http://www.smhc.org.cn/uploadfiles/2014/09/20140929090442442.pdf

A Meta-Analysis of Cytokines in Major Depression

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.

We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (ON these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.

/pdf/so-depression-is-an-inflammatory-disease-but-where-does-the-2843tu0lea.pdf

So depression is an inflammatory disease, but where does the inflammation come from?

Objective
To conduct a systematic review and meta-analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs).

Method
The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random-effects models.

Result
Eighty-two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon-gamma levels were lower in MDD (Hedge's g = −0.477, P = 0.043). Levels of IL-1β, IL-2, IL-4, IL-8, the soluble IL-6 receptor (sIL-6R), IL-5, CCL-3, IL-17, and transforming growth factor-beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I2: 51.6–97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index).

Conclusion
Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.

/pdf/peripheral-cytokine-and-chemokine-alterations-in-depression-3u6rtrppnv.pdf

Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.

The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.

Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression.

The purpose of this case–control genetic association study was to explore potential relationships between polymorphisms in the limbic system-associated membrane protein (LSAMP) gene and mood and anxiety disorders. A total of 21 single-nucleotide polymorphisms (SNPs) from the LSAMP gene were analyzed in 591 unrelated patients with the diagnoses of major depressive disorder (MDD) or panic disorder (PD) and in 384 healthy control subjects. The results showed a strong association between LSAMP SNPs and MDD, and a suggestive association between LSAMP SNPs and PD. This is the first evidence of a possible role of LSAMP gene in mood and anxiety disorders in humans.

/pdf/associations-between-lsamp-gene-polymorphisms-and-major-59pmil9uur.pdf

Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder

Studies so far have provided contradictory results on immune system markers during use of antidepressants. There are no data on changes in immune parameters after treatment augmentation. The present study aimed to clarify whether the addition of bupropion in escitalopram-resistant patients with major depression causes changes in the immune system and whether treatment response could be predicted by baseline levels of cytokines. We recruited 28 depressive patients (11 men and 17 women) who did not respond to 12-week treatment with escitalopram (20 mg/d) for an augmentation trial with bupropion (150-300 mg/day). The levels of soluble interleukin-2 receptor, interleukin-8 (IL-8) and tumor-necrosis factor-alpha were measured before and 6 weeks after addition of bupropion. For a control group, we recruited 45 healthy volunteers (19 men and 26 women). The results indicated that the baseline levels of studied cytokines did not predict treatment response to bupropion augmentation. Concentration of IL-8 increased during the treatment similarly in both responder and non-responder groups. Although bupropion augmentation had increased the response rate in escitalopram-resistant patients, this clinical improvement was not accompanied by specific changes in studied cytokine levels.

Effects of bupropion augmentation on pro-inflammatory cytokines in escitalopram-resistant patients with major depressive disorder:

Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD. Case-control association study was performed with seven SNPs from the IL10 gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited. None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the IL10 gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (IL20 and IL24 genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097). Our study established increased risk for MDD related to the IL20 and IL24 haplotype and suggests that cytokines may contribute to the pathogenesis of MDD. Since none of the block 2 SNPs were individually associated with MDD, it is possible that other polymorphisms linked to them contribute to the disease susceptibility. Future studies are needed to confirm the results and to find the possible functional explanation.

/pdf/polymorphisms-in-the-interleukin-10-gene-cluster-are-yp2cs0n8br.pdf

Triin Eller

Papers

Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression.

Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder

Effects of bupropion augmentation on pro-inflammatory cytokines in escitalopram-resistant patients with major depressive disorder:

Polymorphisms in the interleukin-10 gene cluster are possibly involved in the increased risk for major depressive disorder