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Molecular mechanism of noradrenaline during the stress-induced major depressive disorder.

ABSTRACT: Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate. Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression. Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder (MDD) and several antidepressants functions by increasing the monoamine level at the synapses in the brain. However, it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant. Contrary to noradrenergic receptor stimulation, it has been suggested that the desensitization of ?-adrenoceptor is involved in the therapeutic effect of antidepressant. In addition, enhanced noradrenaline (NA) release is central response to stress and thought to be a risk factor for the development of MDD. Moreover, fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus (LC). However, it is unclear how they alter the firing activity of LC neurons. These inconsistent reports about antidepressant effect of NA-reuptake inhibitors (NRIs) and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD. In this review, we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD. We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons, hypothalamic-pituitary-adrenal axis (HPA-axis) and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

SUBMITTER: Seki K

PROVIDER: S-EPMC6065220 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Molecular mechanism of noradrenaline during the stress-induced major depressive disorder.

Seki Kenjiro K Yoshida Satomi S Jaiswal Manoj Kumar MK

Neural regeneration research 20180701 7

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate. Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression. Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder (MDD) and several antidepressants functions by increasing the monoamine level at the synapses in the brain. However, it is undetermined whether the ...[more]

PMID: 30028316

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:IntroductionDissociative symptoms are highly prevalent in patients with trauma-related disorders such as borderline personality disorder (BPD) and posttraumatic-stress disorder (PTSD), and also occur in patients with depressive disorders. Acute dissociative states are theorized to be stress-related, and some individuals experience recurring patterns of dissociation. The relationship between the intensity of dissociative episodes (trait-like dissociation) and acute dissociative states, however, is incompletely understood. In the present study, we investigated how levels of baseline (trait-like) dissociation relate to changes in dissociative states during a laboratory stress induction.MethodsOur female sample comprised 65 patients with BPD and/or PTSD, 84 patients with major depressive disorder (MDD) and 44 non-clinical controls (NCC). Baseline dissociation was assessed at the start of the study using the Dissociation Tension Scale past week version (DSS-7). All participants underwent the Trier Social Stress Test (TSST) and a placebo version (P-TSST). Before and after the TSST or P-TSST, state dissociation was assessed using the Dissociation Tension Scale acute (DSS-4). We used structural equation models to estimate changes in state dissociation items (somatoform dissociation, derealization, depersonalization, analgesia), and to test whether these changes relate to levels of baseline dissociation.ResultsWe found significant increases in all state dissociation items in response to the TSST in patients with BPD and/or PTSD and patients with MDD, but not in NCCs. Increases in somatoform dissociation and derealization during the TSST were significantly related to higher levels of baseline dissociation in patients with BPD and/or PTSD, but not in patients with MDD or NCCs. Results indicate no significant changes in state dissociation during the P-TSST.ConclusionOur results replicate earlier findings that patients with BPD and/or PTSD report higher levels of stress-related state dissociation than NCC and extend them to patients with MDD. In addition, our findings indicate that baseline levels of dissociation relate to stress-induced changes in state dissociation among patients with BPD and PTSD, but not patients with MDD. In clinical applications, measures of baseline dissociation could be used to facilitate the prediction and treatment of stress-related dissociative states in patients with BPD and/or PTSD.

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Molecular mechanism of noradrenaline during the stress-induced major depressive disorder.

Publications

Molecular mechanism of noradrenaline during the stress-induced major depressive disorder.

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