Molecular serum signature of treatment resistant depression

Rationale: A substantial number of patients suffering from major depressive disorder (MDD) do not respond to multiple trials of anti-depressants, develop a chronic course of disease and become treatment resistant. Most of the studies investigating molecular changes in treatment-resistant depression (TRD) have only examined a limited number of molecules and genes. Consequently, biomarkers associated with TRD are still lacking. Objectives: This study aimed to use recently advanced high-throughput proteomic platforms to identify peripheral biomarkers of TRD defined by two staging models, the Thase and Rush staging model (TRM) and the Maudsley Staging Model (MSM). Methods: Serum collected from an inpatient cohort of 65 individuals suffering from MDD was analysed using two different mass spectrometric-based platforms, label-free liquid chromatography mass spectrometry (LC-MSE) and selective reaction monitoring (SRM), as well as a multiplex bead based assay. Results: In the LC-MSE analysis, proteins involved in the acute phase response and complement activation and coagulation were significantly different between the staging groups in both models. In the multiplex bead-based assay analysis TNF-α levels (log(odds) = −4.95, p = 0.045) were significantly different in the TRM comparison. Using SRM, significant changes of three apolipoproteins A–I (β = 0.029, p = 0.035), M (β = −0.017, p = 0.009) and F (β = −0.031, p = 0.024) were associated with the TRM but not the MSM. Conclusion: Overall, our findings suggest that proteins, which are involved in immune and complement activation, may represent potential biomarkers that could be used by clinicians to identify high-risk patients. Nevertheless, given that the molecular changes between the staging groups were subtle, the results need to be interpreted cautiously

Influence of Repressive Coping Style on Cortical Activation during Encoding of Angry Faces

Background: Coping plays an important role for emotion regulation in threatening situations. The model of coping modes designates repression and sensitization as two independent coping styles. Repression consists of strategies that shield the individual from arousal. Sensitization indicates increased analysis of the environment in order to reduce uncertainty. According to the discontinuity hypothesis, repressors are sensitive to threat in the early stages of information processing. While repressors do not exhibit memory disturbances early on, they manifest weak memory for these stimuli later. This study investigates the discontinuity hypothesis using functional magnetic resonance imaging (fMRI). Methods: Healthy volunteers (20 repressors and 20 sensitizers) were selected from a sample of 150 students on the basis of the Mainz Coping Inventory. During the fMRI experiment, subjects evaluated and memorized emotional and neutral faces. Subjects performed two sessions of face recognition: immediately after the fMRI session and three days later. Results: Repressors exhibited greater activation of frontal, parietal and temporal areas during encoding of angry faces compared to sensitizers. There were no differences in recognition of facial emotions between groups neither immediately after exposure nor after three days. Conclusions: The fMRI findings suggest that repressors manifest an enhanced neural processing of directly threatening facial expression which confirms the assumption of hyper-responsivity to threatening information in repression in an early processing stage. A discrepancy was observed between high neural activation in encoding-relevant brain areas in response to angry faces in repressors and no advantage in subsequent memory for these faces compared to sensitizers

converging evidence from an intermediate phenotype approach

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

Genome-wide association for major depression through age at onset stratification

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

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Associations between depression subtypes, depression severity and diet quality: cross-sectional findings from the BiDirect study

Depression is supposed to be associated with an unhealthy lifestyle including poor diet. The objective of this study was to investigate differences in diet quality between patients with a clinical diagnosis of depression and population-based controls. Additionally, we aimed to examine effects of specific depression characteristics on diet by analyzing if diet quality varies between patients with distinct depression subtypes, and if depression severity is associated with diet quality.The study included 1660 participants from the BiDirect Study (n = 840 patients with depression, n = 820 population-based controls). The psychiatric assessment was based on clinical interviews and a combination of depression scales in order to provide the classification of depression subtypes and severity. Diet quality scores, reflecting the adherence to a healthy dietary pattern, were calculated on the basis of an 18-item food frequency questionnaire. Using analysis of covariance, we calculated adjusted means of diet quality scores and tested differences between groups (adjusted for socio-demographic, lifestyle-, and health-related factors).We found no differences in diet quality between controls and patients with depression if depression was considered as one entity. However, we did find differences between patients with distinct subtypes of depression. Patients with melancholic depression reported the highest diet quality scores, whereas patients with atypical depression reported the lowest scores. Depression severity was not associated with diet quality.Previous literature has commonly treated depression as a homogeneous entity. However, subtypes of depression may be associated with diet quality in different ways. Further studies are needed to enlighten the diet-depression relationship and the role of distinct depression subtypes.Corinna Rahe, Bernhard T Baune, Michael Unrath, Volker Arolt, Jürgen Wellmann, Heike Wersching and Klaus Berge