Antidepressant Treatment-Induced State-Dependent Reconfiguration of Emotion Regulation Networks in Major Depressive Disorder

Deficits in emotion regulation are the main clinical features, common risk factors, and treatment-related targets for major depressive disorder (MDD). The neural bases of emotion regulation are moving beyond specific functions and emphasizing instead the integrative functions of spatially distributed brain areas that work together as large-scale brain networks, but it is still unclear whether the dynamic interactions among these emotion networks would be the target of clinical intervention for MDD. Data were collected from 70 MDD patients and 43 sex- and age-matched healthy controls. The dynamic functional connectivity (dFC) between emotion regions was estimated via a sliding-window method based on resting-state functional magnetic resonance imaging (R-fMRI). A k-means clustering method was applied to classify all time windows across all participants into several dFC states reflecting recurring functional interaction patterns among emotion regions over time. The results showed that four dFC states were identified in the emotion networks. Their alterations of state-related occurrence proportion were found in MDD and subsequently normalized following 12-week antidepressant treatment. Baseline strong dFC could predict the reduction rate of Hamilton Depression Rating Scale (HAMD) scores. These findings highlighted the state-dependent reconfiguration of emotion regulation networks in MDD patients owing to antidepressant treatment.

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180 Improvement of Sexual Function Observed During Treatment of Major Depressive Disorder with Adjunctive Pimavanserin

CNS Spectrums ◽

10.1017/s1092852920000954 ◽

2020 ◽

Vol 25 (2) ◽

pp. 313-314

Author(s):

Marlene P. Freeman ◽

Maurizio Fava ◽

Bryan Dirks ◽

Manish K. Jha ◽

Richard C. Shelton ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Sexual Function ◽

Rating Scale ◽

Sexual Interest ◽

Massachusetts General Hospital ◽

Antidepressant Treatment ◽

Analysis Of Covariance ◽

Inadequate Response ◽

Major Depressive

Abstract:Study Objectives:Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.Method:Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.Results:Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).Conclusions:These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

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Effectiveness of mirtazapine as add-on to paroxetine v. paroxetine or mirtazapine monotherapy in patients with major depressive disorder with early non-response to paroxetine: a two-phase, multicentre, randomized, double-blind clinical trial

Psychological Medicine ◽

10.1017/s0033291719004069 ◽

2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Le Xiao ◽

Xuequan Zhu ◽

Amy Gillespie ◽

Yuan Feng ◽

Jingjing Zhou ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Rating Scale ◽

Antidepressant Treatment ◽

Additional Treatment ◽

Combination Group ◽

Open Label ◽

Major Depressive ◽

Double Blind ◽

Early Improvement

Abstract Background This study aimed to examine the efficacy of combining paroxetine and mirtazapine v. switching to mirtazapine, for patients with major depressive disorder (MDD) who have had an insufficient response to SSRI monotherapy (paroxetine) after the first 2 weeks of treatment. Methods This double-blind, randomized, placebo-controlled, three-arm study recruited participants from five hospitals in China. Eligible participants were aged 18–60 years with MDD of at least moderate severity. Participants received paroxetine during a 2-week open-label phase and patients who had not achieved early improvement were randomized to paroxetine, mirtazapine or paroxetine combined with mirtazapine for 6 weeks. The primary outcome was improvement on the Hamilton Rating Scale for Depression 17-item (HAMD-17) scores 6 weeks after randomization. Results A total of 204 patients who showed early non-response to paroxetine monotherapy were randomly assigned to receive either mirtazapine and placebo (n = 68), paroxetine and placebo (n = 68) or mirtazapine and paroxetine (n = 68), with 164 patients completing the outcome assessment. At week 8, the least squares (LS) mean change of HAMD-17 scores did not significantly differ among the three groups, (12.98 points) in the mirtazapine group, (12.50 points) in the paroxetine group and (13.27 points) in the mirtazapine plus paroxetine combination group. Participants in the paroxetine monotherapy group were least likely to experience adverse effects. Conclusions After 8 weeks follow-up, paroxetine monotherapy, mirtazapine monotherapy and paroxetine/mirtazapine combination therapy were equally effective in non-improvers at 2 weeks. The results of this trial do not support a recommendation to routinely offer additional treatment or a switch in treatment strategies for MDD patients who do not show early improvement after 2 weeks of antidepressant treatment.

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Remote Digital Measurement of Facial and Vocal Markers of Major Depressive Disorder Severity and Treatment Response: A Pilot Study

Frontiers in Digital Health ◽

10.3389/fdgth.2021.610006 ◽

2021 ◽

Vol 3 ◽

Author(s):

Anzar Abbas ◽

Colin Sauder ◽

Vijay Yadav ◽

Vidya Koesmahargyo ◽

Allison Aghjayan ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Treatment Response ◽

Head Movement ◽

Selective Serotonin Reuptake Inhibitors ◽

Rating Scale ◽

Antidepressant Treatment ◽

Digital Measurement ◽

Major Depressive ◽

Patient Responses

Objectives: Multiple machine learning-based visual and auditory digital markers have demonstrated associations between major depressive disorder (MDD) status and severity. The current study examines if such measurements can quantify response to antidepressant treatment (ADT) with selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine uptake inhibitors (SNRIs).Methods: Visual and auditory markers were acquired through an automated smartphone task that measures facial, vocal, and head movement characteristics across 4 weeks of treatment (with time points at baseline, 2 weeks, and 4 weeks) on ADT (n = 18). MDD diagnosis was confirmed using the Mini-International Neuropsychiatric Interview (MINI), and the Montgomery–Åsberg Depression Rating Scale (MADRS) was collected concordantly to assess changes in MDD severity.Results: Patient responses to ADT demonstrated clinically and statistically significant changes in the MADRS [F(2, 34) = 51.62, p < 0.0001]. Additionally, patients demonstrated significant increases in multiple digital markers including facial expressivity, head movement, and amount of speech. Finally, patients demonstrated significantly decreased frequency of fear and anger facial expressions.Conclusion: Digital markers associated with MDD demonstrate validity as measures of treatment response.

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Effect of antidepressant switching between nortriptyline and escitalopram after a failed first antidepressant treatment among patients with major depressive disorder

The British Journal of Psychiatry ◽

10.1192/bjp.2018.302 ◽

2019 ◽

Vol 215 (2) ◽

pp. 494-501 ◽

Cited By ~ 2

Author(s):

Ole Köhler-Forsberg ◽

Erik Roj Larsen ◽

Henriette N. Buttenschøn ◽

Marcella Rietschel ◽

Joanna Hauser ◽

...

Keyword(s):

Major Depressive Disorder ◽

Side Effects ◽

Depressive Disorder ◽

Rating Scales ◽

Rating Scale ◽

Antidepressant Treatment ◽

Linear Regression Models ◽

Major Depressive ◽

Advisory Boards ◽

The Government

BackgroundFor patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).AimsTo compare the switch between the TCA nortriptyline and the SSRI escitalopram.MethodAmong 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.ResultsSwitching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.ConclusionsThese results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.Declarations of interestK.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.

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Association analysis of imbalanced interhemispheric functional coordination and early therapeutic efficacy in major depressive disorder: Evidence from resting state fMRI

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.048 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S87-S88 ◽

Cited By ~ 1

Author(s):

Z. Hou ◽

X. Song ◽

W. Jiang ◽

Y. Yue ◽

Y. Yin ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Rating Scale ◽

Reduction Rate ◽

Anterior Lobe ◽

Precentral Gyrus ◽

Major Depressive ◽

Clinical Prognosis ◽

Potential Marker ◽

Postcentral Gyrus

IntroductionEmerging evidences indicate that the alteration of interhemispheric functional coordination may be involved in the pathogenesis of major depressive disorder (MDD). In present study, we aim to explore the potential marker by using the voxel-mirrored homotopic connectivity (VMHC) approach, which may be contributing to predict the clinical prognosis in MDD.MethodsEighty-two MDD patients and 50 normal control (NC) subjects participated in this study. We divided the MDD group into unremitted and remitted group according to the reduction rate of Hamilton Rating Scale for Depression (HAMD) within 2 weeks.ResultsThe study detected significantly decreased VMHC in bilateral precuneus (pCu), inferior temporal gyrus (ITG) and increased VMHC in middle frontal gyrus (MFG) and caudate nucleus when compared remitted depression (RD) group to unremitted depression (URD) group. Meanwhile, when compared with NC group, the URD group presented reduced VMHC in bilateral cerebellum anterior lobe, thalamus and postcentral gyrus. Furthermore, the VHMC in media frontal gyrus, postcentral gyrus and precentral gyrus were significantly decreased in RD group. Correlation analysis suggested that reduced VMHC in bilateral pCu was negatively correlated with the baseline HAMD score of URD (r = −0.325, P = 0.041). Receiver operating characteristic (ROC) curve indicated that three regional VMHC changes could identify depressed patient with poorer treatment response: ITG [area under curve (AUC) = 0.699, P = 0.002, 95% CI = 0.586–0.812], MFG (AUC = 0.692, P = 0.003, 95% CI = 0.580–0.805), pCu (AUC = 0.714, P = 0.001, 95% CI = 0.603–0.825).ConclusionThe current study combined with previous evidence indicates that the subdued intrinsic interhemispheric functional connectivity might represents a novel neural trait involved in the pathophysiology of MDD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Remote digital measurement of visual and auditory markers of Major Depressive Disorder severity and treatment response.

10.1101/2020.08.24.20178004 ◽

2020 ◽

Author(s):

Isaac Galatzer-Levy ◽

Anzar Abbas ◽

Vijay Yadav ◽

Vidya Koesmahargyo ◽

Allison Aghjayan ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Treatment Response ◽

Head Movement ◽

Selective Serotonin Reuptake Inhibitors ◽

Rating Scale ◽

Antidepressant Treatment ◽

Digital Measurement ◽

Major Depressive ◽

Patient Responses

Objectives: Multiple machine learning-based visual and auditory digital markers have demonstrated associations between Major Depressive Disorder (MDD) status and severity. The current study examines if such measurements can quantify response to antidepressant treatment (ADT) with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine uptake inhibitors (SNRIs). Methods: Visual and auditory markers were acquired through an automated smartphone task that measures facial, vocal, and head movement characteristics across the first five weeks of treatment (with timepoints at 1, 3, and 5 weeks) on ADT (n = 12). The Montgomery-Asberg Depression Rating Scale (MADRS) was collected concordantly through clinical interviews to confirm diagnosis and assess changes in MDD severity. Results: Patient responses to ADT demonstrated clinically and statistically significant changes in the MADRS F(2,34) = 51.62, p <.0001. Additionally, patients demonstrated significant increases in multiple digital markers including facial expressivity, head movement, and amount of speech. Finally, patients demonstrated significant decreased frequency of fear and anger facial expressions. Conclusion: Digital markers associated with MDD demonstrate validity as measures of treatment response.

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Exosomal let-7e, miR-21-5p, miR-145, miR-146a and miR-155 in Predicting Antidepressants Response in Patients with Major Depressive Disorder

Biomedicines ◽

10.3390/biomedicines9101428 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1428

Author(s):

Yi-Yung Hung ◽

Chen-Kai Chou ◽

Yi-Chien Yang ◽

Hung-Chun Fu ◽

El-Wui Loh ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Mononuclear Cells ◽

Rating Scale ◽

Antidepressant Treatment ◽

Toll Like Receptor 4 ◽

Major Depressive ◽

Peripheral Blood Mononuclear ◽

Clinical Changes ◽

Serum Exosomes

The intracellular microRNAs that negatively regulate Toll-like receptor 4 signaling pathways in peripheral blood mononuclear cells are associated with major depressive disorder (MDD). However, that the distribution of these microRNAs in exosomes could be a biomarker of central nervous system diseases is just beginning to be explored. In the present study, we isolated serum exosomes from patients with MDD and healthy controls to explore the levels of exosomal microRNAs, including let-7e, miR-21-5p, miR-223, miR-145, miR-146a, and miR-155. We also investigated the changes of these exosomal microRNAs after antidepressant treatment and their association with clinical changes in scores on the Hamilton Depression Rating Scale. An ANCOVA adjusted by age, sex, BMI, and smoking showed higher expression levels of miR-146a (p = 0.006) in patients with MDD compared to controls. Patients who achieved remission showed significantly lower let-7e, miR-21-5p, miR-145, miR-146a, and miR-155 levels before treatment and increased levels after antidepressant treatment compared with the non-remission group. Through receiver operating characteristic (ROC) analysis, let-7e, miR-145, and miR-146a showed acceptable discrimination between the remission and non-remission groups, whereas miR-21-5p and miR-155 showed poor discrimination. These findings demonstrate that exosomal microRNAs may play essential roles in predicting antidepressants response.

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Association of activation syndrome with life-time hypomanic symptoms and Ghaemi criteria

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.714 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S528-S529

Author(s):

O. Gökçen ◽

S. Özer

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Test Scores ◽

Rating Scale ◽

Antidepressant Treatment ◽

Time History ◽

Life Time ◽

Major Depressive ◽

Significant Difference ◽

Activation Syndrome

ObjectiveActivation syndrome consists of 10 suicides associated symptoms, which is induced by antidepressant treatment. These are anxiety, agitation, manic episodes, sleep disruption, irritability, hostility, aggressiveness, impulsivity, akathisia and mania/hypomania. This syndrome is reported to be associated with a bipolar disorder diathesis. The aim of this study is to evaluate lifetime hypomanic symptoms with major depressive disorder, who are prescribed antidepressant medication, and to investigate whether there is a relationship between these symptoms and the development of AS.MethodsSixty consecutive outpatients with the diagnosis of major depressive disorder who were naturalistically given antidepressant treatment were examined prospectively. Patients were assessed three times; at baseline, 2 and 4 weeks later. At baseline visit, clinical characteristics of patients including Ghaemi criteria were assessed, life-time history of hypomanic symptoms were assessed with the Hypomania-Checklist-32. In all three interviews, Barnes Akathisia Rating Scale, Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale and Young Mania Rating Scale were applied to detect the symptoms of AS. The patients who present at least one of the 10 symptoms were considered to have AS.ResultsOf the 60 patients 25(41.7%) developed AS. The most prevalent symptoms of AS are insomnia (31.7%), anxiety (25%) and irritability (15%). Significant difference was found between patients with and without AS, with regard to HCL-32 test scores. A moderate correlation between the number of AS symptoms and HCL-32 test scores were determined. AS was found to be significantly more frequent in patients with mere hypersomnia and both increased appetite and hypersomnia those without these symptoms.Disclosure of interestThe findings of this study suggest that certain features of BPS might be associated with the development of AS. Antidepressant treatment of depressive illnesses in this spectrum which are misdiagnosed as unipolar may reveal these symptoms that will complicate the current episode and destabilize the longitudinal course. For this reason, clinicians should evaluate the patients who present antidepressant induced symptoms meticulously and be careful not to overlook the characteristics of BPS.

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Increased Matrix Metalloproteinases in Cerebrospinal Fluids of Patients With Major Depressive Disorder and Schizophrenia

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa049 ◽

2020 ◽

Vol 23 (11) ◽

pp. 713-720

Author(s):

Wataru Omori ◽

Kotaro Hattori ◽

Naoto Kajitani ◽

Mami Okada-Tsuchioka ◽

Shuken Boku ◽

...

Keyword(s):

Major Depressive Disorder ◽

Matrix Metalloproteinases ◽

Depressive Disorder ◽

Rating Scale ◽

Clinical Symptoms ◽

Japanese Patients ◽

Brain Inflammation ◽

Extracellular Proteases ◽

Major Depressive ◽

State Dependent

Abstract Background Chronic inflammation of the brain has a pivotal role in the pathophysiology of major depressive disorder (MDD) and schizophrenia (SCZ). Matrix metalloproteinases (MMPs) are extracellular proteases involved in pro-inflammatory processes and interact with interleukin-6, which is increased in the cerebrospinal fluid (CSF) of patients with MDD and SCZ. However, MMPs in the CSF in patients with MDD and SCZ remain unclear. Therefore, we compared MMPs in the CSF of patients with MDD and SCZ with those of healthy controls (HC). Methods Japanese patients were diagnosed with DSM-IV-TR and clinical symptoms were assessed with the Hamilton Rating Scale for Depression for MDD and the Positive and Negative Syndrome Scale for SCZ. CSF was obtained from MDD (n = 90) and SCZ (n = 86) and from age- and sex-matched HC (n = 106). The levels of MMPs in CSF were measured with multiplex bead-based immunoassay. Results The levels of MMP-2 in CSF were higher in both MDD and SCZ than HC and were positively correlated with clinical symptomatic scores in MDD, but not in SCZ. Regardless of diagnosis, the levels of MMP-2, -7, and -10 were positively correlated with each other, and the levels of MMP-7 and -10 were higher in MDD, but not in SCZ, compared with HC. Conclusion Increased CSF levels of MMP-2 in MDD and SCZ may be associated with brain inflammation. State-dependent alteration of MMP-2 and activation of cascades involving MMP-2, -7, and -10 appeared to have a role in the pathophysiology of MDD.

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Structural Changes in Hippocampal Subfields in Patients with Continuous Remission of Drug-Naive Major Depressive Disorder

International Journal of Molecular Sciences ◽

10.3390/ijms21093032 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3032 ◽

Cited By ~ 1

Author(s):

Asuka Katsuki ◽

Keita Watanabe ◽

LeHoa Nguyen ◽

Yuka Otsuka ◽

Ryohei Igata ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Rating Scale ◽

Antidepressant Treatment ◽

Critical Role ◽

Granule Cell Layer ◽

Limbic Structure ◽

Major Depressive ◽

Hippocampal Subfields ◽

Drug Naïve

Objective: Hippocampal volume is reduced in patients with major depressive disorder (MDD) compared with healthy controls. The hippocampus is a limbic structure that has a critical role in MDD. The aim of the present study was to investigate the changes in the volume of the hippocampus and its subfields in MDD patients who responded to antidepressants and subsequently were in continuous remission. Subjects and Methods: Eighteen patients who met the following criteria were enrolled in the present study: the DSM-IV-TR criteria for MDD, drug-naïve at least 8 weeks or more, scores on the 17-items of Hamilton Rating Scale for Depression (HAMD) of 14 points or more, and antidepressant treatment response within 8 weeks and continuous remission for at least 6 months. All participants underwent T1-weighted structural MRI and were treated with antidepressants for more than 8 weeks. We compared the volumes of the hippocampus, including its subfields, in responders at baseline to the volumes at 6 months. The volumes of the whole hippocampus and the hippocampal subfields were measured using FreeSurfer v6.0. Results: The volumes of the left cornu Ammonis (CA) 3 (p = 0.016) and the granule cell layer of the dentate gyrus (GC-DG) region (p = 0.021) were significantly increased after 6 months of treatment compared with those at baseline. Conclusions: Increases in volume was observed in MDD patients who were in remission for at least 6 months.

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