Novel loci and potential mechanisms of major depressive disorder,bipolar disorder,and schizophrenia

Science China Life Sciences - Different psychiatric disorders share genetic relationships and pleiotropic loci to certain extent. We integrated and analyzed datasets related to major depressive...     

Chipping away at major depressive disorder

An intriguing recent study examines the role of miR-1202, a glutamate receptor regulating microRNA, in regulating major depressive disorder.     

Genome-wide DNA methylation scan in major depressive disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.     

Dysregulation of brain dopamine systems in major depressive disorder

Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression—no established mechanism can explain all aspects of the disease. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. This mini-review focuses on dysregulation of brain dopamine (DA) systems in the pathophysiology of MDD and describing new cellular targets for potential medication development focused on DA-modulated micro-circuits. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through dopaminergic substrates in the brain.     

药物成瘾的神经生物学机制研究

药物滥用既是全球普遍存在的公共卫生问题,又是危害严重的社会问题。药物成瘾的本质是一种以药物引起的基因表达和神经突触可塑性改变为基础的病理性记忆。主要介绍国内外近年的重要研究成果。     

Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology,mechanisms and management

Populations with common physical diseases – such as cardiovascular diseases, cancer and neurodegenerative disorders – experience substantially higher rates of major depressive disorder (MDD) than the general population. On the other hand, people living with MDD have a greater risk for many physical diseases. This high level of comorbidity is associated with worse outcomes, reduced adherence to treatment, increased mortality, and greater health care utilization and costs. Comorbidity can also result in a range of clinical challenges, such as a more complicated therapeutic alliance, issues pertaining to adaptive health behaviors, drug-drug interactions and adverse events induced by medications used for physical and mental disorders. Potential explanations for the high prevalence of the above comorbidity involve shared genetic and biological pathways. These latter include inflammation, the gut microbiome, mitochondrial function and energy metabolism, hypothalamic-pituitary-adrenal axis dysregulation, and brain structure and function. Furthermore, MDD and physical diseases have in common several antecedents related to social factors (e.g., socioeconomic status), lifestyle variables (e.g., physical activity, diet, sleep), and stressful live events (e.g., childhood trauma). Pharmacotherapies and psychotherapies are effective treatments for comorbid MDD, and the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. This paper aims to provide a detailed overview of the epidemiology of the comorbidity of MDD and specific physical diseases, including prevalence and bidirectional risk; of shared biological pathways potentially implicated in the pathogenesis of MDD and common physical diseases; of socio-environmental factors that serve as both shared risk and protective factors; and of management of MDD and physical diseases, including prevention and treatment. We conclude with future directions and emerging research related to optimal care of people with comorbid MDD and physical diseases.     

重性抑郁障碍发病的表观遗传调控假说

表观遗传学是研究主要受控于DNA甲基化、染色质结构变化的可遗传和逆转的基因组功能的调控。近年来, 越来越多的证据表明表观遗传因素在精神分裂症、双相障碍、药物成瘾等重性精神障碍的发病中扮演着重要角色。文章综述了表观遗传现象的分子机制, 介绍了表观遗传修饰与复杂性疾病的关系, 并在此基础上对重性抑郁障碍(Major depressive disorder, MDD)发病的表观遗传调控假说及最新研究进展进行了总结。     

Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder

Background

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).

Methodology/Principal Findings

We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.

Conclusions/Significance

These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.     

Computational phenotyping of brain-behavior dynamics underlying approach-avoidance conflict in major depressive disorder

Adaptive behavior requires balancing approach and avoidance based on the rewarding and aversive consequences of actions. Imbalances in this evaluation are thought to characterize mood disorders such as major depressive disorder (MDD). We present a novel application of the drift diffusion model (DDM) suited to quantify how offers of reward and aversiveness, and neural correlates thereof, are dynamically integrated to form decisions, and how such processes are altered in MDD. Hierarchical parameter estimation from the DDM demonstrated that the MDD group differed in three distinct reward-related parameters driving approach-based decision making. First, MDD was associated with reduced reward sensitivity, measured as the impact of offered reward on evidence accumulation. Notably, this effect was replicated in a follow-up study. Second, the MDD group showed lower starting point bias towards approaching offers. Third, this starting point was influenced in opposite directions by Pavlovian effects and by nucleus accumbens activity across the groups: greater accumbens activity was related to approach bias in controls but avoid bias in MDD. Cross-validation revealed that the combination of these computational biomarkers were diagnostic of patient status, with accumbens influences being particularly diagnostic. Finally, within the MDD group, reward sensitivity and nucleus accumbens parameters were differentially related to symptoms of perceived stress and depression. Collectively, these findings establish the promise of computational psychiatry approaches to dissecting approach-avoidance decision dynamics relevant for affective disorders.     

Hypermethylation in the ZBTB20 gene is associated with major depressive disorder

Background

Although genetic variation is believed to contribute to an individual’s susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder.

Results

Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder.

Conclusions

Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.     

Social rhythm regularity moderates the relationship between sleep disruption and depressive symptoms in veterans with post-traumatic stress disorder and major depressive disorder

ABSTRACT

Approximately 50% to 80% of individuals with posttraumatic stress disorder (PTSD) also meet criteria for major depressive disorder (MDD). Sleep disturbance is a major concern in both PTSD and MDD, and is associated with poor treatment response, poor functional outcome and increased suicide risk. Social rhythm regularity, or the consistency of daily habitual behaviors, is theoretically linked to circadian rhythms and may be disturbed in both PTSD and MDD. The present study examined the relationship between social rhythm regularity, sleep disruption and MDD and PTSD symptoms in a sample of veterans with comorbid PTSD and MDD. Baseline data were obtained from 56 male veterans who met DSM-IV criteria for PTSD and MDD. Veterans completed the Social Rhythm Metric (SRM), a self-report questionnaire that assesses the regularity of routines by determining how regularly individuals completed 17 different types of activities. In a linear regression model, increased minutes awake after sleep onset (WASO) was a significant predictor of increased depression scores on the Hamilton Rating Scale for Depression (p < .05). SRM scores did not significantly predict depressive symptoms, however the interaction of WASO and SRM significantly predicted depressive symptoms (p = <.05), with significant relationships found at SRM scores less than 3.62. Neither minutes awake after sleep onset, SRM scores, nor their interaction was associated with PTSD symptom severity. Social and possibly circadian rhythm regularity may represent a risk or resilience factor for individuals with comorbid PTSD and MDD. Findings highlight the importance of exploring the interactions of sleep and social/circadian rhythms in depression in order to inform continued treatment development.     

Dissecting the genetic etiology of major depressive disorder using linkage analysis

Major depressive disorder (MDD) is clinically and genetically heterogeneous. Studies suggest that recurrence, early onset and comorbid phenotypes define more genetically homogeneous sub-samples. The concordance of linkage findings in recent studies using such approaches is encouraging. Sex-specific analyses and broader phenotypes have also yielded interesting results. These findings indicate that future research should consider comorbid disorders and sex-specific analyses. However, this direction must be approached with caution, owing to the complex multiple-testing issues that arise when considering numerous related phenotypes. With appropriate interpretation, these findings indicate a new potential for positional cloning efforts to locate genes in consensus regions. Genes found might influence specific subtypes of MDD or broader phenotypes, leading to enhanced clinical characterization and management of MDD.     

Plasma metabonomics as a novel diagnostic approach for major depressive disorder

Major depressive disorder (MDD) is a socially detrimental psychiatric disorder, contributing to increased healthcare expenditures and suicide rates. However, no empirical laboratory-based tests are available to support the diagnosis of MDD. In this study, a NMR-based plasma metabonomic method for the diagnosis of MDD was tested. Proton nuclear magnetic resonance ((1)H NMR) spectra of plasma sampled from first-episode drug-na??ve depressed patients (n = 58) and healthy controls (n = 42) were recorded and analyzed by orthogonal partial least-squares discriminant analysis (OPLS-DA). The OPLS-DA score plots of the spectra demonstrated that the depressed patient group was significantly distinguishable from the healthy control group. Moreover, the method accurately diagnosed blinded samples (n = 26) in an independent replication cohort with a sensitivity and specificity of 92.8% and 83.3%, respectively. Taken together, NMR-based plasma metabonomics may offer an accurate empirical laboratory-based method applicable to the diagnosis of MDD.     

Altered negative unconscious processing in major depressive disorder: an exploratory neuropsychological study

Objective

Major depressive disorder (MDD) has been characterized by abnormalities in emotional processing. However, what remains unclear is whether MDD also shows deficits in the unconscious processing of either positive or negative emotions. We conducted a psychological study in healthy and MDD subjects to investigate unconscious emotion processing and its valence-specific alterations in MDD patients.

Methods

We combined a well established paradigm for unconscious visual processing, the continuous flash suppression, with positive and negative emotional valences to detect the attentional preference evoked by the invisible emotional facial expressions.

Results

Healthy subjects showed an attentional bias for negative emotions in the unconscious condition while this valence bias remained absent in MDD patients. In contrast, this attentional bias diminished in the conscious condition for both healthy subjects and MDD.

Conclusion

Our findings demonstrate for the first time valence-specific deficits specifically in the unconscious processing of emotions in MDD; this may have major implications for subsequent neurobiological investigations as well as for clinical diagnosis and therapy.