Major depressive disorder (MDD) is a complex multifactorial condition with an estimated heritability of 40%, characterized by episodes of depressed mood, loss of interest and additional symptoms such ...as weight changes, sleep disturbances and fatigue. Both a high relapse and recurrence risk of MDD are known from epidemiological studies, however, biomarkers that could facilitate early detection and prediction of prognosis are lacking. DNA methylation (DNAm) has been suggested as a potential molecular marker for disorder states and traits due to its capacity to integrate both genetic and environmental signals into an epigenetic memory. In a sample of individuals with a lifetime diagnosis of MDD and healthy controls, we here performed a longitudinal analysis of blood-based DNAm profiles with regard to case-control status and longitudinal readouts, including the number of depressive episodes, number of hospitalizations and phase of illness at measurement.
For 185 MDD cases and 188 age- and sex-matched healthy controls drawn from the deeply phenotyped German FOR2107 cohort, DNAm at baseline and at a two-year follow-up study visit was profiled with the Infinium MethylationEPIC BeadChip in peripheral blood. Data quality control and stratified quantile normalization of methylation signals were conducted in R using the minfi and ewastools packages, resulting in a longitudinal analysis sample of 178 MDD cases and 178 healthy controls with two measurements each. Differential methylation was examined across more than 760k CpG sites with linear mixed models using the limma package, including proband identity as a random effect. For each independent variable of interest, a separate model was fitted. As fixed effect covariates, sex, age, cell type composition estimated with the Houseman approach, ten genotyping-based principal components (PC) as well as ten methylation control-probe PCs were included in each model. Associations with p < 9e-8 were considered methylome-wide significant.
In the analysis of case-control status, significant differential methylation was detected at four CpG sites, including hypomethylation of cg04847273, which is located within the GABRD gene encoding a GABA receptor subunit. Regarding the number of depressive episodes and hospitalizations, 13 and 40 CpG sites, respectively, showed significant differential methylation. When comparing different categories reflecting phase of illness (acute episode, partial remission, full remission, healthy), significant differential methylation was visible between samples of MDD cases in full remission and healthy controls at two CpG sites.
To the best of our knowledge, our study represents one of the largest methylome-wide longitudinal investigations of MDD so far. The detected differences in blood-based DNAm profiles provide a promising starting point for the identification of trait- and state-dependent biomarkers in MDD. The hypomethylation within GABRD appears to be particularly interesting, as it might be related to GABAergic dysregulation in mood disorders implicated by previous studies. Larger sample sizes and a higher number of longitudinal measurements per individual are required to increase statistical power, and any identified associations should be replicated in independent cohorts.
BackgroundMajor depressive disorder (MDD) has been associated with alterations in brain white matter (WM) microstructure. However, diffusion tensor imaging studies in biological relatives have ...presented contradicting results on WM alterations and their potential as biomarkers for vulnerability or resilience. To shed more light on associations between WM microstructure and resilience to familial risk, analyses including both healthy and depressed relatives of MDD patients are needed.MethodsIn a 2 (MDD v. healthy controls, HC) × 2 (familial risk yes v. no) design, we investigated fractional anisotropy (FA) via tract-based spatial statistics in a large well-characterised adult sample (N = 528), with additional controls for childhood maltreatment, a potentially confounding proxy for environmental risk.ResultsAnalyses revealed a significant main effect of diagnosis on FA in the forceps minor and the left superior longitudinal fasciculus (ptfce−FWE = 0.009). Furthermore, a significant interaction of diagnosis with familial risk emerged (ptfce−FWE = 0.036) Post-hoc pairwise comparisons showed significantly higher FA, mainly in the forceps minor and right inferior fronto-occipital fasciculus, in HC with as compared to HC without familial risk (ptfce−FWE < 0.001), whereas familial risk played no role in MDD patients (ptfce−FWE = 0.797). Adding childhood maltreatment as a covariate, the interaction effect remained stable.ConclusionsWe found widespread increased FA in HC with familial risk for MDD as compared to a HC low-risk sample. The significant effect of risk on FA was present only in HC, but not in the MDD sample. These alterations might reflect compensatory neural mechanisms in healthy adults at risk for MDD potentially associated with resilience.
Stressful life events (SLEs) in adulthood are a risk factor for various disorders such as depression, cancer or infections. Part of this risk is mediated through pathways altering brain physiology ...and structure. There is a lack of longitudinal studies examining associations between SLEs and brain structural changes. High‐resolution structural magnetic resonance imaging data of 212 healthy subjects were acquired at baseline and after 2 years. Voxel‐based morphometry was used to identify associations between SLEs using the Life Events Questionnaire and grey matter volume (GMV) changes during the 2‐year period in an ROI approach. Furthermore, we assessed adverse childhood experiences as a possible moderator of SLEs‐GMV change associations. SLEs were negatively associated with GMV changes in the left medial prefrontal cortex. This association was stronger when subjects had experienced adverse childhood experiences. The medial prefrontal cortex has previously been associated with stress‐related disorders. The present findings represent a potential neural basis of the diathesis‐stress model of various disorders.
Up to 70% of patients with major depressive disorder present with psychomotor disturbance (PmD), but at the present time understanding of its pathophysiology is limited. In this study, we capitalized ...on a large sample of patients to examine the neural correlates of PmD in depression. This study included 820 healthy participants and 699 patients with remitted (n = 402) or current (n = 297) depression. Patients were further categorized as having psychomotor retardation, agitation, or no PmD. We compared resting-state functional connectivity (ROI-to-ROI) between nodes of the cerebral motor network between the groups, including primary motor cortex, supplementary motor area, sensory cortex, superior parietal lobe, caudate, putamen, pallidum, thalamus, and cerebellum. Additionally, we examined network topology of the motor network using graph theory. Among the currently depressed 55% had PmD (15% agitation, 29% retardation, and 11% concurrent agitation and retardation), while 16% of the remitted patients had PmD (8% retardation and 8% agitation). When compared with controls, currently depressed patients with PmD showed higher thalamo-cortical and pallido-cortical connectivity, but no network topology alterations. Currently depressed patients with retardation only had higher thalamo-cortical connectivity, while those with agitation had predominant higher pallido-cortical connectivity. Currently depressed patients without PmD showed higher thalamo-cortical, pallido-cortical, and cortico-cortical connectivity, as well as altered network topology compared to healthy controls. Remitted patients with PmD showed no differences in single connections but altered network topology, while remitted patients without PmD did not differ from healthy controls in any measure. We found evidence for compensatory increased cortico-cortical resting-state functional connectivity that may prevent psychomotor disturbance in current depression, but may perturb network topology. Agitation and retardation show specific connectivity signatures. Motor network topology is slightly altered in remitted patients arguing for persistent changes in depression. These alterations in functional connectivity may be addressed with non-invasive brain stimulation.
Abstract While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of ...left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.
Aberrant brain structural connectivity in major depressive disorder (MDD) has been repeatedly reported, yet many previous studies lack integration of different features of MDD with structural ...connectivity in multivariate modeling approaches. In n = 595 MDD patients, we used structural equation modeling (SEM) to test the intercorrelations between anhedonia, anxiety, neuroticism, and cognitive control in one comprehensive model. We then separately analyzed diffusion tensor imaging (DTI) connectivity measures in association with those clinical variables, and finally integrated brain connectivity associations, clinical/cognitive variables into a multivariate SEM. We first confirmed our clinical/cognitive SEM. DTI analyses (FWE‐corrected) showed a positive correlation of anhedonia with fractional anisotropy (FA) in the right anterior thalamic radiation (ATR) and forceps minor/corpus callosum, while neuroticism was negatively correlated with axial diffusivity (AD) in the left uncinate fasciculus (UF) and inferior fronto‐occipital fasciculus (IFOF). An extended SEM confirmed the associations of ATR FA with anhedonia and UF/IFOF AD with neuroticism impacting on cognitive control. Our findings provide evidence for a differential impact of state and trait variables of MDD on brain connectivity and cognition. The multivariate approach shows feasibility of explaining heterogeneity within MDD and tracks this to specific brain circuits, thus adding to better understanding of heterogeneity on the biological level.
In this article, we analyzed a large cohort of n = 595 major depressive disorder (MDD) patients using structural equation modeling of brain connectivity, clinical, and cognitive parameters to identify the relation of anhedonia, neuroticism, and state anxiety as well as cognitive control. Results show a brain structural overlap of anhedonia and cognitive control as well as of neuroticism and cognitive control, contributing to disconnection in MDD.
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