1,293 publications from this institution
Abstract Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor-bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2-bearing immunocytes. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2+ and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 µg/mL, 1.0 µg/mL, or 10.0 µg/mL CBD. CB2+ was significantly higher in CD20+ than CD3+ and CD4+ and CD 8+ cells. Stimulation with anti-CD3/CD8 increases the number of CB2-bearing CD3+, CD4+ and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+ CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterised by lowered basal FoxP3+ CB1+% and higher CD20+ CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety and current suicidal behaviours) is explained by CD20+ CB2+ % (positively) and CD3+ CB2+% (inversely). All five immune cell populations were significantly increased by 10 µg/mL of CBD administration. Reductions in FoxP3+ CB1+% and CD3+ /CD4+ CB2+% contribute to deficits in immune homoeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity.
ABSTRACT— Some researchers have found that the administration of 5‐hydroxytryptophan (5‐HTP) results in increased cortisol secretion in major depressives but not in healthy controls. Other authors observed gender‐related differences in cortisol responses to 5‐HTP in major depressives. In order to investigate the pituitary/adrenal responsivity to 5‐HTP, the authors measured cortisol, adrenocorticotropic hormone (ACTH) and prolactin (PRL) in 30 healthy controls and in 90 depressed patients; the hormone levels were determined in baseline conditions and 60, 90 and 120 min after 125 ma L‐5‐HTP (orally, non‐enteric coated). We found [hat healthy men had significantly higher cortisol responses to L‐5‐HTP than healthy women. In the major depressives with melancholia and/or psychotic features these differences were reversed: women exhibited significantly higher cortisol and PRL responses than men. In the female group the most severely depressed patients had increased cortisol and PRL responses to L‐5‐HTP. The amplitudes of the cortisol, ACTH and PRL responses to L‐5‐HTP were significantly and positively correlated. It was concluded that the central serotonergic regulation of ACTH and PRL is significantly different between the sexes and between healthy controls, minor depressives and severely depressed patients.
Adjunctive minocycline shows promise in treating affective and psychotic disorders; however, the therapeutic mechanism remains unclear. Identifying relevant biomarkers may enhance the efficacy of novel adjunctive treatment candidates. We thus investigated the peripheral immune-inflammatory profile in a randomized controlled trial (RCT) of minocycline in major depressive disorder (MDD).This sub-study investigated serum samples from a RCT evaluating minocycline (200 mg/day, 12 weeks) in addition to treatment as usual for MDD (ACTRN12612000283875). Of the original sample (N = 71), serum assays were conducted in 47 participants (placebo n = 24; minocycline n = 23) targeting an array of 46 immune-inflammatory analytes including cytokines, chemokines, and acute-phase reactants. General estimating equations (GEE) were used to assess whether analyte concentration at baseline (effect modification) and change in analytes (change association) influenced change in Montgomery-Åsberg Depression Rating Scale (MADRS) score over time. The Benjamini-Hochberg approach was applied when adjusting for false discovery rates (FDR).GEE models revealed several interaction effects. After adjusting for FDR several change association-models survived correction. However, no such models remained significant for effect modification. Three-way group × time × marker interactions were significant for complement C3 (B = -10.46, 95%CI [-16.832, -4.095], q = 0.019) and IL-1Ra (B = -9.008, 95%CI [-15.26, -2.751], q = 0.036). Two-way group × biomarker interactions were significant for ICAM-1/CD54 (B = -0.387, 95%CI [-0.513, -0.26], q < 0.001) and IL-8/CXCL8 (B = -4.586, 95%CI [-7.698, -1.475], q = 0.036) indicating that increases in the serum concentration of these analytes were associated with an improvement in MADRS scores in the minocycline group (compared with placebo).Change in complement C3, IL-1Ra, IL-8/CXCL8, and ICAM-1 may be associated with greater change in depressive scores following adjunctive minocycline treatment in MDD. Further investigations are needed to assess the utility of these biomarkers.
Objectives The aim of the current study was to assess the associations between dynapenia and the onset and persistence of depression and anxiety among older adults.Methods This prospective cohort study enrolled community-living older adults (N = 5271; 51.1% females) aged ≥ 50 years (mean age = 63.2, standard deviation = 9.0) from The Irish Longitudinal Study on Aging (TILDA), Ireland. At baseline, participants completed a handgrip assessment. Depression was defined by a score ≥ 16 in the Center of Epidemiology Studies Depression (CES-D) tool and anxiety was considered when participants scored ≥ 8 on the anxiety section of the Hospital Anxiety and Depression Scale (HADS). Outcomes were incident and persistent depression and anxiety at two years follow-up. Multivariable logistic regression models were built for each outcome.Results After controlling for age, sex, education, marital status, employment status, smoking, body mass index, number of chronic conditions, physical activity, and cognitive function, low handgrip strength indicative of dyapenia (< 30 Kg for men and < 20 Kg for women) was associated with a greater likelihood for incident depressive (OR = 1.44; 95%CI: 1.08–1.92) as well as for persistent depressive (OR = 1.61; 95% CI: 1.01–2.58) and anxiety (OR = 1.61; 95% CI: 1.20–2.14) symptoms.Conclusions Dynapenia was associated with a higher odds of developing depressive symptoms as well as a greater likelihood to persistent depressive and anxiety symptoms among older adults. Our data suggest that interventions targeting muscle strength may prevent the onset of late-life depression and also may hold promise as novel therapeutic opportunities for depression and anxiety in later life.
There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.
The biological underpinnings that drive the plethora of breastfeeding benefits over formula-feeding is an area of intense research, given the cognitive and emotional benefits as well as the offsetting of many childhood- and adult-onset medical conditions that breast-feeding provides. In this article, we review the research on the role of melatonin in driving some of these breastfeeding benefits. Melatonin is a powerful antioxidant, anti-inflammatory and antinociceptive as well as optimizing mitochondrial function. Melatonin is produced by the placenta and, upon parturition, maternal melatonin is passed to the infant upon breastfeeding with higher levels in night-time breast milk. As such, some of the benefits of breastfeeding may be mediated by the higher levels of maternal circulating night-time melatonin, allowing for circadian and antioxidant effects, as well as promoting the immune and mitochondrial regulatory aspects of melatonin; these actions may positively modulate infant development. Herein, it is proposed that some of the benefits of breastfeeding may be mediated by melatonin's regulation of the infant's gut microbiota and immune responses. As such, melatonin is likely to contribute to the early developmental processes that affect the susceptibility to a range of adult onset conditions. Early research on animal models has shown promising results for the regulatory role of melatonin.
Abstract Background Two distinct symptom dimensions were identified in older adults who did not have major depressive disorder (MDD): a) a dimension associated with mild cognitive dysfunction, and b) a dimension related to distress symptoms of old age (DSOA). It is uncertain whether previous findings regarding the features of amnestic mild cognitive impairment (aMCI) remain valid when patients with MDD are excluded. Objectives To examine, in participants without MDD, the neurocognitive characteristics of aMCI and the objective cognitive characteristics of DSOA. Neurocognition was evaluated utilizing the Cambridge Neurological Test Automated Battery (CANTAB) and memory tests. Results This research demonstrated that CANTAB tests have the capability to differentiate between aMCI and controls. The One Touch Stockings of Cambridge, probability solved on first choice (OTS_PSFC), Rapid Visual Information Processing, A prime, and the Motor Screening Task, mean latency (MOT_ML), were identified as the significant discriminatory CANTAB tests. 37.6% of the variance in the severity of aMCI was predicted by OTS_PSFC, RVP_A’, word list recognition scores, and education. Psychosocial stressors (adverse childhood experiences, negative life events), subjective feelings of cognitive impairment, and RVP, probability of false alarm, account for 40.0% of the DSOA score. Discussion When MDD is ruled out, aMCI is linked to deficits in attention, executive functions, and memory. Psychosocial stressors did not have a statistically significant impact on aMCI or its severity. Enhanced false alarm response bias coupled with heightened psychological stress (including subjective perception of cognitive decline) may contribute to an increase in DSOA among the elderly. Keys word: depression, mild cognitive impairment, adverse childhood experiences, stress, anxiety
An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-&kappa;B, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.
Increased IL-6 and soluble IL-6 receptor (sIL-6R) levels in depressed patients was first shown over 20 years ago. The pro-inflammatory effects of IL-6 are predominantly mediated by IL-6 trans-signalling via the sIL-6R, whereas IL-6R membrane signalling has anti-inflammatory effects.We review data on IL-6 and sIL-6R in inflammation, depression, animal models of depression and the effects of different classes of antidepressants. The biological context for IL-6 trans-signalling as a pathogenic factor in depression involves its role in the acute phase response, disorders in zinc and the erythron, hypothalamic-pituitary-adrenal axis activation, induction of the tryptophan catabolite pathway, oxidative stress, bacterial translocation, transition towards sensitisation, autoimmune processes and neuroprogression and the multicausal aetiology of depression, considering that psychosocial stressors and comorbid immune-inflammatory diseases are associated with the onset of depression.The homeostatic functions of IL-6 imply that ubiquitous IL-6 inhibitors, for example, tocilizumab, may not be the optimal treatment target in depression. A more promising target may be to increase soluble glycoprotein 130 (sgp130) inhibition of IL-6 trans-signalling, while allowing the maintenance of IL-6R membrane signalling. Future research should delineate the effects of treatments with sgp130Fc in combination with antidepressants in various animal models of chronic depression.
Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.
