Dataset Information

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

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

SUBMITTER: Cooper CM

PROVIDER: S-EPMC6543260 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Cooper Crystal M CM Chin Fatt Cherise R CR Jha Manish M Fonzo Gregory A GA Grannemann Bruce D BD Carmody Thomas T Ali Aasia A Aslan Sina S Almeida Jorge R C JRC Deckersbach Thilo T Fava Maurizio M Kurian Benji T BT McGrath Patrick J PJ McInnis Melvin M Parsey Ramin V RV Weissman Myrna M Phillips Mary L ML Lu Hanzhang H Etkin Amit A Trivedi Madhukar H MH

EClinicalMedicine 20190401

<h4>Background</h4>Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could "accurately" identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a la ...[more]

PMID: 31193824

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Project description:BackgroundMajor depressive disorder (MDD) may be associated with accelerated brain aging (higher brain age than chronological age). This report evaluated whether brain age is a clinically useful biomarker by checking its test-retest reliability using magnetic resonance imaging scans acquired 1 week apart and by evaluating the association of accelerated brain aging with symptom severity and antidepressant treatment outcomes.MethodsBrain age was estimated in participants of the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study using T1-weighted structural magnetic resonance imaging (MDD n = 290; female n = 192; healthy control participants n = 39; female n = 24). Intraclass correlation coefficient was used for baseline-to-week-1 test-retest reliability. Association of baseline Δ brain age (brain age minus chronological age) with Hamilton Depression Rating Scale-17 and Concise Health Risk Tracking Self-Report domains (impulsivity, suicide propensity [measures: pessimism, helplessness, perceived lack of social support, and despair], and suicidal thoughts) were assessed at baseline (linear regression) and during 8-week-long treatment with either sertraline or placebo (repeated-measures mixed models).ResultsMean ± SD baseline chronological age, brain age, and Δ brain age were 37.1 ± 13.3, 40.6 ± 13.1, and 3.1 ± 6.1 years in MDD and 37.1 ± 14.7, 38.4 ± 12.9, and 0.6 ± 5.5 years in healthy control groups, respectively. Test-retest reliability was high (intraclass correlation coefficient = 0.98-1.00). Higher baseline Δ brain age in the MDD group was associated with higher baseline impulsivity and suicide propensity and predicted smaller baseline-to-week-8 reductions in Hamilton Depression Rating Scale-17, impulsivity, and suicide propensity with sertraline but not with placebo.ConclusionsBrain age is a reliable and potentially clinically useful biomarker that can prognosticate antidepressant treatment outcomes.

Project description:Background and objectivesDepression is common in patients on hemodialysis, but data on the benefits and risks of antidepressants in this setting are limited. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness.Design, setting, participants, & measurementsPatients on hemodialysis at five United Kingdom renal centers completed the Beck Depression Inventory II. Those scoring ≥16 and not already on treatment for depression were invited to undergo diagnostic interview to confirm major depressive disorder. Eligible patients with major depressive disorder were randomized to receive the study medication-either sertraline or placebo. Outcomes included recruitment and dropout rates, change in the Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory II, and qualitative information to guide design of a large-scale trial.ResultsIn total, 709 patients were screened and enrolled between April of 2013 and October of 2014; 231 (32.6%) had Beck Depression Inventory II scores ≥16, and 68 (29%) of these were already receiving treatment for depression. Sixty-three underwent diagnostic interview, 37 were diagnosed with major depressive disorder, and 30 were randomized; 21 completed the trial: eight of 15 on sertraline and 13 of 15 on placebo (P=0.05). Dropouts due to adverse and serious adverse events were greater in the sertraline group. All occurred in the first 3 months. Over 6 months, depression scores improved in both groups. Beck Depression Inventory II score fell from 29.1±8.4 to 17.3±12.4 (P<0.001), and Montgomery-Asberg Depression Rating Scale score fell from 24.5±4.1 to 10.3±5.8 (P<0.001). There were no differences between sertraline and placebo groups.ConclusionsAlthough small, this is the largest randomized trial to date of antidepressant medication in patients on hemodialysis. Our results highlight recruitment issues. No benefit was observed, but trial size and the substantial dropout render consideration of benefit inconclusive. A definitive trial could use shorter follow-up and include depressed patients already taking antidepressants.

Project description:Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n?=?35) or placebo (n?=?40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, ?(2)(1) ?=?0.75, p?=?0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.

Project description:BackgroundEsketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission.MethodsPost hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined.ResultsThe median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up.ConclusionTreatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality.Trial registrationClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:OBJECTIVES:To evaluate the short-term efficacy and safety of desvenlafaxine (25-50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). METHODS:Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. RESULTS:The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). CONCLUSION:Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50 mg/d was generally safe and well tolerated in children and adolescents in this study.

Dataset Information

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

Publications

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

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