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Early Symptom Improvement as a Predictor of Response to Extended Release Quetiapine in Major Depressive Disorder.

ABSTRACT: The aim of this post-hoc analysis was to determine whether early symptom improvement with extended release quetiapine (quetiapine XR) may predict treatment outcome in patients with major depressive disorder. Data were from 6, double-blind, placebo-controlled studies of quetiapine XR (2 fixed-dose and 2 flexible-dose monotherapy and 2 adjunct studies) in adult patients with major depressive disorder. Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression-Severity Score (CGI-S) were assessed at baseline, weeks 2, 4, and 6. Hamilton Rating Scale for Depression (HAM-D) was assessed at baseline and week 6. The MADRS improvement at week 2 (15%, 20%, 25%, 30%) was used to predict response and remission, based on MADRS (50% improvement; total score ? 12) or HAM-D (50% improvement; total score ? 7). The CGI-S improvement (1 point) at week 2 was used to predict final outcome (CGI-S score ? 2). The predictive value for early improvement with quetiapine XR was found to be "very strong" (Yule's Q coefficient, a combined measure of sensitivity and specificity) using 30% MADRS improvement as the threshold. This was relatively comparable for response and remission and for fixed-dose, flexible-dose, and adjunct studies. This was also observed for placebo. Exceptions were: adjunct studies (where predictivity was lower for ongoing antidepressant/placebo), and for remission (predictivity for remission appeared lower than for response with placebo). In conclusion, outcome at week 6 with quetiapine XR for a major depressive episode could be predicted by 30% improvement after 2 weeks, a finding that could give doctors confidence to continue treatment and may facilitate adherence in patients.

SUBMITTER: McIntyre RS

PROVIDER: S-EPMC4898901 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Early Symptom Improvement as a Predictor of Response to Extended Release Quetiapine in Major Depressive Disorder.

McIntyre Roger S RS Gorwood Philip P Thase Michael E ME Liss Charlie C Desai Dhaval D Chen Ji J Bauer Michael M

Journal of clinical psychopharmacology 20151201 6

The aim of this post-hoc analysis was to determine whether early symptom improvement with extended release quetiapine (quetiapine XR) may predict treatment outcome in patients with major depressive disorder. Data were from 6, double-blind, placebo-controlled studies of quetiapine XR (2 fixed-dose and 2 flexible-dose monotherapy and 2 adjunct studies) in adult patients with major depressive disorder. Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression-Severity Score ( ...[more]

PMID: 26474010

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Project description:OBJECTIVES:To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD). PATIENTS AND METHODS:This was a 10-week (8-week active treatment/2-week post-treatment) randomized, double-blind, placebo- and active-controlled study (D1448C00004). Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) at week two received double-dose treatment. The primary end point was week eight change from randomization in MADRS total score. Secondary end points included MADRS response (?50% improvement) and remission (score ?8); Hamilton Rating Scale for Depression total and item 1; Hamilton Rating Scale for Anxiety total, psychic, and somatic; Clinical Global Impressions - Severity of Illness total; Pittsburgh Sleep Quality Index (PSQI) global; and Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form percentage maximum total scores. Tolerability was assessed throughout. RESULTS:A total of 471 patients was randomized. No significant improvements in MADRS total score were observed at week eight (last observation carried forward) with either active treatment (quetiapine XR, -17.21 [P=0.174]; escitalopram, -16.73 [P=0.346]) versus placebo (-15.61). There were no significant differences in secondary end points versus placebo, with the exception of week-eight change in PSQI global score (quetiapine XR, -4.96 [P<0.01] versus placebo, -3.37). Mixed-model repeated-measures analysis of observed-case data suggested that the primary analysis may not be robust. Most commonly reported adverse events included dry mouth, somnolence, and dizziness for quetiapine XR, and headache and nausea for escitalopram. CONCLUSION:In this study, neither quetiapine XR (150/300 mg/day) nor escitalopram (10/20 mg/day) showed significant separation from placebo. Both compounds have been shown previously to be effective in the treatment of MDD; possible reasons for this failed study are discussed. Quetiapine XR was generally well tolerated, with a profile similar to that reported previously.

Project description:Background: Sleep disturbances, such as early wakening, are frequently observed in patients with major depressive disorder (MDD). The suprachiasmatic nuclei (SCN), which controls circadian rhythm, is innervated by the raphe nucleus, a region where Tryptophan hydroxylase-2 (TPH-2) gene is primarily expressed. Although TPH-2 is often implicated in the pathophysiology of depression, few studies have applied a genetic and imaging technique to investigate the mechanism of early wakening symptom in MDD. We hypothesized that TPH-2 variants could influence the function of SCN in MDD patients with early wakening symptom. Methods: One hundred and eighty five MDD patients (62 patients without early wakening and 123 patients with early wakening) and 64 healthy controls participated in this study. Blood samples were collected and genotyping of rs4290270, rs4570625, rs11178998, rs7305115, rs41317118, and rs17110747 were performed by next-generation sequencing (NGS) technology. Logistic regression model was employed for genetic data analysis using the PLINK software. Based on the allele type, rs4290270, which was significant in the early wakening MDD group, participants were categorized into two groups (A allele and T carrier). All patients underwent whole brain resting-state functional magnetic resonance imaging (rs-fMRI) scanning and a voxel-wise functional connectivity comparison was performed between the groups. Results: rs4290270 was significantly linked to MDD patients who exhibited early wakening symptom. The functional connectivities of the right SCN with the right fusiform gyrus and right middle frontal gyrus were increased in the T carrier group compared to the A allele group. In addition, the functional connectivities of the left SCN with the right lingual gyrus and left calcarine sulcus were decreased in the T carrier group compared to the A allele group. Conclusion: These findings suggested that the TPH-2 gene variant, rs4290270, affected the circadian regulating function of SCN. The altered functional connectivities, observed between the SCN and right fusiform gyrus, right middle frontal gyrus, the right lingual gyrus and left calcarine sulcus, could highlight the neural mechanism by which SCN induces sleep-related circadian disruption in T carrier MDD patients. Hence, rs4290270 could potentially serve as a reliable biomarker to identify MDD patients with early wakening symptom.

Project description:In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales.SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score ? 4) to mild-no impairment (score ? 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score ? 7) baseline impairment to moderate-no (score ? 6) or mild-no impairment (score ? 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked-extreme impairment, were also evaluated.A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P < .01). Depending on the SDS subscale, 48%-55% of levomilnacipran ER-treated patients with moderate-extreme impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%-47%) of levomilnacipran ER-treated patients versus only about one-third (29%-34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains.These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant.ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and EudraCT identifier: 2006-002404-34.

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:We aimed to compare the degree of symptom relief to psychosocial functional (abbreviated as "functional") improvement and explore the relationships between symptom relief and functional improvement during acute electroconvulsive therapy for patients with major depressive disorder.Major depressive disorder inpatients (n=130) requiring electroconvulsive therapy were recruited. Electroconvulsive therapy was generally performed for a maximum of 12 treatments. Symptom severity, using the 17-item Hamilton Depression Rating Scale, and psychosocial functioning (abbreviated as "functioning"), using the Modified Work and Social Adjustment Scale, were assessed before electroconvulsive therapy, after every 3 electroconvulsive therapy treatments, and after the final electroconvulsive therapy. Both 17-item Hamilton Depression Rating Scale and Modified Work and Social Adjustment Scale scores were converted to T-score units to compare the degrees of changes between depressive symptoms and functioning after electroconvulsive therapy. Structural equation modeling was used to test the relationships between 17-item Hamilton Depression Rating Scale and Modified Work and Social Adjustment Scale during acute electroconvulsive therapy.One hundred sixteen patients who completed at least the first 3 electroconvulsive therapy treatments entered the analysis. Reduction of 17-item Hamilton Depression Rating Scale T-scores was significantly greater than that of Modified Work and Social Adjustment Scale T-scores at assessments 2, 3, 4, and 5. The model analyzed by structural equation modeling satisfied all indices of goodness-of-fit (chi-square = 32.882, P =.107, TLI = 0.92, CFI = 0.984, RMSEA = 0.057). The 17-item Hamilton Depression Rating Scale change did not predict subsequent Modified Work and Social Adjustment Scale change.Functioning improved less than depressive symptoms during acute electroconvulsive therapy. Symptom reduction did not predict subsequent functional improvement. Depressive symptoms and functional impairment are distinct domains and should be assessed independently to accurately reflect the effectiveness of electroconvulsive therapy.

Dataset Information

Early Symptom Improvement as a Predictor of Response to Extended Release Quetiapine in Major Depressive Disorder.

Publications

Early Symptom Improvement as a Predictor of Response to Extended Release Quetiapine in Major Depressive Disorder.

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