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Comparison of Immunological and Endocrinological Markers Associated with Major Depression
Abstract
Natural-killer-(NK)-cell activity and blood levels of interleukin 2 (IL-2), dehydro-epiandrosterone (DHEA), DHEA sulphate (DHEA-S) and cortisol were measured in 17 patients with major depression and 10 control subjects. Depression severity was evaluated using the Zung Self-rating Depression Scale. NK-cell activity and IL-2 levels were measured using a chromium-51 release test and an enzyme-linked immunosorbent assay, respectively. Radio-immunoassays were used to measure serum cortisol, DHEA and DHEA-S. As would be expected, patients with major depression had a higher score on the Zung Self-rating Depression Scale than healthy controls. Compared with controls, NK-cell activity and levels of cortisol and DHEA were reduced in patients with major depression, whereas IL-2 levels were increased. No difference was observed in DHEA-S levels between patients and controls. A reduction in NK-cell activity and DHEA levels, and an increase in IL-2 levels appear to be associated with major depression. Whether these changes are the cause or the consequence of the depression remains to be determined.
... They went on to suggest that lower DHEA levels are an additional state of abnormality in adult depression, alongside hypercortisolaemia, i.e. blunted cortisol response (Osran et al., 1993). Additionally, the results of Jozuka et al., 2003 study further justify this argument (Jozuka et al., 2003). In this study the cortisol and DHEA levels were observed to be radically lower in MDD patients compared to healthy controls, albeit in a smaller sample size of 17 MDD patients and 10 healthy participants. ...
... They went on to suggest that lower DHEA levels are an additional state of abnormality in adult depression, alongside hypercortisolaemia, i.e. blunted cortisol response (Osran et al., 1993). Additionally, the results of Jozuka et al., 2003 study further justify this argument (Jozuka et al., 2003). In this study the cortisol and DHEA levels were observed to be radically lower in MDD patients compared to healthy controls, albeit in a smaller sample size of 17 MDD patients and 10 healthy participants. ...
Psychological stress and its inevitable trajectory toward mental health deteriorations such as clinical and major depression has become an unprecedented global burden. The diagnostic procedures involved in the characterization of mental illnesses commonly follow qualitative and subjective measures of stress, often leading to greater socioeconomic burdens due to misdiagnosis and poor understanding of the severity of such illnesses, further fueled by the stigmatization surrounding mental health. In recent years, the application of cortisol and stress hormone measurements has given rise to an alternative, quantifiable approach for the psychological evaluation of stress and depression. This review comprehensively evaluates the current state-of-the-art technology for measuring cortisol and dehydroepiandrosterone (DHEA) and their applications within stress monitoring in humans. Recent advancements in these fields have shown the importance of measuring stress hormones for the characterization of stress manifestation within the human body, and its relevance in mental health decline. Preliminary results from studies considering multimodal approaches toward stress monitoring have showcased promising developments, emphasizing the need for further technological advancement in this field, which consider both neurochemical and physiological biomarkers of stress, for global benefit.
... Depression and cognitive impairment have become major public health problems all over the world, both of which are often comorbid and closely related to the histopathological changes in hippocampus in both human and rodent models [15,16]. The hippocampus is vulnerable to kinds of injuries such as the increased glucocorticoid release induced by hypothalamic-pituitary-adrenal (HPA) axis activation [17][18][19], the inflammation characterized with increased pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) [20], and high oxidative stress [21,22]. Furthermore, these factors can also induce neuronal cells apoptosis, inhibit neurogenesis, and reduce neuroplasticity in hippocampus [23][24][25][26]. ...
... It is well known that continuous activation of the HPA axis can induce abnormal increase of stress hormones such as CORT and ACTH, which has been considered to be closely related with cognitive dysfunction and depressive disorders in rodents and humans [17][18][19]. As the final secretory product of HPA activation, CORT can easily cross the blood-brain barrier and enter the brain, and influence brain functions and behavior by binding to glucocorticoid receptors in hippocampus, etc. ...
Tris-(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), an emerging brominated flame retardant, possesses the characteristics of candidate persistent organic pollutants and has displayed toxicity to fish and rodents. TDBP-TAZTO can pass through the blood brain barrier and accumulate in brain. However, the neurotoxicity of TDBP-TAZTO has not yet studied in rodents. We hypothesize that TDBP-TAZTO could induce the neurotoxicity in rat hippocampal neurons. The male adult rats were exposed to TDBP-TAZTO of 5 and 50 mg/kg by gavage, daily for 6 months. TDBP-TAZTO resulted in cognitive impairment and depression-like behaviors, which may be related with TDBP-TAZTO-induced hypothalamic-pituitary-adrenal axis hyperactivation, upregulation of inflammatory and oxidative stress markers, overexpression of pro-apoptotic proteins, downexpression of neurogenesis-related proteins in hippocampus, and hippocampal neurons damage in DG, CA1 and CA3 areas. Our findings suggested that TDBP-TAZTO induces significant hippocampal neurotoxicity, which provokes cognitive impairment and depression-like behaviors in adult rats. Therefore, this research will contribute to evaluate the neurotoxic effects of TDBP-TAZTO in human.
... In the process of margination, leukocytes are pushed out from the main bloodstream toward the blood vessel wall. Then leukocytes come into contact with the endothelium of vessel wall and are subjected to rolling [41,42]. This process occurs by temporary binding of leukocyte receptors with selectins. ...
... Studies have shown that initially elevated levels of pro-inflammatory cytokines such as IL-12, IFN-g were reduced after treatment with drugs from the group of selective serotonin reuptake inhibitors (SSRI). SSRIs increase the concentration of antiinflammatory cytokines (e.g., IL-10, IL-4, tumor necrosis factor-b1) in the serum of patients suffering from depression [42]. Moreover, these drugs, similarly to antidepressants with other mechanisms of action, affect the expression of genes encoding neurotrophins, which are associated with mechanisms of synaptic plasticity. ...
Development of depression is associated with the body's response to prolonged stress, which adversely affects the functioning of the nervous, endocrine and immune systems. Prolonged stress can lead to the development of a so-called allostatic load and reduction of concentration of brain-derived neurotrophic factor. These changes result in impairment of neurogenesis and synaptic remodeling process. This article illustrates the involvement of key mediators of allostasis such as the neuroendocrine and immune systems, in the pathogenesis of depression. The literature concerning the contribution of the neuroendocrine and immune systems to depression incidence was reviewed. Development of depression is associated with disturbance of the body's allostasis and inflammatory activation of the immune system. It leads to a chronic increase in the concentration of cortisol and proinflammatory cytokines, which results in an allostatic load. This load leads to neurodegeneration, eventually causing irreversible cognitive impairment and permanent disability. Determination of the concentration of chemokines and their receptors is an important indicator of activation of the immune and neuroendocrine systems. The activity of these systems reflects the severity of the disease and provides important information for effective antidepressant treatment.
... Altogether, these findings indicate that cortisol may play a more significant role in the clinical management and outcome of MDD patients than previously anticipated. In MDD patients, our meta-analysis also further supported a correlation between antidepressant drug therapy and a reduction in peripheral levels of IL-2, a cytokine secreted by T lymphocytes [92] that is upregulated in MDD patients [93]. Although previous evaluations did not identify a significant association of IL-2 levels with the response to antidepressant drug treatment [6,9], those analyses may suffer from low statistical power due to the limited number of analyzed studies. ...
Objective
To conduct a systematic review and meta-analysis of the effects of antidepressant drug therapy (with or without physical exercise) on peripheral inflammatory markers in patients with major depressive disorder (MDD).
Methods
MEDLINE, PyscINFO, Embase, and Google Scholar databases were searched until May 2020. Randomized trials that measured at least one inflammatory biomarker and included adult outpatients with MDD under antidepressant drug therapy (any drug) with or without physical exercise (any modality) were eligible. Results were summarized using the standardized mean difference (SMD) with 95% confidence intervals (95% CI) under a random-effects model. The Cochrane risk of bias tool (2010) was used to evaluate the risk of bias in the included trials.
Results
Sixty-three trials were identified, encompassing data from 3482 patients, and 20 investigated biomarkers. Trials had biases across multiple domains, rising concerns primarily to selection bias/performance bias/detection bias/attrition bias. SMDs between pre- and post-results indicated a significant reduction in the levels of IL-2 (SMD, − 0.25; 95% CI, − 0.41 to − 0.09, P = 0.002), IL-6 (SMD, − 0.19; 95% CI, − 0.35 to − 0.025, P = 0.024), IL-10 (SMD, − 0.32; 95% CI, − 0.57 to − 0.07, P = 0.011), and serum cortisol (SMD, − 0.35; 95% CI, − 0.58 to − 0.12, P = 0.002). Evidence supporting the influence of physical exercise combined with antidepressant drugs on peripheral inflammatory markers in MDD is sparse and heterogeneous.
Conclusion
There is some evidence that antidepressant drug therapy is associated with an overall positive reduction in inflammatory markers, but the evidence is heterogeneous. Further research linking how inflammatory biomarkers modulate physiology related to antidepressant response is required.
Trial registration
CRD42020220735
... However, it is generally recognized that chronic stress plays an important role in the development of depression. Long-term chronic stress can lead to dysfunction of the HPA axis and increased secretion of corticosteroids, both of which are considered to be closely involved in the pathogenesis of human depression (Jozuka et al., 2003;Xing et al., 2015). The HPA axis is one of the complex neurobiological mechanisms contributing to the occurrence and development of depression (Xing et al., 2015). ...
The Aquilaria sinensis (Lour.) Gilg (CX)–Aucklandia costus Falc. (MX) herbal pair is frequently used in traditional Chinese medicine prescriptions for treating depression. The volatile oil from CX and MX has been shown to have good pharmacological activities on the central nervous system, but its curative effect and mechanism in the treatment of depression are unclear. Therefore, the antidepressant effect of the volatile oil from CX–MX (CMVO) was studied in chronic unpredictable mild stress (CUMS) rats. The suppressive effects of CMVO (25, 50, 100 μL/kg) against CUMS-induced depression-like behavior were evaluated using the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT). The results showed that CMVO exhibited an antidepressant effect, reversed the decreased sugar preference in the SPT and prolongation of immobility time in the FST induced by CUMS, increased the average speed, time to enter the central area, total moving distance, and enhanced the willingness of rats to explore the environment in the OFT. Inhalational administration of CMVO decreased levels of adrenocorticotropic hormone and corticosterone in serum and the expression of corticotropin-releasing hormone mRNA in the hypothalamus, which indicated regulation of over-activation of the hypothalamic–pituitary–adrenal (HPA) axis. In addition, CMVO restored levels of 5-hydroxytryptamine (5-HT), dopamine, norepinephrine and acetylcholine in the hippocampus. The RT-PCR and immunohistochemistry results showed that CMVO up-regulated the expression of 5-HT1A mRNA. This study demonstrated the antidepressant effect of CMVO in CUMS rats, which was possibly mediated via modulation of monoamine and cholinergic neurotransmitters and regulation of the HPA axis.
... No differences in morning cortisol levels were observed in pregnant women with MDD compared to healthy pregnant women (Hellgren et al., 2016). In addition, decreased morning cortisol level are reported in Jozuka et al. (2003). At midday Whalley et al. (1986) reported no differences between MDD and healthy controls. ...
It is debated as to whether major depressive disorder (MDD) and the burnout syndrome represent different aspects of the same syndrome or whether they reflect separate entities. A dysregulation of the hypothalamus-pituitary-adrenal-axis has been related to both conditions separately. Dissecting the pathophysiology of the conditions and describing differences and similarities with regard to stress physiological systems might further clarify whether underlying etiological models of these syndromes differ. A systematic literature search including MDD and the burnout syndrome and peripheral cortisol measures was performed and resulted in 190 studies for inclusion in the qualitative synthesis. For MDD, findings suggest a general state of hypercortisolism and glucocorticoid resistance reflected by increased basal cortisol levels, reduced reactivity to psychosocial stress and a reduced cortisol suppression in pharmacological challenge tests. For the burnout syndrome, two central factors limit further conclusions: i) there is not a suf cient amount of studies examining the burnout syndrome and different cortisol secretion patterns to provide an evidence base, ii) the burnout syndrome is assessed heterogeneously reflecting imprecision of the measured constructs. Large prospective cohort studies examining both conditions in parallel rigorously controlling for confounders are required to further elucidate the differences and similarities of the HPA axis in MDD and the burnout syndrome.
... Seven studies reported C-reactive protein (CRP) levels (20,37,44,45,47,49,50), one study reported eosinophil cationic protein (ECP) levels (27), one study reported eosinophil chemotactic protein-2 (EOTAXIN-2) levels (27), five studies reported interferon-γ (IFN-γ) levels (22,27,36,39,43), six studies reported IL-1β levels (23,31,38,40,43,46), two studies reported IL-1 receptor antagonist (IL-1RA) levels (31,47), five studies reported IL-2 levels (23,24,26,30,39), two studies reported (22), three studies reported IL-10 levels (22,25,39), one study reported monocyte chemoattractant protein-1 (MCP-1) levels (25), one study reported regulated on activation, normal T cell expressed and secreted (RANTES) levels (27), one study reported soluble IL-2 Receptor (sIL-2R) levels (41), 15 studies reported TNF-α levels (24, 25, 27, 28, 32-36, 37, 39, 44, 46, 48, 50), and one study reported vascular endothelial growth factor (VEGF) levels (25). ...
Background: Glucocorticoid resistance-reduced function of the glucocorticoid receptor (GR)-is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. Purpose: We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), GR expression levels, and the results of in vitro assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. Results: After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [d = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [d = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine-plasma (d = 1.04; 95% CI, 0.57-1.50) versus in vitro (d = 0.24; 95% CI, -0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53-2.18). Combining our analyses of studies that reported DST results with those that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls (d = 1.02; 95% CI, 0.55-1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Conclusions: Our work provides some support for a model conceptualizing glucocorticoid resistance as a requisite for increased inflammation in depression. The limited number of studies identified highlights the need for purpose-designed investigations that directly examine the relationship between glucocorticoid resistance and cytokine production in depression.
... The cytokine hypothesis holds that depression is a psychoneuroimmune disorder due to the chronic stress promoting inflammatory responses via the sympathetic and parasympathetic nervous system pathways (Zunszain et al., 2011). Since Maes (1995) proposed the cytokine hypothesis of the etiology of depression, some studies have demonstrated that depression is often accompanied by an immune response, which is manifested by the increased secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) (Hernández et al., 2008;Jayandharan et al., 2011;Jozuka et al., 2003;Raison et al., 2006). Several reviews, systematic reviews, and meta-analyses have been published on the wealth of findings on inflammation in mental disorders (Baumeister et al., 2014;Dowlati et al., 2010;Köhler et al., 2017). ...
This cross-sectional study aimed at measuring the correlation and association between serum levels of cortisol, inflammatory cytokines, and depression and to measure the detection accuracy of serum levels of cortisol in serum samples. In total, 89 male participants were recruited into this study from June 15, 2017, to September 31, 2017. The Hamilton Depression Rating Scale, Beck Anxiety Inventory, and Pittsburgh Sleep Quality Index were used to investigate the mental health status of the participants. Serum concentrations of cortisol and inflammatory cytokines were determined. The serum cortisol concentration, anxiety level, and sleep quality were included in the final logistic regression model. Serum cortisol was able to accurately distinguish between patients with depression and those without depression. There was a significant positive correlation between serum cortisol levels and Hamilton Depression Rating Scale scores.
... All these cytokines were In this study, we observed that IL-2 was significantly higher in MDD adolescents than in healthy volunteers, which is in agreement with previous reports in adolescents with mood disorders [19,28]. In contrast, the studies concerning adult patients are controversial since there are reports of both high [29][30][31][32] and low values [7,26,33,34]. The effects of SSRIs on IL-2 levels depend on the drug being used; while sertraline does not affect IL-2 levels in adult patients [30], fluoxetine lowers them after 20 weeks of administration [34]. ...
Changes in cytokine levels in major depression and during treatment have been reported in adults. However, few studies have examined cytokine levels in an adolescent sample despite this being a common age of onset. Methods . We measured proinflammatory (IL-2, IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15) and anti-inflammatory (IL-4, IL-5, IL-13, IL-1Ra, and IL-10) cytokine serum levels in 22 adolescents with major depression and 18 healthy volunteers. Cytokines were measured by multiplex bead-based immunoassays at baseline, and 4 and 8 weeks after commencement of fluoxetine administration in the clinical group. Results . Compared to healthy volunteers, adolescents with major depression at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1Ra and IL-10. Significant changes were observed in fluoxetine treatment compared to baseline: proinflammatory cytokines IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15 were decreased only at week 4 whereas IL-2 was increased only at week 8; anti-inflammatory cytokines IL-4 and IL-5 were increased at week 8 while IL-1Ra was reduced only at week 4. There were no significant correlations between cytokine levels and symptomatic improvement in HDRS. Discussion . The results suggest a significant interplay between cytokine levels, the depressive state, and the stage of treatment with an SSRI. To the best of our knowledge, this is the first report in depressed adolescents with elevated IL-12, IL-13, and IL-15 levels. Further studies are necessary to clarify the role and mechanisms of altered cytokine levels in the pathogenesis and physiopathology of major depressive disorder.
... In general, the HPA axis provides a negative feedback mechanism so that glucocorticoid levels in the circulatory system remain within a normal range. However, the hyperactivity of the HPA axis induced by long-term stress exposure might cause continuous increases in CORT and ACTH levels, both of which are closely related to depressive disorder in rodents and humans (Jozuka et al. 2003). Our data indicated that AEC could modify the hyperactivity of HPA axis by reducing the levels of plasma ACTH and serum CORT in CUMS-induced rats. ...
Camellia euphlebia (family, Theaceae) is a Chinese folk medicine, known for its multiple pharmacological properties. The present study aimed to provide further insights into the therapeutic basis of C. euphlebia using several animal behavioral tests and physiological indexes. Tail suspension test, forced swimming test, open-field test, chronic unpredictable mild stress (CUMS), reversal of reserpine-induced hypothermia and palpebral ptosis, and 5-hydroxytryptophane-induced head-twitch response were used to evaluate the antidepressant effect of aqueous extract of Camellia euphlebia (AEC) on mice. The possible underlying mechanism was explored by investigating the changes associated with several parameters of animal behavior, as well as the changes in monoamine neurotransmitter and stress hormone levels in these animals during the tests. Mice administered AEC at 100 and 200 mg/kg/day doses for 7 days showed significantly reduced immobility duration in forced swimming test and tail suspension test, whilst exhibiting no apparent changes in locomotor activity. Additionally, administration of AEC also effectively antagonized reserpine-induced palpebral ptosis and hypothermia and enhanced 5-hydroxytryptophane-induced head-twitch response. AEC significantly elevated the levels of serotonin, noradrenaline and dopamine in the blood and brain compared to non-treated mice. After 28 days of administration, the maximum AEC dose (100 mg/kg/day) significantly reversed CUMS-induced inhibition of weight gain and sucrose intake, while decreasing the levels of plasma adrenocorticotropic hormone and serum corticosterone. The antidepressant effect of AEC appeared to involve the alteration of hypothalamic-pituitary-adrenal axis and monoaminergic systems.
... Il a été suggéré qu'une production accrue des cytokines proinflammatoires IL-2, IL-6 et interféron d (IFN-d) serait impliquée dans l'étiologie de la dépression (Maes et al. 1999). Une étude récente par Jozuka et al. (2003) a révélé qu'une réduction de l'activité chez le sujet déprimé et une augmentation des cellules TN et du niveau IL-2 semble être associée à la dépression. Il est probable que l'IL-10 joue également un rôle dans le processus de la dépression (Mesquita et al. 2008). ...
On a souvent rapporte que la depression s'installe suite a des perturbations des activites de l'axe corticotrope et du systeme immunitaire. L'objectif de cette etude etait d'explorer les effets du ketoconazole, un derive d'imidazole, inhibiteur de la steroidogenese gonadique et surrenalienne, sur les variations du nombre de leucocytes totaux et des pourcentages de sous-populations leucocytaires, au cours de la nage forcee chez le rat (test de Porsolt), un test consiste a tester l'efficacite des antidepresseurs. Des catheters ont ete implantes, sous anesthesie generale, dans la carotide droite, et des prises de sang (0,2 mL) ont ete realisees a des intervalles de 15 min au cours de l'experimentation, alors que les animaux pouvaient se comporter librement. Les degres d'anxiete et d'activite locomotrice des rats ont ete mesures au labyrinthe en croix surelevee et au test des champs ouverts. La nage forcee a provoque des fluctuations du systeme immunitaire et de la testosteronemie, lesquelles qui ont ete inhibees suite au traitement des animaux au ketoconazole. Cet effet a ete obtenu egalement sur le plan comportemental (labyrinthe en croix surelevee, nage forcee) dans le sens d'une amelioration (effets anxiolytique et antidepresseur). Ces resultats suggerent que les reponses comportementales et physiologiques sont inter-reliees d'une maniere multifactorielle et que la corticosterone joue un role cle dans la pathogenie des maladies psychiatriques.
... Moreover, decreasing TNF-␣ and IL-6 levels during treatment are associated with treatment response [13,54], whereas high IL-6 and TNF-␣ levels are associated with the degree of treatment resistance [55]. In addition to the pro-inflammatory cytokines, serum levels of IL-10, one of the main anti-inflammatory cytokines, are also reported to be significantly enhanced by the effective antidepressants imipramine, venlafaxine [56] and fluoxetine, in patients with depression [57,58]. Therefore, cytokines are thought to be a biomarker of depression [17], although the role of cytokines in the molecular mechanism of depression is still not clearly understood [59]. ...
Little is known about the physiological or pharmacological properties of alarin, a new neuropeptide belonging to the galanin family. We previously showed that alarin has an antidepressant-like effect and is associated with a decrease in the hyperactivity of hypothalamic–pituitary–adrenal (HPA) axis that is observed in patients with depression using unpredictable chronic mild stress (UCMS) mouse model of depression. However, the mechanisms underlying these effects have not been uncovered. Inflammatory cytokines are reportedly associated with depression. Animal studies and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology and potently activate the HPA axis, whereas anti-inflammatory cytokines may decrease activation. Thus, we first determined the levels of inflammatory cytokines in the blood and brain to evaluate whether the antidepressant-like effect of alarin in UCMS-treated mice is related to its regulation of these inflammatory cytokines. Pro-inflammatory cytokines disrupt the function and/or expression of glucocorticoid receptors (GRs), which mediate the negative feedback of glucocorticoids on the HPA axis to keep it from being overactivated. We next explored the expression level of GRs in the brains of mice subjected to UCMS and to the administration of alarin. We found that intracerebroventricular administration of alarin significantly ameliorated depression-like behaviors in the UCMS-treated mice. Alarin restored the UCMS-induced an increase in the levels of the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α and a decrease in the anti-inflammatory cytokine IL-10 level in the blood, prefrontal cortex, hippocampus and hypothalamus. Alarin also reversed the UCMS-induced down-regulation of GR expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring altered pro-inflammatory and anti-inflammatory cytokine levels and GR expression to decrease HPA axis hyperactivity. Our findings provide additional knowledge to interpret the pathophysiology of depression.
... Some authors have reported reduced DHEAS concentration in patients with depression (Eser et al. 2006b;Maninger et al. 2009) or dysthymia (Markianos et al. 2007). No difference in DHEAS plasma levels was found in other studies (Jozuka et al. 2003;Paslakis et al. 2010). ...
... This is surprising given the relative absence of significant differences in prior studies in at least one meta-analysis (Dowlati et al., 2010). However, both the methods and results were highly heterogeneous in prior studies and one study showed significant differences between MDD and controls (Jozuka et al., 2003). ...
Many people with major depressive disorder (MDD) show evidence of systemic inflammation, including elevations in inflammatory factors, but the cause is unclear. The purpose of this analysis was to determine if obesity might contribute to the pro-inflammatory state in MDD patients. Blood was obtained from 135 MDD patients and 50 controls. Serum was extracted and assayed for interleukin (IL) -1β, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), C-reactive protein (CRP), leptin, and adiponectin using single- or multi-plex human immunoassay kits. The primary analysis contrasted IL-6, TNFα, and CRP between MDD and control groups with body mass index (BMI) as a covariate. The other analytes were compared in an exploratory fashion. IL-6 (but not TNFα or CRP) showed significant differences between MDD and controls even after covarying for BMI. Obese controls and obese MDD groups were significantly higher in IL-6 than both lean groups, but the two obese groups did not differ from each other. In the exploratory analyses, the IL-2 level showed robust and significant differences between MDD and controls even after covarying for BMI. Both lean and obese MDD were higher than lean and obese controls. Adiponectin levels were also lower in the MDD sample than controls. Prior findings of higher IL-6, and CRP in MDD patients may be explained, at least in part, based on obesity. High IL-2, however, was associated with depression and not obesity. The results have significant implications for the understanding of pathophysiology and, potentially treatment of MDD.
... Our findings are consistent with previous reports of suppressed NK cell cytotoxicity in depressed individuals (Irwin et al. 1990;Jozuka et al. 2003;Kronfol et al. 1989;Maes et al. 1994), and the literature also supports our conclusion that this suppression in NK cell cytotoxicity in depressed patients is not a result of alterations in numbers of circulating NK cells (Darko et al. 1988;Maes et al. 1994) or a result of alterations in CD56 dim / CD56 bright NK cell distribution or CD16 +ve NK cells. Interestingly, we have also found an association between depression scores and NK cell cytotoxicity in hip fracture patients, which has been reported in people undergoing severe life stressors, such as bereavement (Irwin et al. 1987a). ...
NK cell cytotoxicity (NKCC) reduces with age and this has been associated previously with increased mortality. The immune response is also modulated by stress, and here, we assessed the effect of the physical stress of hip fracture and the psychological stress of depression on NKCC in an aged immune system. NKCC was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and in 50 healthy age-matched controls (28 female). Thirty-eight patients were depressed at 6 weeks post-injury, and NKCC was reduced in patients who developed depression compared with non-depressed hip fracture patients (p = 0.004) or controls (p < 0.02). NKCC remained lower in the depressed patients compared to those without depression 6 months post-fracture (p = 0.017). We found reduced expression of perforin in NK cells of depressed hip fracture patients compared with controls at 6 weeks (p = 0.001) post-fracture. Serum cortisol levels were also elevated in patients with depression compared to non-depressed patients at 6 weeks (p = 0.01) and 6 months (p = 0.05). NK cells treated with dexamethasone showed a concentration-dependent reduction in NKCC and perforin expression. We propose that depression is the major factor affecting NK cell immunity after hip fracture.
... Adrenal androgens such as dehydroepiandrosterone (DHEA) signify the start of adrenarche prior to gonadarche, and have been shown to activate the immune response [130]. Other research has shown that DHEA [131] levels are decreased in adult patients with MDD. It seems likely that biological mechanisms underlying these processes differ in pre-pubescent children that are experiencing an initial increase in adrenal androgens compared to adults or elderly patients. ...
Depression often has its first onset during adolescence and is associated with obesity. Furthermore, inflammatory processes have been implicated in both depression and obesity, although research amongst adolescents is limited. This review explores associations between depression and obesity, depression and inflammation, and obesity and inflammation from a developmental perspective. The temporal relations between these factors are examined to explore whether obesity and elevated inflammation act as either risk factors for, or outcomes of, adolescent-onset depression. Sex differences in these processes are also summarized. We propose a model whereby increases in sex hormones during puberty increase risk for depression for females, which can lead to obesity, which in turn increases levels of inflammation. Importantly, this model suggests that inflammation and obesity are outcomes of adolescent depression, rather than initial contributing causes. Further research on biological and psychosocial effects of sex hormones is needed, as is longitudinal research with children and adolescents.
... Our meta-analysis included a total of 10 case-control studies that provided information on the correlation of DHEAS protein expression with depression (Assies et al., 2004;Goodyer et al., 1996;Hsu et al., 2009;Jozuka et al., 2003;Kurita et al., 2013;Markianos et al., 2007;Oulis et al., 2014;Phillips et al., 2011;Si et al., 2010;Takebayashi et al., 1998). Five studies were conducted in populations of Asian descent and another 5 in populations of Caucasian descent, including 4496 subjects total (493 patients with depression and 4003 healthy controls). ...
... Już wtedy zwrócono uwagę na możliwość terapii zaburzeń psychicznych poprzez wpływ na układ odpornościowy [1]. Obecnie prowadzi się coraz więcej badań, które wskazują na rolę zaburzeń im-munologicznych w depresji [2][3][4][5], schizofrenii [6][7][8], w chorobie Alzheimera [9][10][11][12] i innych. W zaburzeniach snu współistniejących zarówno z chorobami somatycznymi, jak i psychicznymi także obserwuje się współistniejącą nieprawidłowość w funkcjonowaniu układu odpornościowego [13][14][15]. ...
Sleep has a property of regenerating both body and psyche of humans. Disturbances of sleep accompany disturbances of immune system. Also, disturbances of sleep may be observed in many inflammatory diseases, for example in bacterial infections. These findings validate the attempts to seek relation between sleep process and immune system condition. Regulation of sleep is a complex phenomenon, which involves interaction between neuropeptides, neurotransmitters from nerve system, hormones from endocrine system, and cytokines from the immune system.
Much research is concerned with the role of cytokines in disturbances of sleep. Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) are currently believed to be among the most important cytokines influencing the central nervous system and physiological sleep process. This work gives a review of current data on the role of the abovementioned and other cytokines of the immune system in sleep disturbances.
... In contrast, we did not detect any changes in the expression of the adhesion molecules on nonlymphocytic leukocyte populations. Additionally, we observed an increased percentage of natural killer cells after IFN-␣ treatment, which is in line with the studies suggesting a role of this cell population in depression [69][70][71] . ...
... Il a été suggéré qu'une production accrue des cytokines proinflammatoires IL-2, IL-6 et interféron d (IFN-d) serait impliquée dans l'étiologie de la dépression (Maes et al. 1999). Une étude récente par Jozuka et al. (2003) a révélé qu'une réduction de l'activité chez le sujet déprimé et une augmentation des cellules TN et du niveau IL-2 semble être associée à la dépression. Il est probable que l'IL-10 joue également un rôle dans le processus de la dépression (Mesquita et al. 2008). ...
On a souvent rapporté que la dépression s’installe suite à des perturbations des activités de l’axe corticotrope et du système immunitaire. L’objectif de cette étude était d’explorer les effets du kétoconazole, un dérivé d’imidazole, inhibiteur de la stéroïdogénèse gonadique et surrénalienne, sur les variations du nombre de leucocytes totaux et des pourcentages de sous-populations leucocytaires, au cours de la nage forcée chez le rat (test de Porsolt), un test consiste à tester l’efficacité des antidépresseurs. Des cathéters ont été implantés, sous anesthésie générale, dans la carotide droite, et des prises de sang (0,2 mL) ont été réalisées à des intervalles de 15 min au cours de l’expérimentation, alors que les animaux pouvaient se comporter librement. Les degrés d’anxiété et d’activité locomotrice des rats ont été mesurés au labyrinthe en croix surélevée et au test des champs ouverts. La nage forcée a provoqué des fluctuations du système immunitaire et de la testostéronémie, lesquelles qui ont été inhibées suite au traitement des animaux au kétoconazole. Cet effet a été obtenu également sur le plan comportemental (labyrinthe en croix surélevée, nage forcée) dans le sens d’une amélioration (effets anxiolytique et antidépresseur). Ces résultats suggèrent que les réponses comportementales et physiologiques sont inter-reliées d’une manière multifactorielle et que la corticostérone joue un rôle clé dans la pathogénie des maladies psychiatriques.
... The increase in serum cortisol noticed in this work are in accordance with different other studies (31,32). Cortisol hypersecretion in depressed patients has been documented by elevated plasma corticosteroid concentrations (31) and increased levels of cortisol metabolites (33). ...
Psychiatric disorders especially depression are associated with a variety of changes in immunity parameters. In this work, an attempt was carried out to make estimation about the correlation between immunity and depression through the measuring of IgG, IgA, and IgM and complements (C3 and C4) levels in the serum of patients and comparing them with the corresponding levels of healthy control group. The results showed a significant increase in serum level of C3, C4, cortisol, IgG and no significant differences were noticed in the level of IgA and IgM in the depressed patients group as compared with control group. A slight positive correlation was observed between cortisol versus IgG in depressed patients that is not found in normal subjects. Thus in depression, human body defenses psychologically and sometimes this defense transformed into immunological resistance that is expressed as different measurable changes in immunological parameters.
... Continuous activation of the HPA axis, especially abnormally increased CORT and ACTH levels, leads to hormonal imbalance and even to more severe diseases such as depressive disorder both in rodents and humans (Asnis et al., 1987;Ayensu et al., 1995). A previous study has suggested a close association between depressive disorder and neuroendocrine alterations (Jozuka et al., 2003). In the present study, the endocrine changes in the HPA axis were observed following CUMS, mirroring those changes seen in human depression. ...
Fructus Akebiae is a common ingredient in many traditional Chinese medicine complex prescriptions for the treatment of mental disorders. Previous studies indicate that the main chemical compositions of Fructus Akebiae are triterpenoid saponins with hederagenin as their sapogenin. In the present study, we enriched hederagenin from the extracts of Fructus Akebiae with a purity of approximately 70%. Using behavioral tests sensitive to antidepressant drugs, we demonstrated that acute and sub-chronic administration of the extracts of Fructus Akebiae produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in forced swim and tail suspension tests in mice and reversal of chronic unpredicted mild stress-induced inhibition of sucrose consumption in rats. In addition, the extracts decreased the levels of plasma adrenocorticotrophic hormone and serum corticosterone in rats exposed to chronic unpredicted mild stress. Both behavioral and biochemical effects of the extracts were mimicked by the proven antidepressant escitalopram. These results suggest that the extracts of Fructus Akebiae exert antidepressant activity. Administration of the extracts may be beneficial for patients with depressive disorders.
... Il a été suggéré qu'une production accrue des cytokines proinflammatoires IL-2, IL-6 et interféron d (IFN-d) serait impliquée dans l'étiologie de la dépression (Maes et al. 1999). Une étude récente par Jozuka et al. (2003) a révélé qu'une réduction de l'activité chez le sujet déprimé et une augmentation des cellules TN et du niveau IL-2 semble être associée à la dépression. Il est probable que l'IL-10 joue également un rôle dans le processus de la dépression (Mesquita et al. 2008). ...
Disturbances in the activity of the corticotropic axis and immune system have been widely reported to be linked to the development of depression. The aim of this study was to explore the effects of ketoconazole, an imidazole derivative that inhibits gonadal and adrenal steroidogenesis, on changes in the total leukocyte count and the percentages of leukocyte subpopulations during the Porsolt forced swimming test (commonly used to measure the efficiency of antidepressants) in rats. Catheters were implanted in the carotid under general anesthesia, and blood samples (0.2 mL) were taken at 15 min intervals. Animals were allowed to move freely throughout the experiments. The levels of anxiety and locomotor activity were measured using the elevated plus-maze and open-field tests. Forced swimming induced changes in both the testosteronemia and the immune system, and these changes were inhibited by treatment with ketoconazole. An improvement (anxiolytic and antidepressant effects) in the behavioral response (elevated plus maze, forced swim) was also observed. These results suggest that the relationship between behavioral and physiological responses is multifactorial and that corticosterone plays a major role in the pathogenesis of psychiatric disorders.
... 3,23 -28 Several authors have reported that men with depression have reduced circulating levels of TT 3,23 and/or DHEA/DHEAS. 24 According to Shores et al., testosterone deficiency predicted the development of depression in elderly men during a 2-year follow-up. 3 Testosterone 25 and DHEA therapy 26 can improve mood in men with major depression and elderly men with marked depressive symptoms. ...
Elderly men with androgen deficiencies are prone to develop late-onset depression. We investigated links between circulating androgens and depression, and their combined impact on outcome in men with chronic heart failure (CHF).
Serum total testosterone (TT) and dehydroepiandrosterone sulphate (DHEAS) were measured using immunoassays in 163 men with stable systolic CHF [age: 60 +/- 10 years, NYHA class (I/II/III/IV): 27/84/46/6] and 316 healthy men. Depression was assessed using Beck Depression Inventory (BDI) and defined as BDI > or =16 points. In men with CHF, reduced TT and DHEAS, advanced NYHA class, elevated N-terminal pro-B type natriuretic peptide (NT-proBNP), reduced glomerular filtration rate, and reduced haemoglobin independently predicted severity of depressive symptoms (all P < 0.05). Depression was present in 20, 37 and 77% of men with no androgen deficiency, either TT or DHEAS deficiency, and both androgen deficiencies, respectively (P < 0.0001). During follow-up (median: 28 months), there were 87 (53%) cardiovascular deaths or unplanned hospitalizations. TT and DHEAS deficiencies (defined as < or = the 10th percentile of serum androgen levels in healthy controls) and BDI > or =16 points independently predicted unfavourable outcome (all P < 0.05).
TT and DHEAS deficiencies predict severity of depression in men with CHF. Depression and combined androgen deficiencies are independently related to poor outcome in these patients.
... As time and techniques improved, more studies started to include a wider range of outcome measures, including measurement of various inflammatory cytokines. In a small study of patients with major depression (n = 17), in addition to decreased NKCA, the patients also had increased IL-2 levels, compared with the control group (n = 10) [7]. IL-2 is a cytokine which increases inflammatory responses and normally increases NKCA, but even with higher levels of IL-2 the patients in this study still had lower natural killer cell functioning. ...
This research reports immune function and health outcomes in women with depression, as compared with a non-depressed control group. Using Psychoneuroimmunolgy theory and a descriptive comparison design, scores on the Beck Depression Inventory (BDI) were used to divide 40 non-hospitalized Caucasian women between the ages of 18 and 65 years into either the control or depression comparison group. Women with depression were found to report significantly more incidences of illness over the previous two months and they were found to have significantly more indicators of illness at the time of the exam as compared to the controls. However, contrary to what has been documented in some earlier studies of depression, women with depression were not found to have significantly different immune function measures as compared to the control group. There was also no significant correlation between scores on the BDI and natural killer cell cytotoxicity in this study. While these findings support a connection between depression and both increased self-report of illness and increased signs and symptoms of minor illness or inflammation on physical exam, this study was not able to document that these effects were related to decreased immune function, as measured by natural killer cell activity or white blood cell counts.
... Our results show an increase in the population of NK cells in MDD patients. Some reports show a functional deficit in NK cells along with an increased population of these cells in MDD patients (Jozuka et al., 2003; Zorrilla et al., 2001). On this basis, we propose that the increase in the population of NK cells before SSRI treatment in our study may represent an immune mechanism triggered to compensate for their functional deficit. ...
To date, only the effect of a short-term antidepressant treatment (<12 weeks) on neuroendocrinoimmune alterations in patients with a major depressive disorder has been evaluated. Our objective was to determine the effect of a 52-week long treatment with selective serotonin-reuptake inhibitors on lymphocyte subsets. The participants were thirty-one patients and twenty-two healthy volunteers. The final number of patients (10) resulted from selection and course, as detailed in the enrollment scheme. Methods used to psychiatrically analyze the participants included the Mini-International Neuropsychiatric Interview, Hamilton Depression Scale and Beck Depression Inventory. The peripheral lymphocyte subsets were measured in peripheral blood using flow cytometry. Before treatment, increased counts of natural killer (NK) cells in patients were statistically significant when compared with those of healthy volunteers (312+/-29 versus 158+/-30; cells/mL), but no differences in the populations of T and B cells were found. The patients showed remission of depressive episodes after 20 weeks of treatment along with an increase in NK cell and B cell populations, which remained increased until the end of the study. At the 52nd week of treatment, patients showed an increase in the counts of NK cells (396+/-101 cells/mL) and B cells (268+/-64 cells/mL) compared to healthy volunteers (NK, 159+/-30 cells/mL; B cells, 179+/-37 cells/mL). We conclude that long-term treatment with selective serotonin-reuptake inhibitors not only causes remission of depressive symptoms, but also affects lymphocyte subset populations. The physiopathological consequence of these changes remains to be determined.
... In contrast, we did not detect any changes in the expression of the adhesion molecules on nonlymphocytic leukocyte populations. Additionally, we observed an increased percentage of natural killer cells after IFN-␣ treatment, which is in line with the studies suggesting a role of this cell population in depression [69][70][71] . ...
Interferon-alpha (IFN-alpha) is used in the treatment of many viral and malignant diseases. Although IFN-alpha administration is highly efficacious, treatment is often complicated by psychiatric side effects such as depression, which may require discontinuation of the therapy. Unfortunately, the mechanisms underlying IFN-alpha-induced depression are still not well understood.
In this study, we explored behavioral and immune effects of IFN-alpha administration in mice. BALB/c mice received daily intraperitoneal injections of 60,000 U/kg murine IFN-alpha for 8 days. Behavioral and immunological analysis was performed at least 15 h after injection to avoid any acute IFN-alpha effect. We monitored depression and anxiety-like behavior in mice using the Forced Swimming Test (FST), Tail Suspension Test (TST), and Elevated Plus Maze (EPM). Moreover, we studied the expression of adhesion molecules on peripheral blood leukocytes and analyzed the recruitment of lymphocyte subsets into the brain.
IFN-alpha administration resulted in increased immobility of mice in the late phase of FST, without significant effects in TST and EPM. Increased percentages of natural killer cells and lymphocytes expressing LFA-1 or Mac-1 were observed in peripheral blood. The percentages of CD4+ and CD8+ lymphocytes as well as the percentages of LFA-1-expressing CD4+ and CD8+ lymphocytes were increased in the brains of IFN-alpha-treated mice.
Our data suggest that IFN-alpha administration leads to an increase in peripheral blood cells with migratory potential, accompanied by an increased number of lymphocytes in brain, whilst the detectable modulation of the behavior was rather modest.
Background
Mental health disorders in systemic lupus erythematosus (SLE) are gradually getting recognized; however, less is known regarding the actual structure and compositional alterations in gut microbiome and metabolism and the mechanisms of how they affect depression development in SLE patients.
Methods
Twenty-one SLE patients with depression (SLE-d), 17 SLE patients without depression (SLE-nd), and 32 healthy controls (HC) were included in this study. Fecal samples were collected for 16S rRNA gene sequencing and ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) based metabolomics.
Results
The structure of gut microbiome in the SLE-d group changed compared with that in the other two groups. The microbiome composition of SLE-d group showed decreased species richness indices, characterized by low ACE and Chao1 indices, a decrease in the ratio of phylum Firmicutes to Bacteroidetes, genus Faecalibacterium and Roseburia . A downregulation of the metabolite fexofenadine involved in bile secretion was positively correlated with the genus Faecalibacterium , Subdoligranulum and Agathobacter . Compared with the SLE-nd group, the SLE-d group had elevated serum levels of IL-2 and IL-6 and decreased BDNF. Interestingly, abundance of the genus Faecalibacterium and Roseburia was negatively correlated with IL-6, abundance of the genus Roseburia was negatively correlated with IL-2, and abundance of the genus Bacteroides was positively correlated with IL-2.
Conclusion
This study identified specific fecal microbes and their metabolites that may participate in the development of SLE-d. Our findings provide a new perspective for improving depression in SLE patients by regulating the gut–brain axis.
With the unique and comprehensive understanding of human’s body and various pathological conditions, Traditional Chinese Medicine (TCM) has undoubtedly become a field of increasing interests from doctors, researchers, and even patients these years. A number of specialties benefited from the combination of TCM and themselves, for example, cardiology, oncology, orthopedics, etc. Psychiatry is no exception. The complexity and chronicity of psychiatric disorders requires flexible medication throughout the course of disease, yet the patient’s conditions, for instance, age, social status, overall health condition, severity of disease, comorbidity, tolerance to drugs, etc., keep changing, which makes it difficult to maintain a good compliance. Hence, a new method capable of taking care of all the aforementioned aspects, especially from a patient-oriented perspective, is in need. An increasing number of clinical evidence has found that certain herbs of TCM could be the same effective as antidepressant for patients with depression. Other herbs/medicinals of TCM could alleviate the adverse drug reactions induced by antipsychotic/antidepressive agents. The flexible rule employed in TCM formula makes it possible to keep a complicated yet beneficial balance of many sides, including severity of disease, comorbidity, tolerance, etc. TCM, to some extent, meets the requirements for a new method in need. In this chapter, typical herbs, medicinals, formulae of TCM with acknowledged property to treat certain psychiatric disorders, along with most recent evidence, will be introduced.
Background
Diabetic foot ulcers (DFUs) are a major complication of diabetes mellitus and a leading cause of lower limb amputation. Interventions to reduce psychological stress may have the potential to improve self-care and greatly reduce the morbidity and mortality associated with DFU. This review is focused on the consequences of psychological stress in wound healing and reflects on the effects of currently used psychological stress-reducing interventions in patients with DFU, proposing new applications for currently used stress-reduction interventions.
Results
Stress is a natural and fundamental survival mechanism that becomes harmful when chronic. DFU is associated with high levels of anxiety and chronic psychological stress. Chronic stress induced cortisol and adrenaline release impairs wound healing, independently of the stressor. Psychological stress-reducing interventions, such as relaxation with guided imagery, biofeedback-assisted relaxation, mindfulness-based strategies, and hypnosis can lead to a reduction in perceived stress and improve wound healing, by reducing wound inflammation and pain, while improving glycemic control. All stress reduction interventions also lead to pain relief and improved patient’s quality of life.
Importance
The magnitude and variability of cytokine alterations in depression are not clear.
Objective
To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation.
Data Sources
Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined.
Study Selection
Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected.
Data Extraction and Synthesis
Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.
Main Outcomes and Measures
Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR).
Results
A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g=0.71; 95%CI: 0.50-0.92; p<0.0001); IL-3 (g=0.60; 95%CI: 0.31-0.89; p<0.0001); IL-6 (g=0.61; 95%CI: 0.39-0.82; p<0.0001); IL-12 (g=1.18; 95%CI: 0.74-1.62; p<0.0001); IL-18 (g=1.97; 95%CI: 1.00-2.95; p<0.0001); sIL-2R (g=0.71; 95%CI: 0.44-0.98; p<0.0001); and TNFα (g=0.54; 95%CI: 0.32-0.76; p<0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR=0.85; 95%CI: 0.75-0.98; p=0.02); IL-12 (CVR=0.61; 95%CI: 0.46-0.80; p<0.01); and sIL-2R (CVR=0.85; 95%CI: 0.73-0.99; p=0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α.
Conclusions and Relevance
Acute depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.
Background
Water extract of the fixed combination of Gardenia jasminoides Ellis fruit, Citrus aurantium L. fruit and Magnolia officinalis Rehd. et Wils. bark, traditional name – Zhi-Zi-Hou-Po (ZZHPD) is used for treatment of depressive-like symptoms in traditional Chinese medicine for centuries.
Hypothesis/Purpose
The present study aimed to explore antidepressant-like effects and potential mechanisms of ZZHPD in a rat model of chronic unpredictable mild stress (CUMS).
Study design
Antidepressant-like effects of ZZHPD were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system, neurotrophin and hippocampal neurogenesis.
Methods
Antidepressant-like effects of ZZHPD (3.66, 7.32 and 14.64 g/kg/day) were estimated through coat state test, sucrose preference test, forced swimming test and open-field test. Effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were evaluated by hormones measurement and dexamethasone suppression test. In addition, the expression of brain-derived neurotrophic factor (BDNF) in hippocampus was measured, as well as hippocampal neurogenesis was investigated by doublecortin (DCX) and 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN).
Results
The results demonstrated that ZZHPD significantly reversed the depressive-like behaviors, normalized the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), restored the negative feedback loop of HPA axis and improved the levels of BDNF, DCX and BrdU/NeuN compared with those in CUMS-induced rats.
Conclusion
The above results revealed that ZZHPD exerted antidepressant-like effects possibly by normalizing HPA axis function, increasing expression of BDNF in hippocampus and promoting hippocampal neurogenesis.
The aim of study was to evaluate the association between serum DHEAS levels and depression with a case-control study together with a meta-analysis. Radioimmunoassay (RIA) was performed to measure the serum DHEAS levels of all participants before and after treatment. Depression Patients were divided into mild depression and severe depression based on Hamilton depression scale (HAMD24) and received 5-hydroxytryptamine (5-HT) and citalopram (20mg/d) for 8 weeks. Case-control studies related to our study theme were enrolled for meta-analysis and Comprehensive Meta-analysis 2.0 (CMA 2.0) was used for statistical analysis. After treatment, DHEAS levels in depression patients were significantly increased, while before and after treatment, DHEAS levels were all lower in depression patients than in controls (all P<0.001); further analysis on age revealed that DHEAS levels were decreased with the rising of age. Meta-analysis results suggested that serum DHEAS levels (ng/mL) were significantly higher in healthy controls compared to depression patients (SMD=0.777, 95%CI=0.156-1.399, P=0.014). In conclusion, our study suggests that serum DHEAS levels are associated with the development of depression and it decreased with the rising of age.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Cytokines and sleep
Sleep has a property of regenerating both body and psyche of humans. Disturbances of sleep accompany disturbances of immune system. Also, disturbances of sleep may be observed in many inflammatory diseases, for example in bacterial infections. These findings validate the attempts to seek relation between sleep process and immune system condition. Regulation of sleep is a complex phenomenon, which involves interaction between neuropeptides, neurotransmitters from nerve system, hormones from endocrine system, and cytokines from the immune system.
Much research is concerned with the role of cytokines in disturbances of sleep. Interleukin-
1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) are currently believed to be among the most important cytokines influencing the central nervous system and physiological sleep process. This work gives a review of current data on the role of the abovementioned and other cytokines of the immune system in sleep disturbances.
Recent research has examined associations between inflammation and mental health, and has increasingly focused on utilizing younger samples to characterize the temporal relationship between inflammatory responses and the emergence of other symptoms. These studies have typically used blood to measure inflammation, although rates of detection for many inflammatory markers appear to be low. Saliva is a safe and low-cost alternative, and adult research has shown that levels of some salivary markers correlate well with those in serum. However, no research has examined this association in young people. This study examined 16 inflammatory markers in serum and saliva in 17 depressed adolescents and 18 healthy controls, aged 13-18 years. In general, detection rates were higher in saliva compared to in serum. When non-detectable levels were excluded, serum levels of C-reactive protein (CRP) correlated with salivary CRP (r = 0.424, p = 0.015), and this correlation appeared to only exist for those individuals with high levels of serum CRP (r = 0.599, p = 0.014). However, when non-detectable levels were included as zero, salivary levels of CRP, interleukin (IL)-2, IL-12p70, and interferon (IFN)-γ correlated with their serum counterparts. No significant clinical group differences in any acute phase proteins or cytokines were present. This study suggests that saliva can be used to measure inflammation in studies with adolescent participants, especially CRP, as it appears to correlate with systemic inflammation for those individuals who are expected to have high levels of inflammation. Implications for future directions in research on salivary inflammatory markers are discussed.
There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD).
Ethnopharmacological relevance:
Cimicifuga foetida L., a traditional Chinese medicine, has been developed for the treatment of perimenopausal symptoms including depression in China (Brand name: XIMINGTING(®), XMT). The primary active constituents are believed to be the triterpene glycosides. Nevertheless, there are no studies about the antidepressant-like effects of XMT in rodents.
Aims of the study:
The present study aimed to evaluate antidepressant-like effects of XMT.
Materials and methods:
Antidepressant-like activity of XMT was studied using forced swimming test (FST) and tail suspension test (TST) in female mice, as well as chronic mild stress (CMS) procedure in female rats. In addition, 5-hydroxytryptophan (5-HTP)-induced head-twitch test and yohimbine toxicity potentiation test in female mice were conducted to propose the possible serotonergic or noradrenergic mechanisms in the antidepressant-like effects of XMT. In mice, XMT was administrated acutely and for 7 consecutive days (20, 40 and 80 mg/kg/day, p.o.); and in rats for 28 consecutive days (10, 20 and 40 mg/kg/day, p.o.).
Results:
XMT significantly reduced immobility duration in FST and TST without affecting locomotor activity, increased swimming and climbing durations in FST, and enhanced 5-HTP-induced head-twitch response while did not affect yohimbine-induced lethality in female mice. XMT also normalized the inhibition of sucrose intake and decreased the levels of plasma adrenocorticotropic hormone and serum corticosterone and adrenal gland weight in CMS-treated female rats.
Conclusions:
These data indicate XMT processes antidepressant-like properties in rodents, which could be related to its serotonergic and noradrenergic activation and normalization of the hypothalamic-pituitary-adrenal axis.
According to the vulnerability-stress concept patients with mood disorders and schizophrenia display increased sensitivity
to stress. The hypothalamopituitary-adrenal (HPA) axis is one of the major hormonal systems mediating physical and psychological
stress responses. Evidence for disturbances in HPA activation and abnormal HPA regulatory mechanisms in psychiatric illnesses
is accumulating. A body of evidence has accrued demonstrating particularly dysfunction of the HPA axis leading to elevated
peripheral cortisol levels in a proportion of patients. Recently there has been increased interest in the role of neurosteroids,
particularly dehydroepiandrosterone (DHEA), which in its sulfated form (DHEAS) is one of the most abundant in humans. This
chapter reviews the area around the study of these steroids in mood disorders and schizophrenia, particularly the evidence
for the utility of the molar ratio of cortisol to DHEA and/or DHEAS as a peripheral biomarker.
Family and twin studies have consistently documented that schizophrenia is familial and heritable, but efforts to identify
specifi c susceptibility genes have been complicated by the disorder's genetic and phenotypic complexity. Genetic linkage
studies have implicated numerous chromosomal regions: genes related to dopaminergic (COMT, MAOA, DBH, DAT1, DA receptors, AKT1), serotonergic (5-HTTLPR, 5-HT2C and 5-HT2A receptors) and glutamatergic (NMDA receptors [GRIN1, GRIN2A, GRIN2B], GMR3, G72 or DAOA, NRG1) neurotransmissions, CAG repeats
at the KCNN3 locus, and candidate genes with other mechanisms (DTNBP1, MTHFR, NPAS3, DISC1, RGS4, HOPA, RTN4R, PPP3CC). The
use of symptom dimensions of schizophrenia as quantitative phenotypes instead of categorical defi nitions (DSM IV or ICD-10)
may be more useful in order to reduce the heterogeneity of schizophrenia. Indeed, some of these genes show affect clinical
features with or without altering susceptibility to illness. Although the available supporting evidence for symptom dimensions
is variable, this chapter will be focused on the specifi c genetic polymorphisms that may be associated with symptom dimensions
of schizophrenia. Authors propose that all genetic and endophenotypes studies of major psychosis should routinely include
the exploration of symptom dimensions as well as the other “usual suspects” such as cognitive functions, personality fea-
features, etc. We hope delineating relationships between genetic polymorphisms and symptom dimensions may be an important
step in understanding the genetics of group of psychoses named today as schizophrenia.
In depression an increase, decrease, or a relative deficiency of dehydroepiandrosterone (DHEA) and the beneficial effects of its administration were observed. The correlation of low serum DHEA level and increased cardiac risk was confirmed in healthy subjects only in men (not in women). Taking into consideration the increased risk of heart disease in depression, it is interesting to investigate the level of DHEA, DHEA-S, and cortisol, as so its correlation with lipid profile, and reaction to treatment in women with depression.
To assess serum ACTH, cortisol, DHEA and DHEA-S, and their relationship with lipid profile in depressed females, including the treatment response and stress load.
In 11 healthy females and 18 with depression, the following were examined before and after treatment: the severity of symptoms (on the Hamilton and Beck Inventory Depression scale), serum cortisol, DHEA, DHEA-S, and lipidogram. The results were compared in healthy and depressed females, and in relation to the therapy and stress load. The correlation of DHEA, DHEAS, and cortisol with lipid profile was analysed.
In females poorly responsive to antidepressant treatment higher serum cortisol, ACTH and DHEA. The lipid profile did not vary in the depressed and healthy females. Serum DHEA correlated negatively with serum cholesterol (total and LDL fraction) in healthy women but not in depressed women.
DHEA deficiency and the rationale for its supplementation were not confirmed in depressed women. The protective action of DHEA to hypercholesterolemia was confirmed in healthy, but not in the depressed women.
Many studies have explored the association between soluble interleukin-2 receptor (sIL-2R), cytokines and major depressive disorder (MDD). However, the results of these studies were not consistent. The aim of our study is to compare the levels of sIL-2R and cytokines in the blood between MDD patients and controls by a meta-analysis and to identify moderators accounting for potential heterogeneity in the levels of sIL-2R and cytokines in MDD patients versus controls by meta-regression analyses.
A comprehensive literature search was performed to identify studies comparing the levels of sIL-2R and cytokines between MDD patients and controls. We pooled the effect sizes for standardized mean differences (SMD) of the levels of sIL-2R and cytokines. We also performed meta-regression and sensitivity analyses to investigate the roles of age, gender, sample type, ethnic origin and selected studies' quality in explaining potential heterogeneity and differences in results respectively.
Twenty-nine studies were selected for this analysis. The levels of sIL-2R, TNF-α and IL-6 in MDD patients were significantly higher than those of healthy controls (SMD=0.555, p<0.001, SMD=0.567, p=0.010; SMD=0.680, p<0.001). Mean age of all subjects was a significant moderator to explain the high heterogeneity of IL-6. Sensitivity analysis found that European but not non-European subjects have higher levels difference of sIL-2R, TNF-α and IL-1β between MDD patients and controls.
The severity of MDD was not considered.
The blood levels of sIL-2R, TNF-α and IL-6 were significantly higher in MDD patients than controls. Age, samples source and ethnic origins may play a potential role in heterogeneity.
Depression occurs in 18% to 45% of patients with coronary artery disease (CAD) where it is associated with an increased risk of acute coronary events and mortality. Our objective was to quantitatively summarize the data on the efficacy and tolerability of antidepressant (AD) treatment for depression in CAD.
We performed a meta-analysis of randomized, placebo-controlled, double-blind trials with a database search of the English literature (to March 2008) and manual search of references.
Four clinical trials with ADs (mirtazapine, citalopram, fluoxetine, and sertraline) of a 9- to 24-week duration involving 798 subjects (402 ADs, 396 placebo) with documented CAD and meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for depression were included. ADs were superior to placebo for decreasing Hamilton Depression Rating Scale (HDRS) scores (402 ADs, 396 placebo; weighted mean difference 1.41, 95% CI 0.53 to 2.29, P = 0.002) and Beck Depression Inventory (BDI) scores (373 ADs, 369 placebo; weighted mean difference 2.27, 95% CI 0.60 to 3.94, P = 0.008). The proportion of patients (216 ADs, 213 placebo) who responded (a 50% or more reduction in HDRS scores, OR 1.72, 95% CI 1.17 to 2.54) and remitted (HDRS of 8 or less at final assessment, OR 1.80, 95% CI 1.18 to 2.74), were also significantly higher with AD, compared with placebo, with no significant differences between the 2 groups for overall dropouts (OR 0.84, 95% CI 0.42 to 1.68) or dropout owing to adverse events (OR 1.30, 95% CI 0.75 to 2.25). The combined studies were homogeneous except for overall dropout rate (P = 0.01).
Treatment with ADs for depression in CAD results in significant therapeutic effects without substantially increased rates of discontinuation.
Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls.
We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references.
Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-alpha, 9 for interleukin (IL)-1beta, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-gamma. There were significantly higher concentrations of TNF-alpha (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied.
This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.
There is growing interest in the role of Dehydroepiandrosteron (DHEA) in depression. To evaluate the validity of its administration in depression, the role of DHEA in the mechanism of depression and cardiovascular risk, as so the results of clinical trials must be considered. According to accessible literature, both concepts of depression--monoaminergic and glucocorticoid--are related. The key role may be played the impairment in regulatory function of monoaminergic, glucocorticoid and GABAergic receptors in the limbic area of the brain, caused by a genetic factor or acquired by stress. Consequently even weak stimulation could lead to inefficiency of the Limbic- hypothalamic-pituitary-adrenal (LHPA) homeostasis, with overproduction of cortisol. The excess of cortisol is facilitating the development of depression by damaging the limbic, especially hippocampal neurons. Furthermore, the cortisol is increasing cardiovascular risk by its atherogenic properties. The DHEA, because of its antiglucocorticoid activity is supposed to be a protective factor against depression and cardiovascular risk. Positive effects of administration of DHEA in depression were observed in clinical trials. However the results of estimation of DHEA and SDHEA in the blood of depressed patients were inconsistent. In animals, administration of high doses of DHEA was decreasing the experimental atherogenesis. However the investigation in numbered human populations showed correlation of increased level of DHEA with a decreased risk of cardiovascular disorder in men--but not in women. Further research on relation between depression, DHEA and cardiovascular risk, with special concern upon the differences in men and women is needed.
There is an increasing body evidence pointing to a close integration between the central nervous system (CNS) and immunological functions with lymphocytes playing therein a central role. The authors provide arguments to consider blood lymphocytes as a convenient probe of--an albeit--limited number of cellular functions, including gene expression. The use of brain biopsies of living patients is unrealistic for biochemical investigation, therefore lymphocytes may be a convenient and accessible alternative. Numerous studies showed similarities between receptor expression and mechanisms of transduction processes of cells in the nervous system (e.g. neurons and glia) and lymphocytes. In several neuropsychiatric disorders, alteration of metabolism and cellular functions in the CNS, as well as disturbances in the main neurotransmitter and hormonal systems are concomitant with altered function and metabolism of blood lymphocytes. We summarize relevant investigations on depression, stress, Alzheimer's disease (AD) and schizophrenia. New techniques such as cDNA microarray gene expression and proteomics may give clues to define molecular abnormalities in psychiatric disorders and could eventually reveal information for diagnostic and treatment purposes. Taken together, these considerations suggest that lymphocyte could reflect the metabolism of brain cells, and may be exploited as a neural and possible genetic probe in studies of psychiatric disorders.
Synopsis
The association between basal cortisol, dehydroepiandrosterone (DHEA), its sulphate (DHEAS) and major depression was investigated in 8- to 16-year-olds. Eighty-two subjects with major depression, 25 non-depressed psychiatric cases and 40 community controls were systematically assessed for current mental state and hormone levels at 08.00, 12.00 and 20.00 h, assayed from salivary samples collected over a 48 h period. The average mean of the two time points was compared between the three groups. Evening cortisol hypersecretion and morning DHEA hyposecretion were significantly, and independently, associated with major depression. High evening cortisol (> 0·594 ng/ml) and low morning DHEA (< 0·200 ng/ml) identified subgroups of depressives with different types of adrenal hormone dysregulation. The association between high evening cortisol or low morning DHEA and MDD was not affected by either age or gender.
Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects.
A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.
Leukocytes or other types of cells produce soluble proteins or glycoproteins termed cytokines that serve as chemical communicators from one cell to another. Cytokines are usually secreted, although some may be expressed on a cell membrane or maintained in reservoirs in the extracellular matrix. Cytokines combine with surface receptors on target cells that are linked to intracellular signal transduction and second messenger pathways. Their effects may be autocrine, acting on cells that produce them, or paracrine acting on neighboring cells and only rarely endocrine, acting on cells at distant sites.
RECENT development and use of the Self-Rating Depression Scale (SDS) has Proven to be a valuable tool in the assessment of depressive disorders in a group of hospitalized inpatients.1 There is a similar need in outpatient clinics to quantitate the amount of depressive symptomatology present or absent in the patients seen for treatment. Depressive symptoms may be present in any of the psychiatric disturbances seen in such a clinic, and a diagnosis of depressive disorder must still be made on a clinical basis. However, the use of such a scale is valuable in documenting and quantitating initial symptoms and complaints, and following changes in the patient's clinical course subsequent to treatment, using any of the modalities available.
The purpose of a self-rating depression scale to be used in such an outpatient clinic setting would be similar to the ones stated previously with respect to its
Natural killer (NK) cell activity was evaluated in 34 ambulatory patients with Major Depressive Disorder (MDD) and 21 healthy controls. No mean differences between the groups were found. However, female depressives (n = 19) exhibited higher NK activity than female controls (n = 14). The relationship between cortisol secretion and NK activity was examined using an integrated cortisol value derived from multiple blood samples taken between 1:00 and 4:00 pm. This comprehensive assessment of cortisol secretion circumvents spurious “single stick” cortisol values and provides a more accurate determination of hypercortisolemia than the dexamethasone suppression test. NK activity in depressives with cortisol hypersecretion (>11 μg/dl) (n = 7) was no differnt than NK activity in depressives and controls with normal cortisol secretion. Furthermore, there was no correlation between cortisol secretion and NK activity in any of the groups. These results indicate that decreased NK activity is not a consistent finding in MDD and cannot be predicted by the presence of hypercortisolemia in these patients.
Localization and regulation of mineralocorticoid receptor (MR) heteronuclear RNA (hnRNA) was assessed in rat hippocampus using an intron-directed in situ hybridization approach. The presence of hnRNA in the cell nucleus reflects recent gene transcriptional events and can be used as an index of neuronal transcriptional activation or inhibition. In the present study, sections incubated with an MR intron probe labeled cells in all regions known to contain MR mRNA. Signal generated by the intron probe was localized specifically to the nuclear compartment, consistent with recognition of hnRNA. Analysis of distribution across hippocampus indicated that MR hnRNA was particularly abundant in dentate gyrus (DG). In contrast, MR mRNA shows similar levels of expression across all hippocampal subfields. Exposure of animals to acute restraint markedly reduced MR hnRNA levels in CA1 and DG 60 min and 120 min following stress exposure, consistent with reduced gene transcription. These data support the hypothesis that stress-induced glucocorticoid secretion can rapidly affect transcription of between transcriptional changes and changes in cytoplasmic mRNA pools or stimulus-driven alterations in post-transcriptional RNA processing.
Synopsis
Cross-sectional studies have demonstrated that natural killer (NK) cell activity is reduced in depression. To extend these observations and examine further the association between severity of depressive symptoms and values of NK activity, this study used a longitudinal case control design and assessed NK cytotoxicity at intake and at follow-up 6 months after discharge from the hospital in depressed patients and control subjects. From acute hospitalization to follow-up, depression scores significantly ( P < 0·01) decreased following treatment in the depressed patients but did not change in the control subjects. NK activity significantly ( P < 0·05) increased from intake to follow-up in the depressives while lytic activity did not change in the controls. At intake NK activity was significantly ( P < 0·01) reduced in the depressed patients as compared to values in the controls, while at follow-up cytotoxicity was similar between the two groups. These longitudinal data suggest that a reduction of NK cytotoxicity is temporally associated with the state of acute depression.
A reduction of natural killer (NK) cell activity has been found in hospitalized patients with major depressive disorder. To examine whether a reduction of NK activity is found in other psychiatric patients or related to the nonspecific effects of hospitalization, NK cell cytotoxicity was compared in hospitalized depressed patients, schizophrenic inpatients, and two groups of controls separately age matched to each patient group. NK activity was significantly (p less than 0.01) lower in depressed inpatients than control subjects. However, in the hospitalized schizophrenic patients values of natural cytotoxicity did not differ from controls. These findings suggest that reduced NK cytotoxicity in depression is independent of the effects of hospitalization.
We determined the following immune parameters in drug-free, major depressed patients and in age- and sex-matched healthy controls: the number and percentage of interleukin-2 receptor (IL-2R) bearing cells (CD25+, anti-TAC), serum circulating levels of soluble (s)IL-2Rs, the pre- and postdexamethasone phytohemagglutinin (PHA)-induced accumulation of sIL-2Rs in culture supernatant, and the number of T helper (CD4+) and T suppressor (CD8+) cells. In comparison with normal volunteers, patients with major depression had a higher number and percentage of CD25+ cells, higher concentrations of serum circulating sIL-2Rs, higher supernatant sIL-2Rs after stimulation with PHA, and a higher number of CD4+ cells. The CD4+/CD8+ ratio and the number of CD4+ cells were significantly and positively related to the number of cells expressing the CD25+ antigen. These results may indicate that depressed patients display an increased number of T cells in an early phase of activation.
A circannual rhythm of corticosteroid excretion has been identified in healthy subjects but is lost in patients who have recovered from a depression associated with dexamethasone nonsuppression. The loss of circannual variation as well as the persistent elevation and increased peak frequency of cortisol excretion could be instrumental in the development of depressive symptoms. A model for this phenomenon can be found in the entity known as intermittent Cushing's disease. That hypercortisolemia could be etiologically related to depression is supported by the case reported here in which a rise in UFC preceded the emergence of psychiatric symptomatology on two occasions. Further investigation into this possibility is clearly warranted.
Patients with the acquired immunodeficiency syndrome (AIDS) exhibit a variety of disorders of cellular immunity, including a deficient ability to generate cytotoxic T cells and depressed levels of natural killer (NK) cell activity. Interleukin 2 (IL 2) in vitro can markedly augment these depressed immune functions. Because IL 2 can induce the release of interferon-gamma (IFN-gamma) from normal peripheral blood lymphocytes (PBL), and because IFN-gamma may play a role in the regulation of NK cell activity, this study was performed to determine if the IL 2 enhancement of the NK cell activity of patients with AIDS was an IFN-gamma-dependent effect. PBL from eight healthy heterosexual donors and from nine patients with AIDS were studied for their ability to release IFN-gamma in response to IL 2 at a concentration of 100 U/ml. After 60 hr of culture, the PBL of all eight healthy donors produced IFN-gamma with a mean titer of 113 U/ml (range 40 to 320 U/ml). In contrast, the PBL from only two of nine patients with AIDS released measurable amounts of IFN-gamma (40 U/ml each) in response to IL 2 with a mean titer of 13.5 U/ml for all nine. Although the PBL from patients with AIDS were deficient in their capacity to produce IFN-gamma in response to 100 U/ml of IL 2, significant enhancement of NK cell activity could be obtained after only 1 hr of PBL treatment with 10 U/ml of IL 2, with an optimal NK enhancing effect occurring at doses of 50 to 100 U/ml of IL 2. The use of an anti-IFN-gamma monoclonal antibody resulted in complete neutralization of the IFN released from the normal PBL cultured with IL 2, but failed to inhibit the IL 2 enhancement of NK cell activity. Exogenous IFN-gamma exhibited different kinetics of enhancement of NK cell activity when compared to IL 2, requiring substantially more than 1 hr of pretreatment of PBL. These results indicate that the PBL from patients with AIDS usually do not release IFN-gamma when cultured with IL 2, and that IL 2 enhancement of the depressed NK cell activity of these patients may be an IFN-gamma-independent event. These results may have important implications for the therapy of AIDS.
Cytokine production by peripheral blood mononuclear cells (PBMC) was assessed in 10 major depressed patients (5 men and 5 women) before and after 4 weeks of clomipramine treatment and in age- and gender-matched healthy controls. A significant reduction in interleukin-1B (IL-1B), interleukin-2 (IL-2) and interleukin-3-like activity (IL-3-LA) was observed in untreated depressed patients when compared to controls. IL-1B and IL-3-LA synthesis was significantly increased after drug treatment. The suppression of cytokine production by PBMC in depressed patients may be attributed to the depression per se, or it may be related to depression-associated hyperactivity of the hypothalamic-pituitary-adrenal axis. The mode of interaction between depression and cellular immune function and the mediators responsible for the reduced cytokine production need to be studied further.
We conducted research to determine compounds in human urine which show high values in healthy individuals, decrease with failing health (or bodily decay), clearly decline with advancing illness and finally reach very low values during terminal and severe illness. We have initially established that 17-ketosteroid sulfates (17-KS-S) are the substances we were searching for. Hans Selye regarded stress as the rate of wear and tear and 17-OHCS (cortisol) as its indicator. He further considered that stress is distinct from aging: There is no difference in the stress of ordinary life between young and old people, and there is no difference in 17-OHCS levels between the two. Aging is, however, accompanied by decreased adaptability. In terms of adaptability, we consider that, different from inanimate objects, energy transforming live organisms exist in a dynamic balance between "wear and tear" and "repair and recovery". This shows the need to determine the organism's adaptability to at least these two factors. We regarded 17-OHCS as a compound related to tissue "wear and tear" and searched for a compound related to tissue "repair and recovery", leading us to an identification of 17-KS-S. In other words, we have been considering the relation between "repair and recovery" and "wear and tear". The measurement of 17-KS-S which decreases with failing health, when combined with 17-OHCS, may make it possible to evaluate distortion of adaptation in a Yin-Yang like fashion, which can demonstrate the presence of illness, susceptibility to illness and progress of disease in individuals. It further adds a new dimension to clinical diagnostic acumen in an objective evaluation of psychosocial stress where results of routine clinical tests are often within normal limits, thus facilitating the monitoring of health and illness.
Immune-inflammatory markers and their correlations were examined in patients with major depression. Plasma concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), transferrin receptor (TfR), C-reactive protein (CRP), and alpha 1-acid glycoprotein (AGP), as well as the microheterogeneity of AGP, were measured in 49 major depressed patients during an acute phase of the illness and compared with concentrations in 15 normal control subjects. Plasma concentrations of IL-6, sIL-6, sIL-2R, TfR, CRP, and AGP were significantly higher in major depressed patients than in healthy control subjects. Patients with higher values of AGP microheterogeneity coefficient (AGP-RC > 1.5) had significantly higher concentrations of AGP, IL-6, and TfR. The correlations between cytokines and acute phase proteins studied point to a significant role of elevated IL-6 secretion in the induction of Type I AGP microheterogeneity changes that are characteristic of some inflammatory conditions.
Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.
We found an association between low levels of 17-Ketosteroid Sulfates (17-KS-S) in subjects under psychosocial stress. Stress associated with overwork and lack of sleep resulted in decreased levels of 17-KS-S and an increase in 17-Hydroxycorticosteroids (17-OHCS) levels. Alleviation of stress condition was associated with a restoration of the ratio of 17-KS-S/17-OHCS resulting from a slow increase in 17-KS-S and a decrease in 17-OHCS. In subjects with severe mental stress the ratio of 17-KS-S/17-OHCS showed markedly reduced values with a transient marked increase in 17-OHCS. There was a decrease in the levels of 17-KS-S in depressives, which was more pronounced during severe depression. There was no significant difference in 17-OHCS levels. In a cohort experiencing bereavement, there was a reduction in the levels of 17-KS-S, which remained low for about 50 days. With time, the level of 17-KS-S returned to the basal level established prior to spousal death. In this case, there was no significant change in the levels of 17-OHCS. Persistent severe stress over several months in a physician, led to a Herpes Zoster outbreak and Arrhythmia, resulting in hospital admission. The levels of 17-KS-S gradually decreased over this time reaching 1/3 of the normal baseline value, while 17-OHCS levels remained within normal ranges. These results suggest that measurement of 17-KS-S is indispensable for current research on psychosocial stress.
We attempted to determine compounds in human urine which, differing from cortisol (17-OHCS), show high values in healthy individuals, decrease with failing health, clearly decline with advancing disease and finally reach very low values in severe disease. We have eventually established that 17-ketosteroid sulfate conjugates (17-KS-S) are the compounds we were searching for. Hans Selye regarded stress as the rate of wear and tear and 17-OHCS as its indicator, but we considered that, differing from inanimate objects, living organisms consume energy to cope with stress and "repair" "wear and tear" of the tissue and "recover" its function. This concept led us to determine the organism's requirement for two mechanisms: "Wear and tear" which could be represented by the secretion of 17-OHCS (Selye), and "repair and recovery", which could be determined by the amounts of 17-KS-S derived from dehydroepiandrosterone (DHEA)-sulfate, a product of the adrenal cortex, which enhances neuronal survival, longterm memory, maintains the function of peripheral tissues, and stimulates immune system (17-KS mainly consists of 17-KS-S and 17-KS glucuronides 17-KS-G, the latter derived from cortisol, DHEA and testosterone). We hold that stress response is a series of biological process, beginning from CRH.ACTH and catecholamines, cortisol (17-OHCS), followed by insulin, acting as an anabolic agent and finally DHEA (17-KS-S) leads the tissues to repair by utilizing produced energy. Balanced changes of hormones, such as 17-KS-S, 17-OHCS, cortisol, catecholamines and insulin are seen in healthy individuals under healthy lifestyles and disruption of the balance brings apparent reduction in 17-KS-S. From this standpoint, we wish to develop research in interrelations between biologically antagonistic 17-KS-S and 17-OHCS, focusing particularly at 17-KS-S, which represents a contact point for mind and body, the healthy state of which is kept by appropriate sleeping and exercise programs on the basis of adequate food intake. The above three factors, 17-KS-S, 17-OHCS, and 17-KS-G, are expressed in creatinine ratio (mg/g creatinine).
Depressed mood has been associated with reduced natural killer cell activity (NKCA). Further, amelioration of depressive symptoms by pharmacotherapy has resulted in augmented NKCA. Serotonin, an indoleamine implicated in the pathophysiology of affective disorders, enhances NKCA in vitro and lymphocytes possess serotonin transporters and receptors. The present study evaluated NKCA in depressed outpatients before and during treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac(R)). Further, the SSRIs, fluoxetine and paroxetine (Paxil(R)), were also incubated in vitro with lymphoid cells to evaluate possible direct effects of SSRIs on NKCA. Depressed outpatients were administered fluoxetine (20 mg/day) for 4 weeks. NKCA and severity of depression were evaluated at weeks 0, 1, 2, and 4. Serum concentrations of fluoxetine and norfluoxetine were obtained as well. Mononuclear cells obtained from nonpatient volunteers were incubated with pharmacologic concentrations of fluoxetine or paroxetine and NKCA measured with a standard chromium release assay. Fluoxetine treatment resulted in decreased symptoms of depression and increased serum concentrations of fluoxetine and norfluoxetine. Further, fluoxetine treatment was associated with augmented NKCA in a subgroup of depressed outpatients exhibiting low NKCA at baseline. Fluoxetine had no effect on NKCA in depressed individuals exhibiting high NKCA at baseline. Incubation of mononuclear cells with fluoxetine and paroxetine augmented NKCA in vitro. The enhancing effects of antidepressants on NKCA in vivo and in vitro indicate a possible direct drug interaction with lymphoid cells during pharmacotherapy, suggesting that pharmacologic treatment of depression may result in enhanced immune competence as indexed by enhanced NKCA and that NKCA could be pharmacologically augmented with antidepressants in individuals with compromised immune function.
An interaction of genetic factors with environmental factors, including stress and infectious agents, is assumed to play a
causal role in the pathogenesis of major depression. Since the rate of major depression in genetically succeptible populations
has continued to increase over the past years, the identification of these environmental factors would provide targets for
more effective antidepressant agents.
Substantial evidence has shown that major depression is associated with immune variations. In a meta-analytic review of over
thirty-five independent study samples conducted through 1991, depression was found to be associated with reliable alterations
in several enumerative measures and in functional assays such as mitogen induced lymphocyte proliferation and natural killer
(NK) cell activity (Herbert & Cohen, 1993a). Since 1991, many additional studies on the relationship between depression and
immune measures have been published which has led to a recent reevaluation of the immune findings in depression (Zorrilla,
Luborsky, McKay, Rosenthal, Houldin, Tax, McCorkle, Seligman, & Schmidt, 1998). While both reviews observed similar relations
between depression and several immune measures including major immune cell classes, lymphocyte proliferation, and NK activity,
conflicting results were obtained for many other measures. An enormous heterogeneity in the findings is suggested by the discrepancies
between these two large meta-analytic reviews.
Psychoneuroimmunology was for the first time comprehensively described about 20 years ago. The influence of mental status on the course and outcome of a number of diseases, however, was suspected a long time before. Also the links between mental affective disorders and the immune status were repeatedly suggested. The authors in this paper shortly reviewed the most important clinical as well as experimental evidence which at present strongly supports the concept of a close and bidirectional communication between central nervous, neuroendocrine and immune systems. The most important anatomical, physiological as well as pharmacological experimental data, which were obtained by the authors during 20 years of research in this field, are presented. The data strongly suggest that in the very next future we will not only better understand a very complex communication between mind and body, but also completely new types of compounds might become available.
St. John's Wort (Hypericum perforatum; H. perforatum) is a popular herbal supplement used to treat mild to moderate depression. H. perforatum possesses serotonergic properties such as inhibition of serotonin (5-hydroxytryptamine; 5-HT) reuptake. Serotonergic pharmacotherapy is associated with amelioration of depression as well as increases in natural killer (NK) cell activity (NKCA). Also, 5-HT and 5-HT analogs augment NKCA in vitro. Considering the serotonergic properties of H. perforatum, the effects of H. perforatum on NKCA were assessed in vitro. Mononuclear cells (MNCs) from normal donors were exposed in vitro to an extract of H. perforatum (LI160s) or established 5-HT stimulators of NKCA. After an overnight incubation, cells were washed and a standard 51Cr-release cytotoxicity assay performed to assess NKCA. LI160s at all concentrations failed to augment NKCA. However, in corroboration of previous studies, 5-HT, the selective serotonin reuptake inhibitors (SSRIs), paroxetine and norfluoxetine, and alpha-interferon augmented NKCA above control levels. Though an efficacious treatment for mild to moderate depression, H. perforatum differs from commonly prescribed serotonergic antidepressants insofar as H. perforatum fails to enhance NKCA in vitro. Therefore, the present results are consistent with pharmacologic studies indicating that H. perforatum possesses, at best, weak serotonergic activity.
There is some evidence that treatment with interleukin-2 (IL-2) and interferon-alpha (IFNalpha) frequently induces depressive symptoms and activation of the inflammatory response system (IRS). There is evidence that major depression is accompanied by lowered serum activity of dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5), a membrane-bound serine protease which catalyses the cleavage of some cytokines and neuro-active peptides and which modulates T cell activation and the production of cytokines, such as IL-2. This study was carried out to examine the effects of immunochemotherapy with IL-2 and IFNalpha, alone and together, in cancer patients on serum DPP IV activity in relation to changes in depressive symptoms and the IRS. The Montgomery and Asberg Rating Scale (MADRS), serum DPP IV activity, and the serum IL-6, and IL-2 receptor (IL-2R) concentrations were measured in 26 patients with metastatic cancers before and three and five days after treatment with IL-2 and IFNalpha, alone or together. Treatment with IL-2 with or without IFNalpha significantly suppressed serum DPP IV activity. The MADRS scores were significantly elevated by treatment with IL-2 with or without IFNalpha, but not IFNalpha alone. The immunochemotherapy-induced decreases in serum DPP IV were significantly and inversely correlated with the increases in the MADRS. Treatment with IL-2 alone or combined with IFNalpha also elevated serum IL-6 and IL-2R. There were significant and inverse correlations between the immuchemotherapy-induced decreases in serum DPP IV and the elevations in serum IL-6 or IL-2R. In conclusion, treatment with IL-2/IFNalpha decreases serum DPP IV activity within 3-5 days and the immunochemotherapy-induced decreases in serum DPP IV activity are significantly and inversely related to treatment-induced increases in severity of depression and signs of activation of the IRS.
We have shown that treatment with interleukin-2 (IL-2) or interferon-alpha (IFN alpha) may induce depressive symptoms and activation of the cytokine network and that IL-2 treatment may diminish serum dipeptidyl pepdidase IV (DPP IV) activity. DPP IV (EC 3.4.14.5) is a membrane bound serine protease which catalyzes the cleavage of some cytokines and neuroactive peptides which modulate T cell activity. The aims of the present study were to examine the effects of IFN alpha-based immunotherapy on serum DPP IV activity in relation to induction of the inflammatory response system. In 18 patients with chronic active hepatitis C, we determined the Montgomery and Asberg Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A), serum DPP IV activity, the kynurenine/tryptophan (K/T) quotient, which is an indicator of cytokine (in particular IFN)-induced catabolism of tryptophan, and serum interleukin-8 (IL-8) before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFN alpha. IFN alpha-immunotherapy significantly suppressed serum DPP IV 2--4 weeks and 16--24 weeks after starting IFN alpha-based immunotherapy. The reduction in serum DPP IV activity was more pronounced 16--24 weeks after starting immunotherapy than after 2--4 weeks. The IFN alpha-induced suppression of serum DPP IV activity was significantly correlated to IFN alpha-induced increases in the MADRS and HAM-A and increases in the K/T quotient and serum IL-8. In conclusion, long-term immunotherapy with IFN alpha suppresses serum DPP IV activity and the immunotherapy-induced changes in DPP IV are related to increases in severity of depression, anxiety and activation of the inflammatory response system.
This article reviews evidence that shows a bidirectional relationship between the brain and the immune system. As a result of this relationship, mental factors such as stress and depression have been shown to affect immune system functioning, with both immunosuppression and immune activation being reported. Stress and depression also have been associated with worse outcomes in immune-related disorders including cancer and infectious diseases suggesting that stress/depression effects on the immune system are clinically relevant to disease expression. Conversely, several lines of evidence suggest that immune system activation such as during infectious diseases, cancer, and autoimmune disorders is associated with the development of behavioral symptoms similar to those seen in the context of chronic stress or major depression. These findings implicate a role for the immune system in the cause of behavioral disorders in a wide range of medical illnesses. Finally, a paradigm is proposed in which abnormal functioning of either the hypothalamic-pituitary-adrenal (HPA) axis or the inflammatory response system disrupts feedback regulation of both neuroendocrine and immune systems contributing to the development of neuropsychiatric and immunologic disorders.
The fact that there is a need for assessing depression, whether as an affect, a symptom, or a disorder is obvious by the numerous scales and inventories available and in use today.