatment refractory courses still are a major challenge in the treatment of depression. Providing algorithm-guided antidepressant treatments is considered an important strategy to optimize treatment delivery and avoid or overcome treatment-resistant courses of major depressive disorder (MDD). The clinical benefits of algorithms in the treatment of inpatients with MDD have been investigated in large-scale, randomized controlled trials. Results showed that a stepwise treatment regimen (algorithm) with critical decision points at the end of each treatment step based on standardized and systematic measurements of response and an algorithm-guided decision-making process increases the chances of achieving remission and optimizes prescription behaviors for antidepressants. In conclusion, research in MDD revealed that systematic and structured treatment procedures, the diligent assessment of response at critical decision points, and timely dose and treatment type adjustments make the substantial difference in treatment outcomes between algorithm-guided treatment and treatment as usual.

Worsening Anxiety, Irritability, Insomnia, or Panic Predicts Poorer Antidepressant Treatment Outcomes: Clinical Utility and Validation of the Concise Associated Symptom Tracking (CAST) Scale.

Background: We report on the psychometric properties of the 16-item Concise Associated Symptom Tracking Scale self-report scale and its clinical utility. Methods: The 5-domain (irritability, anxiety, mania, insomnia, and panic) structure of Concise Associated Symptom Tracking Scale was validated with confirmatory factor analysis in Combining Medications to Enhance Depression Outcomes trial participants at baseline (n=664). Correlations with other clinical measures were used for convergent and divergent validity. In participants with at least one postbaseline visit (n=630), worsening in each Concise Associated Symptom Tracking Scale domain was defined as ≥1.28 SD increase from baseline for each visit (weeks 1, 2, 4, and 6) only. Worsening in any domain (except mania) was defined as overall worsening. Association of domain-specific and overall worsening with remission was tested with logistic regression analyses. Results: The 5-domain structure had adequate model fit on confirmatory factor analysis (GFI=0.93, CFI=0.89, and RMSEA=0.07). Scores on anxiety, panic, insomnia, and mania significantly correlated with Hamilton Rating Scale for Depression anxiety subscale (rs=0.27), Psychiatric Diagnostic Screening Questionnaire-panic scale (rs=0.35), sum of 3 Quick Inventory of Depressive Symptomatology Self-Report insomnia items (rs=0.55), and Altman Self-Rating Mania scale (rs=0.41), respectively. From baseline to week 6, 5.2%, 7.5%, 47.6%, 15.6%, 6.2%, and 27.6% participants (n=630) experienced irritability, anxiety, mania, insomnia, panic, and overall worsening, respectively. Participants with overall worsening were less likely to remit (31.6%) than those without any worsening (43.9%; odds ratio=0.53, 95% CI=0.36, 0.78). Conclusion: The 16-item Concise Associated Symptom Tracking Scale self-report has acceptable psychometric properties. Clinically significant worsening of irritability, anxiety, insomnia, or panic with antidepressant treatment is associated with poorer outcomes.

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

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