Dataset Information

Different cytokine patterns associate with melancholia severity among inpatients with major depressive disorder.

ABSTRACT: Background:Six melancholic features (MFs) of the Hamilton Depression Rating Scale (HAM-D6) represent the construct of melancholia along a continuum of severity (from least to most severe: depressed mood, work and activities, somatic symptoms, psychic anxiety, guilty feelings, psychomotor retardation). We aimed to evaluate the association between these MFs and inflammatory cytokines (IC) in the blood. Methods:Each IC [interferon gamma (IFN-?), tumor necrosis factor alpha (TNF-?), interleukin 2 (IL-2), IL-4, IL-6, IL-10, and IL-17] was associated with the HAM-D6 MFs of 139 severely depressed inpatients, using multiple linear regressions adjusted for covariates. Levels were compared with those of 100 healthy controls. Results:Depressed mood was associated with higher levels of IL-4 (??=?0.167; p?=?0.041). Psychic anxiety: lower IL-17 levels (??=?-0.173; p?=?0.039). Guilt feelings: lower IL-2 levels (??=?-0.168; p?=?0.041) Psychomotor retardation: higher IL-6 levels (??=?0.195; p?=?0.017). Depressed patients' TNF-?, INF-?, and IL-4 levels were not significantly different from controls. Depressed patients' IL-2, IL-6, IL-10, and IL-17 levels were higher than those of controls (p?<0.001). Conclusion:Less severe MFs (depressed mood, psychic anxiety, and guilt feelings) were associated with an anti-inflammatory pattern (higher IL-4, lower IL-17 and lower IL-2, respectively). The presence of the most severe MF, psychomotor retardation, was associated with a higher pro-inflammatory response (higher IL-6).

SUBMITTER: Primo de Carvalho Alves L

PROVIDER: S-EPMC7476328 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Different cytokine patterns associate with melancholia severity among inpatients with major depressive disorder.

Primo de Carvalho Alves Lucas L Sica da Rocha Neusa N

Therapeutic advances in psychopharmacology 20200901

<h4>Background</h4>Six melancholic features (MFs) of the Hamilton Depression Rating Scale (HAM-D<sub>6</sub>) represent the construct of melancholia along a continuum of severity (from least to most severe: depressed mood, work and activities, somatic symptoms, psychic anxiety, guilty feelings, psychomotor retardation). We aimed to evaluate the association between these MFs and inflammatory cytokines (IC) in the blood.<h4>Methods</h4>Each IC [interferon gamma (IFN-γ), tumor necrosis factor alpha ...[more]

PMID: 32953039

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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:A cardinal symptom of Major Depressive Disorder (MDD) is the disruption of circadian patterns. Yet, to date, there is no direct evidence of circadian clock dysregulation in the brains of MDD patients. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain was difficult to characterize. Here we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-hour cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ('Controls') and 34 MDD patients. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (AnCg), hippocampus (HC), amygdala (AMY), nucleus accumbens (NAcc) and cerebellum (CB). Several hundred transcripts in each region showed 24-hour cyclic patterns in Controls, and >100 transcripts exhibited consistent rhythmicity and phase-synchrony across regions. Among the top ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERB), DBP, BHLHE40(DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in MDD brains, due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This is the first transcriptome-wide analysis of cyclic patterns in the human brain and demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggest novel molecular targets for treatment of mood disorders. Sample collection, including human subject recruitment and characterization, tissue dissection, and RNA extraction, was described previously (see Evans 2003 Neurobiol Dis 14:240-250, Li 2004 Biol Psychiatry 55:346-352). RNA samples for different regions came from the same set of brains from 86 control subjects. Sample size varied by region: AnCg (n=70 controls), DLPFC (n=83), CB (n=51), AMY (n=32), HC (n=63) and NAcc (n=66). Many of the samples were run on two or more chips, resulting in the following chip counts for each region: AnCg = 124, DLPFC = 161, CB = 79, AMY = 62, HC = 108 and NaCC = 136. We ran each sample on at least two microarrays using the Affymetrix U133-A or U133Plus-v2 GeneChips, however, we only used the U133A part of the U133Plus-v2 GeneChip in our analysis. We applied RMA (Robust Multi-array Analysis) (see Irizarry 2003 Biostatistics 4:249-264, Irizarry 2003 Nucleic Acids Res 31:e15) to summarize probe set expression levels, using a custom Chip Definition File, resulting in expression data for 11,911 ENTREZ transcripts. Microarray data for each region were analyzed separately. All downstream analyses were performed in R. Details of the data processing, including data cleaning and normalization, are located in the Supplementary Materials (section 1). After data filtering, 1,424 microarrays remained, corresponding to 776 unique RNA samples in six regions.

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.

Dataset Information

Different cytokine patterns associate with melancholia severity among inpatients with major depressive disorder.

Publications

Different cytokine patterns associate with melancholia severity among inpatients with major depressive disorder.

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