Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

Psychopathology, trauma and delinquency: subtypes of aggression and their relevance for understanding young offenders

OBJECTIVE: To examine the implications of an ontology of aggressive behavior which divides aggression into reactive, affective, defensive, impulsive (RADI) or "emotionally hot"; and planned, instrumental, predatory (PIP) or "emotionally cold." Recent epidemiological, criminological, clinical and neuroscience studies converge to support a connection between emotional and trauma related psychopathology and disturbances in the emotions, self-regulation and aggressive behavior which has important implications for diagnosis and treatment, especially for delinquent populations. METHOD: Selective review of preclinical and clinical studies in normal, clinical and delinquent populations. RESULTS: In delinquent populations we observe an increase in psychopathology, and especially trauma related psychopathology which impacts emotions and self-regulation in a manner that hotly emotionally charged acts of aggression become more likely. The identification of these disturbances can be supported by findings in cognitive neuroscience. These hot aggressive acts can be delineated from planned or emotionally cold aggression. CONCLUSION: Our findings support a typology of diagnostic labels for disruptive behaviors, such as conduct disorder and oppositional defiant disorder, as it appears that these acts of hot emotional aggression are a legitimate target for psychopharmacological and other trauma specific interventions. The identification of this subtype of disruptive behavior disorders leads to more specific clinical interventions which in turn promise to improve hitherto unimpressive treatment outcomes of delinquents and patients with disruptive behavior

In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS) and autoimmune responses directed against O&NS- damaged neoepitopes

Objective: Depression is accompanied by activation of immuno-inflammatory and oxidative and nitrosative stress (IO&amp;NS) pathways, and increased IgM/IgA responses to lipopolysaccharide (LPS) of gram-negative commensal bacteria. The latter suggests that bacterial translocation has caused IgM/IgA responses directed against LPS. Bacterial translocation may drive IO&amp;NS responses.Method: To examine the associations between IgM/IgA responses to LPS and IO&amp;NS measurements, including plasma/serum interleukin-1 (IL-1), tumor necrosis factor (TNF)&alpha;, neopterin, lysozyme, oxidized LDL (oxLDL) antibodies, peroxides, and IgM (auto)immune responses against malondialdehyde (MDA), azelaic acid, phophatidyl inositol (Pi), NO-tryptophan and NO-tyrosine in depressed patients and controls.Results: We found significant positive associations between IgM/IgA responses to LPS and oxLDL antibodies, IgM responses against MDA, azelaic acid, Pi, NO-tryptophan, and NO-tyrosine. The IgA responses to LPS were correlated with lysozyme. There were no significant positive correlations between the IgM/IgA responses to LPS and IL-1 and neopterin.Conclusion: The findings show that in depression there is an association between increased bacterial translocation and lysozyme production, an antibacterial compound, O&amp;NS processes, and autoimmune responses directed against O&amp;NS generated neoantigenic determinants. It is suggested that bacterial translocation may drive IO&amp;NS pathways in depression and thus play a role in its pathophysiology

Antidepressant-like effects of methanol extract of <it>Hibiscus tiliaceus</it> flowers in mice

<p>Abstract</p> <p>Background</p> <p><it>Hibiscus tiliaceus</it> L. (Malvaceae) is used in postpartum disorders. Our purpose was to examine the antidepressant, anxiolytic and sedative actions of the methanol extract of <it>H. tiliaceus</it> flowers using animal models.</p> <p>Methods</p> <p>Adult male Swiss albino mice were treated with saline, standard drugs or methanol extract of H. tiliaceus and then subjected to behavioral tests. The forced swimming and tail suspension tests were used as predictive animal models of antidepressant activity, where the time of immobility was considered. The animals were submitted to the elevated plus-maze and ketamine-induced sleeping time to assess anxiolytic and sedative activities, respectively.</p> <p>Results</p> <p>Methanol extract of <it>H. tiliaceus</it> significantly decreased the duration of immobility in both animal models of antidepressant activity, forced swimming and tail suspension tests. This extract did not potentiate the effect of ketamine-induced hypnosis, as determined by the time to onset and duration of sleeping time.</p> <p>Conclusion</p> <p>Our results indicate an antidepressant-like profile of action for the extract of <it>Hibiscus tiliaceus</it> without sedative side effect.</p

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1–4 (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators