Publications

Targeting cyclooxygenase-2 in depression is not a viable therapeutic approach and may even aggravate the pathophysiology underpinning depression

Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

Neurodevelopmental pathways in bipolar disorder

Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms

The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder.Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The 'psychosomatic' symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder.'Functional' symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways.

Repeated dexamethasone suppression test in depressed patients

Psychoimmunology as a common pathogenetic pathway in myocardial infarction, depression and cardiac death

Depression is prevalent in about 30% during the first 18 months post myocardial infarction (MI). Depression increases the risk of developing cardiac disease, in particular coronary artery disease and cardiac death. It is an independent risk factor for increased post MI cardiac morbidity and mortality, comparable with well-known risk factors such as hypercholesterolaemia. Both coronary artery disease and depressive disorder are highly prevalent and co-morbid, resulting in poor overall prognosis. Therefore understanding the relationship of both disorders, as well as the effects of treatment of depressive and cardiac functioning, is important, not only from the physical health and quality of life perspectives, but also from an economic perspective. In this paper we review the evidence indicating a pivotal role of inflammatory mediators as a common factor in the pathophysiology of MI, depression and cardiac mortality. The effects of antidepressant treatment on these inflammatory mediators in MI-related depression are reviewed.

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

<title>Abstract</title> Background Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objectives To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α + β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B. Methods IgA<bold>/</bold>IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof. Results Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r = 0.801. Conclusion Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

Author response for "Diagnostic value of structural, functional and effective connectivity in bipolar disorder"

Shared Microglial Mechanisms Underpinning Depression and Fatigue and Their Comorbidities

In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Platelet [alpha]2-adrenoceptor density in humans: relationships to stress-induced anxiety, psychasthenic constitution, gender and stress-induced changes in the inflammatory response system

Background. This study examined the effects of psychological stress on platelet α2-adrenergic receptor (α2-AR) binding sites in relation to stress-induced anxiety and changes in the inflammatory response system (IRS).Methods. The maximum number of binding sites (Bmax) and their affinity (Kd) for [3H]-rauwolscine, a selective α2-AR antagonist, and the stimulated production of tumor necrosis factor-α (TNFα), the Th1-like cytokine, interferon-γ (IFNγ), and the Th2-like cytokines, interleukin-10 (IL-10) and IL-5, were measured in 35 university students a few weeks before (baseline) as well as on the day before a difficult, oral examination (stress condition). The State-Trait-Anxiety Inventory (STAI)- was recorded during both conditions. The Minnesota Multiphase Personality Inventory (MMPI-2TM) was used to assess psychasthenia (Scale 7).Results. Academic examination stress induced a significant increase in α2-AR density in students whose STAI scores increased in the stress period, in female students and in students who scored higher on psychasthenia. There were significant and positive correlations between stress-induced anxiety and changes in α2-AR density. Stress-induced anxiety was accompanied by a pro-inflammatory and Th1-like response, i.e. increased IFNγ and TNFα production. The stress-induced changes in platelet α2-AR density were significantly and positively related to the production of TNFα, IL-10 and IL-5 and negatively to that of IFNγ.Conclusions. Subchronic psychological stress in humans induces increased α2-AR density, which is related to stress-induced anxiety, an anxiety-prone constitution and female sex. Increased α2-AR density is accompanied by a Th2-like response and increased TNFα production. The results suggest that: (i) α2-AR density is sensitive to graded differences in stress-induced anxiety; and (ii) psychological stress is accompanied by intertwined responses in the catecholaminergic system, such as α2-ARs, and the IRS, such as Th1/Th2-like functions and the production of TNFα.

Immune disorders in depression: higher T helper/T suppressor‐cytotoxic cell ratio

This study investigated the leukocyte T helper and T suppressor‐cytotoxic cell (sub)set profile of minor, simple major and melancholic depressives versus normal controls. Using both monoclonal antibody staining and flow cytometry, we determined the absolute numbers and percentages of the following T cell immune subsets: T helper (CD4 + ), T virgin (CD4 + CD45 + ), T memory (CD4 + CD45 ‐ ), T suppressor/cytotoxic (CD8 + ), CD8 + T suppressor (CD8 + CD57 ‐ ) and CD8 + T cytotoxic (CD8 + CD57 + ) cells. After computing the CD4 + /CD8 + ratio, we detected a significantly increased ratio in depressed patients as compared with healthy controls. Depression per se is characterized by a higher percentage of CD4 + and a lower percentage of CD8 + CD57 ‐ cells. Melancholic depressed subjects exhibit a significantly increased number of CD4 + and CD4 + CD45 ‐ cells. The combined use of various percentages of CD4 + and CD8 + (sub)sets yields a high degree of marker positivity for melancholia: through cumulative evaluation of those percentages, the marker positivity increases to 68% (sensitivity) and the specificity is 95%. These results together with our previous reports may refer to a depression‐related state of T cell activation.

Shared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder

Intergeneric transfer and exchange recombination of restriction fragments cloned in pBR322: a novel strategy for the reversed genetics of the Ti plasmids of Agrobacterium tumefaciens.

Minocycline as adjunctive treatment for major depressive disorder: Pooled data from two randomized controlled trials

Background: Randomized controlled clinical trials that have investigated minocycline as an adjunctive treatment for major depressive disorder have proved promising. Data from two studies were pooled to evaluate more definitively whether the addition of minocycline to standard treatment for major depressive disorder leads to an improvement of depressive symptoms when compared with placebo. Methods: Both studies were multi-site, double-blinded, placebo-controlled trials of minocycline 200 mg/day added to treatment as usual during a 12-week period. The primary outcome measure was change in depressive symptoms (Montgomery–Asberg Depression Rating Scale in Dean et al. and Hamilton Depression Rating Scale in Husain et al.). Secondary outcomes were change in depression severity (Montgomery–Asberg Depression Rating Scale for Dean et al. and 9-item Patient Health Questionnaire in Husain et al.), anxiety severity (Hamilton Anxiety Rating Scale in Dean et al. and Generalized Anxiety Disorder 7-item scale in Husain et al.) and functional status, which were also evaluated as potential mediators on the primary outcome. Results: A total of 112 participants were included in the pooled data (Dean et al., n = 71; Husain et al., n = 41). A significant change from baseline to week 12 was noted in depressive symptoms – differential change (Placebo vs Minocycline): 9.0, 95% confidence interval = [4.2, 13.9], Cohen’s D (95% confidence interval): 0.71 [0.29, 1.14], p &lt; 0.001 – anxiety severity – differential change (Placebo vs Minocycline): 0.38, confidence interval = [0.00, 0.75], Cohen’s D (95% confidence interval): 0.41 [0.00, 0.82], p = 0.050) and functional status – differential change (Placebo vs Minocycline): 1.0, 95% confidence interval = [0.4, 1.5], Cohen’s D (95% confidence interval): 0.76 [0.34, 1.19], p = 0.001). Duration of illness, current use of benzodiazepine and pain medication were identified as moderators, whereas functional status as a mediator/predictor. Conclusion: The improvement of depressive symptoms, anxiety severity and functional status is promising and suggests that minocycline has potential as an adjunctive treatment for major depressive disorder. However, further studies are warranted to confirm therapeutic effects of minocycline in major depressive disorder. Trial registrations: NCT02263872, registered October 2014, and ACTRN12612000283875, registered March 2012.

Proinflammatory and anti-inflammatory cytokine profiles in psoriasis: use as laboratory biomarkers and disease predictors

Relationship between the dexamethasone suppression test and the l-tryptophan/competing amino acids ratio in depression

Plasma-soluble interleukin-2 and transferrin receptor in schizoprenia and major depression

High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance

Recent schizophrenia (SCZ) research aims to establish biomarkers with high predictive value for the diagnosis, severity of illness or treatment resistance. SCZ is accompanied by activated immune-inflammatory pathways, including increased levels of cytokines and chemokines, but few studies tried to identify predictive properties of such measures.We included 54 medicated SCZ patients and 118 healthy controls and examined 15 cytokines and chemokines. Possible associations between these immune-inflammatory biomarkers and the diagnosis of SCZ, severity of illness and treatment resistance were investigated.SCZ is associated with a specific cytokine - chemokine profile, i.e., increased CCL11, MIP-1α, sTNF-R1 and sTNF-R2 levels, and decreased levels of IP-10, TNF-α, IL-2 and IL-4. The combination of five biomarkers (sTNF-R1, sTNF-R2, CCL11, IP-10, IL-4) may predict the diagnosis of SCZ with a sensitivity of 70.0% and a specificity of 89.4%. There was a weak association between the negative symptoms and biomarkers, i.e., IL-2 (inversely) and CCL11 (positively). Patients with treatment resistance showed increased levels of sTNF-R1, sTNF-R2 and MCP-1.The findings of this study reinforce that SCZ is associated with a pro-inflammatory profile and suggest that some immune mediators may be used as reliable biomarkers for the diagnosis of SCZ and treatment resistance.