Dataset Information

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

ABSTRACT: BACKGROUND:Definition of response is critical when seeking to establish valid predictors of treatment success. However, response at the end of study or endpoint only provides one view of the overall clinical picture that is relevant in testing for predictors. The current study employed a classification technique designed to group subjects based on their rate of change over time, while simultaneously addressing the issue of controlling for baseline severity. METHODS:A set of latent class trajectory analyses, incorporating baseline level of symptoms, were performed on a sample of 344 depressed patients from a clinical trial evaluating the efficacy of cognitive behavior therapy and two antidepressant medications (escitalopram and duloxetine) in patients with major depressive disorder. RESULTS:Although very few demographic and illness-related features were associated with response rate profiles, the aggregated effect of candidate genetic variants previously identified in large pharmacogenetic studies and meta-analyses showed a significant association with early remission as well as nonresponse. These same genetic scores showed a less compelling relationship with endpoint response categories. In addition, consistent nonresponse throughout the study treatment period was shown to occur in different subjects than endpoint nonresponse, which was verified by follow-up augmentation treatment outcomes. CONCLUSIONS:When defining groups based on the rate of change, controlling for baseline depression severity may help to identify the clinically relevant distinctions of early response on one end and consistent nonresponse on the other.

SUBMITTER: Kelley ME

PROVIDER: S-EPMC6662579 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

Kelley Mary E ME Dunlop Boadie W BW Nemeroff Charles B CB Lori Adriana A Carrillo-Roa Tania T Binder Elisabeth B EB Kutner Michael H MH Rivera Vivianne Aponte VA Craighead W Edward WE Mayberg Helen S HS

Depression and anxiety 20180907 10

<h4>Background</h4>Definition of response is critical when seeking to establish valid predictors of treatment success. However, response at the end of study or endpoint only provides one view of the overall clinical picture that is relevant in testing for predictors. The current study employed a classification technique designed to group subjects based on their rate of change over time, while simultaneously addressing the issue of controlling for baseline severity.<h4>Methods</h4>A set of latent ...[more]

PMID: 30260539

Similar Datasets

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:BACKGROUND:Major depressive disorder and bipolar disorder are prevalent and debilitating psychiatric disorders that are difficult to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. Quantitative protein profile analysis might help to objectively distinguish between these disorders and increase our understanding of their pathophysiology. Thus, this study was conducted to compare the peripheral protein profiles between the two disorders. METHODS:Serum samples were collected from 18 subjects with major depressive disorder and 15 subjects with bipolar disorder. After depleting abundant proteins, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification were performed. Data-dependent acquisition data were statistically analysed from the samples of 15 subjects with major depressive disorder and 10 subjects with bipolar disorder who were psychotropic drug-free. Two-sided t-tests were performed for pairwise comparisons of proteomes to detect differentially-expressed proteins (DEPs). Ingenuity Pathway Analysis of canonical pathways, disease and functions, and protein networks based on these DEPs was further conducted. RESULTS:Fourteen DEPs were significant between subjects with major depressive disorder and those with bipolar disorder. Ras-related protein Rab-7a (t = 5.975, p = 4.3 × 10- 6) and Rho-associated protein kinase 2 (t = 4.782, p = 8.0 × 10- 5) were significantly overexpressed in subjects with major depressive disorder and Exportin-7 (t = -4.520, p = 1.5 × 10- 4) was significantly overexpressed in subjects with bipolar disorder after considering multiple comparisons. Bioinformatics analysis showed that cellular functions and inflammation/immune pathways were significantly different. CONCLUSIONS:Ras-related protein Rab-7a, Rho-associated protein kinase 2, and Exportin-7 were identified as potential peripheral protein candidates to distinguish major depressive disorder and bipolar disorder. Further large sample studies with longitudinal designs and validation processes are warranted.

Project description:Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1?, TNF?, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.

Dataset Information

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

Publications

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets