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Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach.

ABSTRACT: While research concerning brain structural biomarkers of major depressive disorder (MDD) is continuously progressing, our state of knowledge regarding biomarkers of specific clinical profiles of MDD is still limited. The aim of the present study was to investigate brain structural correlates of social anhedonia as a cardinal symptom of MDD. In a cross-sectional study, we investigated n?=?166 patients with MDD and n?=?166 matched healthy controls (HC) using structural magnetic resonance imaging (MRI). Social anhedonia was assessed using the Chapman Scales for Social Anhedonia (SAS). An anhedonia x group ANCOVA was performed in a region of interest approach of the dorsal and ventral striatum (bilateral caudate nucleus, putamen, nucleus accumbens respectively) as well as on whole-brain level. The analyses revealed a significant main effect for social anhedonia: higher SAS-scores were associated with reduced gray matter volume in the bilateral caudate nucleus in both the MDD-group (p_FWE?=?0.002) and the HC-group (p_FWE?=?0.032). The whole-brain analysis confirmed this association (left: p_FWE?=?0.036, right: p_FWE?=?0.047). There was no significant main effect of group and no significant anhedonia x group interaction effect. This is the first study providing evidence for volumetric aberrations in the reward system related to social anhedonia independently of diagnosis, depression severity, medication status, and former course of disease. These results support the hypothesis that social anhedonia has a brain biomarker serving as a possible endophenotype of depression and possibly providing an alternative approach for a more precise and effective treatment.

SUBMITTER: Enneking V

PROVIDER: S-EPMC6461766 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach.

Enneking Verena V Krüssel Pia P Zaremba Dario D Dohm Katharina K Grotegerd Dominik D Förster Katharina K Meinert Susanne S Bürger Christian C Dzvonyar Fanni F Leehr Elisabeth J EJ Böhnlein Joscha J Repple Jonathan J Opel Nils N Winter Nils R NR Hahn Tim T Redlich Ronny R Dannlowski Udo U

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20181127 5

While research concerning brain structural biomarkers of major depressive disorder (MDD) is continuously progressing, our state of knowledge regarding biomarkers of specific clinical profiles of MDD is still limited. The aim of the present study was to investigate brain structural correlates of social anhedonia as a cardinal symptom of MDD. In a cross-sectional study, we investigated n = 166 patients with MDD and n = 166 matched healthy controls (HC) using structural magnetic resonance imaging ( ...[more]

PMID: 30607014

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Project description:Background: Anhedonia is a common, persistent, and disabling phenomenon in treated adults with Major Depressive Disorder (MDD). Hitherto, relatively few antidepressant agents have been evaluated with respect to their effect on anhedonia in MDD. Methods: This is a post-hoc analysis of a primary study that sought to evaluate the sensitivity to change of the THINC-integrated tool (THINC-it) in MDD (ClinicalTrials.gov Identifier: NCT03053362). Adults meeting DSM-5 criteria for MDD with at least moderate depressive symptom severity [i.e., Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥20] were eligible. Subjects were recruited between October 2017 and August 2018 in Toronto, Ontario at the Brain and Cognition Discovery Foundation. All subjects received open-label vortioxetine (10-20 mg/day, flexibly-dosed) for 8 weeks. Herein, the primary outcome of interest was the change from baseline to endpoint in the Snaith-Hamilton Pleasure Scale (SHAPS) total score, as well as the MADRS anhedonia factor. The mediational effects of improvements in anhedonia on general function and quality of life, as measured by the Sheehan Disability Scale (SDS) and the 5-Item World Health Organization Well-Being Index (WHO-5), were secondarily assessed. Results: A total of 100 subjects with MDD were enrolled in the primary study and began treatment with vortioxetine. Vortioxetine significantly improved anhedonia as evidenced by significant baseline to endpoint improvements in SHAPS and MADRS anhedonia factor scores (p < 0.0001). Improvements in the SHAPS and the MADRS anhedonia factor correlated with improvements in general function (i.e., SDS) and quality of life (i.e., WHO-5) (p < 0.0001). Notably, improvements in anhedonia were found to mediate the association between improvements in overall depressive symptom severity (i.e., MADRS total score) and social functioning (i.e., social life component of the SDS) (p = 0.026). Conclusion: The unmet need in depression is to improve patient functioning and other patient-reported outcomes (e.g., quality of life). Antidepressant interventions capable of attenuating anhedonia as well as cognitive dysfunction in MDD may help in this regard, as improvement in these domains have been associated with improvement in psychosocial function and quality of life.

Project description:There is compelling evidence that epigenetic factors contribute to the manifestation of depression, in which microRNA132 (miR-132) is suggested to play a pivotal role in the pathogenesis and neuronal mechanisms underlying the symptoms of depression. Additionally, several depression-associated genes [MECP2, ARHGAP32 (p250GAP), CREB, and period genes] were experimentally validated as miR-132 targets. However, most studies regarding miR-132 in major depressive disorder are based on post-mortem, animal models or genetic comparisons. This work will be the first attempt to investigate how miR-132 dysregulation may impact covariation of multimodal brain imaging data in 81 unmedicated major depressive patients and 123 demographically-matched healthy controls, as well as in a medication-naïve subset of major depressive patients. MiR-132 values in blood (patients > controls) was used as a prior reference to guide fusion of three MRI features: fractional amplitude of low frequency fluctuations, grey matter volume, and fractional anisotropy. The multimodal components correlated with miR-132 also show significant group difference in loadings. Results indicate that (i) higher miR-132 levels in major depressive disorder are associated with both lower fractional amplitude of low frequency fluctuations and lower grey matter volume in fronto-limbic network; and (ii) the identified brain regions linked with increased miR-132 levels were also associated with poorer cognitive performance in attention and executive function. Using a data-driven, supervised-learning method, we determined that miR-132 dysregulation in major depressive disorder is associated with multi-facets of brain function and structure in fronto-limbic network (the key network for emotional regulation and memory), which deepens our understanding of how miR-132 dysregulation in major depressive disorders contribute to the loss of specific brain areas and is linked to relevant cognitive impairments.

Project description:ImportanceCurrently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.ObjectiveTo identify a candidate neuroimaging "treatment-specific biomarker" that predicts differential outcome to either medication or psychotherapy.DesignBrain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy.SettingMood and anxiety disorders research program at an academic medical center.ParticipantsMen and women aged 18 to 60 years with currently untreated major depressive disorder.InterventionRandomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy.Main outcome and measureRemission, defined as a 17-item Hamilton depression rating scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.ResultsPositive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.Conclusions and relevanceIf verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.Trial registrationRegistered at clinicaltrials.gov (NCT00367341).

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:Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.

Dataset Information

Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach.

Publications

Social anhedonia in major depressive disorder: a symptom-specific neuroimaging approach.

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