B. Minner

Bio: B. Minner is an academic researcher from Case Western Reserve University. The author has contributed to research in topics: Dexamethasone suppression test & Adrenocorticotropic hormone. The author has an hindex of 16, co-authored 23 publications receiving 917 citations.

Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining.

Abstract: Several studies have reported a suppressed immune function (e.g. blast transformation) during depression. In an attempt to define the cellular basis of the reported immune disorders, the present study investigates the leukocyte cell subset profile of minor, simple major, and melancholic depressives, versus normal controls. We have counted the number of white blood cells (WBC) lymphocytes, monocytes, and granulocytes, while the number of lymphocyte (sub)populations has been identified by phenotype, using monoclonal antibody staining in conjunction with flow cytometry. The following cell surface antigens were determined: CD3+ (pan T), CD19+ (pan B), CD4+ (T helper/inducer), CD8+ (T suppressor/cytotoxic), CD4+CD45RA (T-memory cells), CD4+CD45RA+ (T-virgin cells), surface Ig, class II MHC HLA-DR, and CD25+ (IL-2 receptor). By means of pattern recognition methods, we established distinct immunological changes in minor and simple major depressed and in melancholic patients, setting them apart from the reference population. Depression, per se, is characterized by a higher number of WBC, monocytes, class II MHC HLA-DR, and memory T cells. Minor and simple major depressives exhibited an increased T helper/suppressor ratio. Increased numbers of IL-2 receptor bearing cells are a hallmark for major depression. Melancholics showed an increased number of pan T, pan B and T suppressor/cytotoxic cells. It was concluded that the established immune cell profile of depressed patients may point towards the existence of a systemic immune activation during that illness.

Impaired lymphocyte stimulation by mitogens in severely depressed patients. A complex interface with HPA-axis hyperfunction, noradrenergic activity and the ageing process.

Abstract: To investigate the relationships between the immune apparatus, major depression, and HPA-axis and noradrenergic activity, the authors measured the lymphocyte stimulation responses to the mitogens phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and concanavalin A (CON A), post-dexamethasone cortisol (DST) values and 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion in 24-hour urine samples from 48 patients. We found that lymphocyte responses to PHA and PWM in melancholic and psychotic depressives were significantly lower than in minor depressives. The lymphocyte responses to PHA, PWM and CON A showed significantly negative correlations with age, DST results and HRSD score. Responses to PHA were significantly negatively correlated with MHPG excretion. Up to +/- 33% of the variance in the three mitogenic lymphocyte responses could be explained by canonical correlation with age, DST results and MHPG values.

Autoimmunity in depression: increased antiphospholipid autoantibodies

Abstract: Some groups have recently reported higher titers of autoantibodies in depressed subjects than in normal controls. The present study investigates whether depressed patients exhibit increased antiphospholipid antibody titers compared with normal controls. The authors measured the binding index (BI) of antiphosphatidylserine (APSA), antipartial thromboplastin (APTA) and anticardiolipin (ACA) in 22 minor, 23 simple major and 20 melancholic depressives, 10 healthy controls and 104 normal controls with negative autoantibody sera. Depressed subjects exhibited significantly higher APSA and APTA antibody titers compared with normal controls. A large number of depressed subjects (+/- 54%) showed APTA and APSA positivity, defined as BI > or = 2 standard deviations above the mean BI of normal controls. There was a significant discrimination (> or = 2.8 standard deviations) between melancholic subjects and healthy controls with respect to BI of ACA, APSA and APTA. However, by using a more conservative value for phospholipid positivity (i.e., BI > or = 5 standard deviations above the mean BI of a reference sample of normal sera), the subject's autoantibody titers were, on the whole, within the normal range. Our results point towards a higher expression of antiphospholipid antibodies during depression but a much lower incidence of positive patients than in classical autoimmune disorders, such as systemic lupus erythematosus.

Suppressant effects of dexamethasone on the availability of plasma L-tryptophan and tyrosine in healthy controls and in depressed patients.

Abstract: Formation in the brain of serotonin from L-tryptophan (L-TRP) and noradrenaline from tyrosine are pathways related to the pathophysiology of major depression and to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In the past, decrements in L-TRP availability and disorders in the HPA axis have repeatedly been observed in major depressed patients; both factors were shown to be inversely correlated. In order to investigate the relationships between glucocorticosteroid activity and the availability of L-TRP and tyrosine, the authors measured L-TRP, tyrosine, valine, leucine, isoleucine and phenylalanine in baseline conditions and after treatment with 1 mg dexamethasone in 16 healthy controls and in 50 depressed patients. The ratios between L-TRP and tyrosine and the sums of the amino acids known to compete with them during transport across the blood-brain barrier were computed as an index of (respectively) the serotonin and noradrenaline synthesis in the brain. We found significantly decreased plasma L-TRP and tyrosine levels after treatment with dexamethasone compared with basal levels. Accordingly, the plasma ratios between L-TRP and tyrosine and the sum of the competing amino acids were significantly reduced by dexamethasone administration. It was hypothesized that through these actions of dexamethasone on peripheral amino acids, the central noradrenaline and serotonin control over the HPA-axis could be altered.

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression

Abstract: Major life stressors, especially those involving interpersonal stress and social rejection, are among the strongest proximal risk factors for depression. In this review, we propose a biologically plausible, multilevel theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental stress with internal biological processes that drive depression pathogenesis. Central to this social signal transduction theory of depression is the hypothesis that experiences of social threat and adversity up-regulate components of the immune system involved in inflammation. The key mediators of this response, called proinflammatory cytokines, can in turn elicit profound changes in behavior, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. This highly conserved biological response to adversity is critical for survival during times of actual physical threat or injury. However, this response can also be activated by modern-day social, symbolic, or imagined threats, leading to an increasingly proinflammatory phenotype that may be a key phenomenon driving depression pathogenesis and recurrence, as well as the overlap of depression with several somatic conditions including asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, obesity, and neurodegeneration. Insights from this theory may thus shed light on several important questions including how depression develops, why it frequently recurs, why it is strongly predicted by early life stress, and why it often co-occurs with symptoms of anxiety and with certain physical disease conditions. This work may also suggest new opportunities for preventing and treating depression by targeting inflammation.

The relationship of depression and stressors to immunological assays: a meta-analytic review.

Abstract: This is a broad meta-analysis of the relations of both depression and stressors to immunological assays. The number of study samples (greater than 180) and measures (greater than 40) is much more extensive than any so far. Analyses are done by both fixed and random effects. By a fixed-effects analysis, both major depression and naturally occurring acute stressors are associated with (1) an overall leukocytosis, (2) mild reductions in absolute NK-cell counts and relative T-cell proportions, (3) marginal increases in CD4/CD8 ratios, and (4) moderate decreases in T- and NK-cell function. However, the degree of heterogeneity of the studies' results raises questions about their robustness. Therefore, we also did the first random effects analysis to estimate what is likely to appear in future studies. For depression, the analysis showed the immunological correlates included (1) an overall leukocytosis, manifesting as a relative neutrophilia and lymphoenia; (2) increased CD4/CD8 ratios; (3) increased circulating haptoglobin, PGE(2), and IL-6 levels; (4) reduced NK-cell cytotoxicity; and (5) reduced lymphocyte proliferative response to mitogen. For stressors, the random effects analysis showed that future studies are likely to find the following effects: (1) an overall leukocytosis, manifesting as an absolute lymphocytosis; (2) alterations in cytotoxic lymphocyte levels, CD4/CD8 ratios, and natural killer cell cytotoxicity with the direction of change depending on the chronicity of the stressor; (3) a relative reduction of T-cell levels; (3) increased EBV antibody titers; (4) reduced lymphocyte proliferative response and proportion of IL-2r bearing cells following mitogenic stimulation; and (5) increased leukocyte adhesiveness. The random-effects analysis revealed that for both major depression and naturally occurring stressors the following effects are shared: leukocytosis, increased CD4/CD8 ratios, reduced proliferative response to mitogen, and reduced NK cell cytotoxicity. The implications for these findings for disease susceptibility and the pathophysiology of these conditions is discussed.

Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders.

Abstract: There is abundant evidence for abnormalities of the norepinephrine (NE) and serotonin (5HT) neurotransmitter systems in depression and anxiety disorders. The majority of evidence supports underactivation of serotonergic function and complex dysregulation of noradrenergic function, most consistent with overactivation of this system. Treatment for these disorders requires perturbation of these systems. Reproducible increases in serotonergic function and decreases in noradrenergic function accompany treatment with antidepressants, and these alterations may be necessary for antidepressant efficacy. Dysregulation of these systems clearly mediates many symptoms of depression and anxiety. The underlying causes of these disorders, however, are less likely to be found within the NE and 5HT systems, per se. Rather their dysfunction is likely due to their role in modulating, and being modulated by, other neurobiologic systems that together mediate the symptoms of affective illness. Clarification of noradrenergic and serotonergic modulation of various brain regions may yield a greater understanding of specific symptomatology, as well as the underlying circuitry involved in euthymic and abnormal mood and anxiety states. Disrupted cortical regulation may mediate impaired concentration and memory, together with uncontrollable worry. Hypothalamic abnormalities likely contribute to altered appetite, libido, and autonomic symptoms. Thalamic and brainstem dysregulation contributes to altered sleep and arousal states. Finally, abnormal modulation of cortical-hippocampal-amygdala pathways may contribute to chronically hypersensitive stress and fear responses, possibly mediating features of anxiety, anhedonia, aggression, and affective dyscontrol. The continued appreciation of the neural circuitry mediating affective states and their modulation by neurotransmitter systems should further the understanding of the pathophysiology of affective and anxiety disorders. Depression and Anxiety, Volume 12, Supplement 1:2–19, 2000. © 2000 Wiley-Liss, Inc.

Evidence for an immune response in major depression: a review and hypothesis

Abstract: 1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression. 2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an "acute" phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1 beta and IL-6 by peripheral blood mononuclear cells. 3. It is hypothesized that increased monocytic production of interleukins (Il-1 beta and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and "acute" phase response, while contributing to hypothalamic-pituitary-adrenal-axis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.

Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis

Abstract: Aims/hypothesis Evidence strongly suggests that depression and type 2 diabetes are associated, but the direction of the association is still unclear. Depression may occur as a consequence of having diabetes, but may also be a risk factor for the onset of type 2 diabetes. This study examined the latter association by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic.