Personalized medication that is based on pharmacogenetic data has long been expected to improve the efficacy of treatments for neurological and psychiatric disorders, including depression. However, ...the complexity of the regulation of gene transcription and its interactions with environmental factors means that straightforward translation of individual genetic information into tailored treatment is unlikely. Nevertheless, when data from genomics, proteomics, metabolomics, neuroimaging and neuroendocrinology are used in combination, they could lead to the development of effective personalized antidepressant treatment that is based on both genotypes and biomarkers. This process will require many further steps and collaboration between basic and clinical neuroscience.
Clinical and preclinical studies have gathered substantial evidence that alterations of the stress hormone system play a major, causal role in the development of depression. In this review article, a ...summary of studies sustaining that view is given and data are presented which demonstrate that depression is associated with an impairment of corticosteroid receptor function that gives rise to an excessive release of neurohormones to which a number of signs and symptoms characteristic of depression can be attributed. The studies referred to in the following unanimously support the concept of an antidepressant mechanism of action that exerts its effects beyond the cell membrane receptors of biogenic amines and particularly includes the improvement of corticosteroid receptor function. When activated by ligands, corticosteroid receptors act as transcription factors in correspondence with numerous other transcription factors already known to be activated by antidepressants. Furthermore, the potential of drugs that interfere more directly with stress hormone regulation, such as corticosteroid receptor antagonists and corticotropin-releasing hormone receptor antagonists, is discussed.
Autophagy is an essential cellular process affecting virus infections and other diseases and Beclin1 (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 ...(SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions.
Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS ...mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.
In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain ...and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.
Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in ...passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
Falling asleep is paralleled by a loss of conscious awareness and reduced capacity to process external stimuli. Little is known on sleep-associated changes of spontaneously synchronized anatomical ...networks as detected by resting-state functional magnetic resonance imaging (rs-fMRI). We employed functional connectivity analysis of rs-fMRI series obtained from 25 healthy participants, covering all non-rapid eye movement (NREM) sleep stages. We focused on the default mode network (DMN) and its anticorrelated network (ACN) that are involved in internal and external awareness during wakefulness. Using independent component analysis, cross-correlation analysis (CCA), and intraindividual dynamic network tracking, we found significant changes in DMN/ACN integrity throughout the NREM sleep. With increasing sleep depth, contributions of the posterior cingulate cortex (PCC)/retrosplenial cortex (RspC), parahippocampal gyrus, and medial prefrontal cortex to the DMN decreased. CCA revealed a breakdown of corticocortical functional connectivity, particularly between the posterior and anterior midline node of the DMN and the DMN and the ACN. Dynamic tracking of the DMN from wakefulness into slow wave sleep in a single subject added insights into intraindividual network fluctuations. Results resonate with a role of the PCC/RspC for the regulation of consciousness. We further submit that preserved corticocortical synchronization could represent a prerequisite for maintaining internal and external awareness.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the
gene, suggesting its ...implication in the association between depression and obesity.
To confirm these findings by investigating the
polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between
, BMI and depression with fixed effects meta-analysis (β = 0.12,
= 2.7 × 10
) and with the Han/Eskin random effects method (
= 1.4 × 10
) but not with traditional random effects (β = 0.1,
= 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12,
= 0.027) being highly significant based on the Han/Eskin model (
= 6.9 × 10
). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of
This meta-analysis provides additional support for a significant interaction between
, depression and BMI, indicating that depression increases the effect of
on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
Steroids influence neuronal function by binding to intracellular receptors that can act as transcription factors and regulate gene expression. In addition, some so-called ‘neuroactive steroids’ are ...potent modulators of an array of ligand-gated ion channels and of distinct G-protein coupled receptors via nongenomic mechanisms, and they can influence sleep and memory. This article describes how these neuroactive steroids modulate neurotransmitter receptors and addresses the neuropsychopharmacological potential that arises from the intracellular crosstalk between genomic and nongenomic steroid effects. Neuroactive steroids could also have a role in the response to stress and the treatment of psychiatric disorders, such as depression, and, as they affect a broad spectrum of behavioral functions through their unique molecular properties, they could constitute a yet unexploited class of drugs.
The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we ...determined that CRHR1 is expressed in forebrain glutamatergic and γ-aminobutyric acid— containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.
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