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The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.
The significant public health burden associated with late-life depression (LLD) is magnified by the high rates of recurrence. In this manuscript, we review what is known about recurrence risk factors, conceptualize recurrence within a model of homeostatic disequilibrium, and discuss the potential significance and challenges of new research into LLD recurrence. The proposed model is anchored in the allostatic load theory of stress. We review the allostatic response characterized by neural changes in network function and connectivity and physiologic changes in the hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system, and circadian rhythm. We discuss the role of neural networks' instability following treatment response as a source of downstream disequilibrium, triggering and/or amplifying abnormal stress response, cognitive dysfunction and behavioral changes, ultimately precipitating a full-blown recurrent episode of depression. We propose strategies to identify and capture early change points that signal recurrence risk through mobile technology to collect ecologically measured symptoms, accompanied by automated algorithms that monitor for state shifts (persistent worsening) and variance shifts (increased variability) relative to a patient's baseline. Identifying such change points in relevant sensor data could potentially provide an automated tool that could alert clinicians to at-risk individuals or relevant symptom changes even in a large practice.
Published by Elsevier Inc.
Major depression is a common and severe psychiatric disorder with a highly polygenic genetic architecture. Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with major depression, but the exact causal genes and biological mechanisms are largely unknown. Tissue-specific network approaches may identify molecular mechanisms underlying major depression and provide a biological substrate for integrative analyses. We provide a framework for the identification of individual risk genes and gene co-expression networks using genome-wide association summary statistics and gene expression information across multiple human brain tissues and whole blood. We developed a novel gene-based method called eMAGMA that leverages tissue-specific eQTL information to identify 99 biologically plausible risk genes associated with major depression, of which 58 are novel. Among these novel associations is Complement Factor 4A (C4A), recently implicated in schizophrenia through its role in synaptic pruning during postnatal development. Major depression risk genes were enriched in gene co-expression modules in multiple brain tissues and the implicated gene modules contained genes involved in synaptic signalling, neuronal development, and cell transport pathways. Modules enriched with major depression signals were strongly preserved across brain tissues, but were weakly preserved in whole blood, highlighting the importance of using disease-relevant tissues in genetic studies of psychiatric traits. We identified tissue-specific genes and gene co-expression networks associated with major depression. Our novel analytical framework can be used to gain fundamental insights into the functioning of the nervous system in major depression and other brain-related traits.
This article reviews the interactions of estrogen changes and psychosocial stress in contributing to vulnerability to major depressive disorder (MDD) in women. Estrogen modulates brain networks and processes related to changes in stress response, cognition, and emotional dysregulation that are core characteristics of MDD. Synergistic effects of estrogen on cognitive and emotional function, particularly during psychosocial stress, may underlie the association of ovarian hormone fluctuation and depression in women. We propose a model of estrogen effects on multiple brain systems that interface with stress-related emotional and cognitive processes implicated in MDD and discuss possible mechanisms through which reproductive events and changes in estrogen may contribute to MDD risk in women with other concurrent risk factors.
BACKGROUND - Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders. Cognitive complaints are commonly reported in MDD and cognitive impairment is a criterion item for MDD diagnosis. As cognitive processes are increasingly understood as the consequences of distributed interactions between brain regions, a network-based approach may provide novel information about the neurobiological basis of cognitive deficits in MDD.
METHODS - 51 Depressed (MDD, n = 23) and non-depressed (control, n = 28) adult participants completed neuropsychological testing and resting-state fMRI (rsfMRI). Cognitive domain scores (processing speed, working memory, episodic memory, and executive function) were calculated. Anatomical regions of interests were entered as seeds for functional connectivity analyses in: default mode (DMN), salience, and executive control (ECN) networks. Partial correlations controlling for age and sex were conducted for cognitive domain scores and functional connectivity in clusters with significant differences between groups.
RESULTS - Significant rsfMRI differences between groups were identified in multiple clusters in the DMN and ECN. Greater positive connectivity within the ECN and between ECN and DMN regions was associated with poorer episodic memory performance in the Non-Depressed group but better performance in the MDD group. Greater connectivity within the DMN was associated with better episodic and working memory performance in the Non-Depressed group but worse performance in the MDD group.
CONCLUSIONS - These results provide evidence that cognitive performance in MDD may be associated with aberrant functional connectivity in cognitive networks and suggest patterns of alternate brain function that may support cognitive processes in MDD.
Copyright © 2018 Elsevier Ltd. All rights reserved.
BACKGROUND - Late-life depression (LLD) has been associated with alterations in intrinsic functional networks, best characterized in the default mode network (DMN), cognitive control network (CCN), and salience network. However, these findings often derive from small samples, and it is not well understood how network findings relate to clinical and cognitive symptomatology.
METHODS - We studied 100 older adults (n = 79 with LLD, n = 21 nondepressed) and collected resting-state functional magnetic resonance imaging, clinical measures of depression, and performance on cognitive tests. We selected canonical network regions for each intrinsic functional network (DMN, CCN, and salience network) as seeds in seed-to-voxel analysis. We compared connectivity between the depressed and nondepressed groups and correlated connectivity with depression severity among depressed subjects. We then investigated whether the observed connectivity findings were associated with greater severity of common neuropsychiatric symptoms or poorer cognitive performance.
RESULTS - LLD was characterized by decreased DMN connectivity to the frontal pole, a CCN region (Wald χ = 22.33, p < .001). No significant group differences in connectivity were found for the CCN or salience network. However, in the LLD group, increased CCN connectivity was associated with increased depression severity (Wald χ > 20.14, p < .001), greater anhedonia (Wald χ = 7.02, p = .008) and fatigue (Wald χ = 6.31, p = .012), and poorer performance on tests of episodic memory (Wald χ > 4.65, p < .031), executive function (Wald χ = 7.18, p = .007), and working memory (Wald χ > 4.29, p < .038).
CONCLUSIONS - LLD is characterized by differences in DMN connectivity, while CCN connectivity is associated with LLD symptomology, including poorer performance in several cognitive domains.
Published by Elsevier Inc.
Substantial work associates late-life depression with hippocampal pathology. However, there is less information about differences in hippocampal subfields and other connected temporal lobe regions and how these regions may be influenced by vascular factors. Individuals aged 60 years or older with and without a DSM-IV diagnosis of Major Depressive Disorder completed clinical assessments and 3 T cranial MRI using a protocol allowing for automated measurement of medial temporal lobe subfield volumes. A subset also completed pseudo-continuous arterial spin labeling, allowing for the measurement of hippocampal cerebral blood flow. In 59 depressed and 21 never-depressed elders (mean age = 66.4 years, SD = 5.8y, range 60-86y), the depressed group did not exhibit statistically significant volumetric differences for the total hippocampus or hippocampal subfields but did exhibit significantly smaller volumes of the perirhinal cortex, specifically in the BA36 region. Additionally, age had a greater effect in the depressed group on volumes of the cornu ammonis, entorhinal cortex, and BA36 region. Finally, both clinical and radiological markers of vascular risk were associated with smaller BA36 volumes, while reduced hippocampal blood flow was associated with smaller hippocampal and cornu ammonis volumes. In conclusion, while we did not observe group differences in hippocampal regions, we observed group differences and an effect of vascular pathology on the BA36 region, part of the perirhinal cortex. This is a critical region exhibiting atrophy in prodromal Alzheimer's disease. Moreover, the observed greater effect of age in the depressed groups is concordant with past longitudinal studies reporting greater hippocampal atrophy in late-life depression.
OBJECTIVE - In the elderly, depression and white matter hyperintensities (WMH) are common and associated with cognitive impairment. This study investigated the possible interactions between depression and WMH in their influences on cognition of the elderly.
METHODS - Using multiple neuropsychological tests, we evaluated the cognitive function of 122 community-dwelling elders with depression at baseline between November 2008 and February 2009. Major depressive disorder, dysthymic disorder, and minor depressive disorder were diagnosed according to DSM-IV criteria. Subsyndromal depressive disorder was operationally defined using a modification of DSM-IV criteria. We visually rated WMH severity according to the modified Fazekas scale and calculated WMH volume using an automated method. We defined WMH (+) as having a score of 2 or higher on the modified Fazekas scale. In the 3-year follow-up study, baseline participants were reassessed between November 2011 and February 2013 with the same methodology.
RESULTS - Baseline depression was associated with a decline over 3 years in the Categorical Verbal Fluency Test (VFT) (P = .001), Word List Memory Test (WLMT) (P = .019), Trail Making Test A (TMT-A) (P = .018), and Mini-Mental State Examination (MMSE) (P = .017), while baseline WMH (+) was associated with a decline in WLMT (P = .039) only. An increase of WMH volume over 3 years was associated with a decline in the performances of VFT (P = .044), WLMT (P = .044), Word List Recall Test (P = .040), Word List Recognition Test (P = .036), and TMT-A (P = .001) over the same period only in the subjects with depression at baseline.
CONCLUSIONS - Depressive disorder and WMH are interactively associated with the poor performance of multiple cognitive functions. Depressive disorder may moderate the cognitive decline associated with the changes of brain WMH.
© Copyright 2018 Physicians Postgraduate Press, Inc.
OBJECTIVE - Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD.
METHODS - In a 12-week open-label outpatient study conducted between November 2016 and August 2017, transdermal nicotine was given to 15 nonsmoking older adults (≥ 60 years of age). Eligible participants met DSM-IV-TR criteria for major depressive disorder with ≥ 15 on the Montgomery-Asberg Depression Rating scale (MADRS) and endorsed subjective cognitive impairment. Transdermal nicotine patches were applied daily and titrated in a rigid dose escalation strategy to a maximum dose of 21.0 mg/d, allowing dose reductions for tolerability. The primary mood outcome was MADRS change measured every 3 weeks, with response defined as ≥ 50% improvement from baseline and remission as MADRS score ≤ 8. The primary cognitive outcome was the Conners Continuous Performance Test (CPT), a test of attention.
RESULTS - Robust rates of response (86.7%; 13/15 subjects) and remission (53.3%; 8/15 subjects) were observed. There was a significant decrease in MADRS scores over the study (β = -1.51, P < .001), with improvement seen as early as 3 weeks (Bonferroni-adjusted P value = .004). We also observed improvement in apathy and rumination. We did not observe improvement on the CPT but did observe improvement in subjective cognitive performance and signals of potential drug effects on secondary cognitive measures of working memory, episodic memory, and self-referential emotional processing. Overall, transdermal nicotine was well tolerated, although 6 participants could not reach the maximum targeted dose.
CONCLUSIONS - Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD. A definitive placebo-controlled trial and establishment of longer-term safety are necessary before clinical usage.
TRIAL REGISTRATION - ClinicalTrials.gov identifier: NCT02816138.
© Copyright 2018 Physicians Postgraduate Press, Inc.