Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial

2020 ◽  
pp. 1-9
Author(s):  
Yuen-Siang Ang ◽  
Gerard E. Bruder ◽  
John G. Keilp ◽  
Ashleigh Rutherford ◽  
Daniel M. Alschuler ◽  
...  
Keyword(s):  
Cognitive Control ◽  
Treatment Response ◽  
Cognitive Processing ◽  
Reuptake Inhibitor ◽  
Verbal Fluency ◽  
Antidepressant Treatment ◽  
Clinical Care ◽  
Antidepressant Response ◽  
Clinical Value ◽  
Reward Responsiveness

Abstract Background Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. Methods In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. Results Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. Conclusion These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

scholarly journals Epigenetic Signatures in Antidepressant Treatment Response: a Methylome-wide Association Study in the EMC Trial

2022 ◽  
Author(s):  
Jan Engelmann ◽  
Lea Zillich ◽  
Josef Frank ◽  
Stefanie Wagner ◽  
Metin Cetin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Treatment Response ◽  
Antidepressant Treatment ◽  
Association Studies ◽  
Genetic Material ◽  
Differential Methylation ◽  
Secondary Outcome ◽  
Genome Wide Association Studies ◽  
Antidepressant Response ◽  
Early Improvement

Abstract Although the currently available antidepressants are well established in the treatment of major depressive disorder (MDD), there is strong variability in the response of individual patients. Reliable predictors to guide treatment decisions before or in an early stage of treatment are needed. DNA-methylation has been proven a useful biomarker in different clinical conditions, but its importance for mechanisms of antidepressant response has not yet been determined. 80 MDD patients were selected out of >500 participants from the Early Medication Change (EMC) cohort with available genetic material based on their antidepressant response after four weeks and stratified into clear responders and age- and sex-matched non-responders (N=40, each). Early improvement after two weeks was analyzed as a secondary outcome. DNA-methylation was determined using the Illumina EPIC BeadChip. Epigenome-wide association studies were performed and differentially methylated regions (DMRs) identified using the comb-p algorithm. Enrichment was tested for hallmark gene-sets and in genome-wide association studies of depression and antidepressant response. No epigenome-wide significant differentially methylated positions were found for treatment response or early improvement. Twenty DMRs were associated with response; the strongest in an enhancer region in SORBS2, which has been related to cardiovascular diseases and type II diabetes. Another DMR was located in CYP2C18, a gene previously linked to antidepressant response. Results pointed towards differential methylation in genes associated with cardiac function, neuroticism, and depression. Linking differential methylation to antidepressant treatment response is an emerging topic and represents a step towards personalized medicine, potentially facilitating the prediction of patients’ response before treatment.

scholarly journals White Matter Microstructure Alterations Associated With Paroxetine Treatment Response in Major Depression

2021 ◽  
Vol 15 ◽  
Author(s):  
Rita Vieira ◽  
Ana Coelho ◽  
Joana Reis ◽  
Carlos Portugal-Nunes ◽  
Ricardo Magalhães ◽  
...  
Keyword(s):  
White Matter ◽  
Major Depression ◽  
Magnetic Resonance ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Antidepressant Treatment ◽  
Antidepressant Response ◽  
Superior Longitudinal Fasciculus ◽  
White Matter Microstructure ◽  
Paroxetine Treatment

More than one-third of depressive patients do not achieve remission after the first antidepressant treatment. The “watch and wait” approach used to find the most effective antidepressant leads to an increased personal, social, and economic burden in society. In order to overcome this challenge, there has been a focus on studying neural biomarkers associated with antidepressant response. Diffusion tensor imaging measures have shown a promising role as predictors of antidepressant response by pointing to pretreatment differences in the white matter microstructural integrity between future responders and non-responders to different pharmacotherapies. Therefore, the aim of the present study was to explore whether response to paroxetine treatment was associated with differences in the white matter microstructure at baseline. Twenty drug-naive patients diagnosed with major depressive disorder followed a 6- to 12-week treatment with paroxetine. All patients completed magnetic resonance brain imaging and a clinical assessment at baseline and 6–12 weeks after treatment. Whole-brain tract-based spatial statistics was used to explore differences in white matter microstructural properties estimated from diffusion magnetic resonance imaging. Voxel-wise statistical analysis revealed a significant increase in fractional anisotropy and a decrease in radial diffusivity in forceps minor and superior longitudinal fasciculus in responders compared to non-responders. Thus, alterations in white matter integrity, specifically in forceps minor and the superior longitudinal fasciculus, are associated with paroxetine treatment response. These findings pave the way for personalized treatment strategies in major depression.

scholarly journals FKBP5 Gene Variants as Predictors for Antidepressant Response in Individuals with Major Depressive Disorder Who Have Experienced Childhood Trauma. A Systematic Review

2020 ◽  
Author(s):  
Natalie Wietfeldt
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Treatment Response ◽  
Childhood Trauma ◽  
Antidepressant Treatment ◽  
Poor Response ◽  
Epigenetic Mechanism ◽  
Gene Variants ◽  
Antidepressant Response ◽  
Major Depressive

FKBP5 gene variants may predict antidepressant treatment response in individuals with Major Depressive Disorder. PubMed and Web of Science were searched systematically for articles studying individuals who had received a diagnosis of Major Depressive Disorder (MDD) and were given antidepressant treatment. Inclusion criteria were studies that researched FKBP5 and its variants and focused on antidepressant treatment response. Previous studies support a potential underlying epigenetic mechanism, demethylation at FKBP5 polymorphisms (rs1360780, rs3800373, rs9470080, and rs4713916) after experiencing childhood trauma, leading to increased hypothalamic-pituitary-adrenal (HPA) axis sensitivity and a propensity for the development of MDD. These polymorphisms informed the search, but additional polymorphisms (rs9380514, rs352428) were also considered. Studies conducted prior to 2008, reviews, meta-analyses, editorials, and non-research based articles were excluded. Studies examined in this article link FKBP5 polymorphisms (rs4713916) and FKBP5 RNA levels with positive antidepressant response. Variants rs1360780, rs3800373, and rs9470080 were associated with both positive response and non-response or lack of remission. Variants rs9380514, rs352428, and rs936882 were associated with poor response to antidepressant treatment or non-remission. Further insights into the role FKBP5 plays in development and antidepressant treatment response may be aided by future studies focused on individuals who previously experienced childhood trauma and later developed MDD.

scholarly journals A distinct transcriptional signature of antidepressant response in hippocampal dentate gyrus granule cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David P. Herzog ◽  
Diego Pascual Cuadrado ◽  
Giulia Treccani ◽  
Tanja Jene ◽  
Verena Opitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dentate Gyrus ◽  
Treatment Response ◽  
Differentially Expressed Genes ◽  
Granule Cells ◽  
Antidepressant Treatment ◽  
Poor Responder ◽  
Differentially Expressed ◽  
Molecular Signatures ◽  
Antidepressant Response

AbstractMajor depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.

scholarly journals Biomarkers of ketamine’s antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology

2021 ◽  
Vol 5 ◽  
pp. 247054702110142
Author(s):  
Alexandra A. Alario ◽  
Mark J. Niciu
Keyword(s):  
Treatment Response ◽  
Antidepressant Treatment ◽  
A Priori ◽  
Antidepressant Effect ◽  
Aspartate Receptor ◽  
Neurophysiological Studies ◽  
All Cause Mortality ◽  
Antidepressant Efficacy ◽  
Glutamate Modulators ◽  
Response Biomarkers

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

scholarly journals Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study

2021 ◽  
Author(s):  
Floor A. M. Postema ◽  
Saskia M. J. Hopman ◽  
Corianne A. J. M. de Borgie ◽  
Cora M. Aalfs ◽  
Jakob K. Anninga ◽  
...  
Keyword(s):  
Screening Tool ◽  
Clinical Care ◽  
False Negative ◽  
Negative Control ◽  
Control Group ◽  
Clinical Value ◽  
Variant Of Uncertain Significance ◽  
Multi Center Study ◽  
Center Study ◽  
Genetic Consultation

AbstractRecognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.

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