Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline ‘Predictors' and Longitudinal ‘Targets'
TL;DR: In this article, the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammatory cytokines (interleukin (IL)-1a, IL-1b), IL-6 and IL-7), macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-a), were tested before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-
About: This article is published in Neuropsychopharmacology.The article was published on 2013-02-01 and is currently open access. It has received 342 citations till now. The article focuses on the topics: Proinflammatory cytokine.
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TL;DR: Current understanding of the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression are detailed.
Abstract: Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
2,133 citations
TL;DR: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression.
Abstract: 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.
987 citations
TL;DR: This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression and potential therapeutic strategies that target inflammatory cytokine signaling.
771 citations
TL;DR: The data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundances of an anti-inflammatoryTaxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis.
761 citations
TL;DR: This meta-analysis confirms a robust link between IL-6, CRP and major depression and the role of TNF-α and IL-1β in major depression remains uncertain.
Abstract: Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p < 0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p < 0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d = −0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
757 citations
References
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TL;DR: The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out and a wide variety of psychiatric rating scales have been developed.
Abstract: The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out by a number of authors. Pasamanick12in a recent article viewed the low interclinician agreement on diagnosis as an indictment of the present state of psychiatry and called for "the development of objective, measurable and verifiable criteria of classification based not on personal or parochial considerations, but on behavioral and other objectively measurable manifestations." Attempts by other investigators to subject clinical observations and judgments to objective measurement have resulted in a wide variety of psychiatric rating scales.4,15These have been well summarized in a review article by Lorr11on "Rating Scales and Check Lists for the Evaluation of Psychopathology." In the area of psychological testing, a variety of paper-and-pencil tests have been devised for the purpose of measuring specific
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TL;DR: The construction of a depression rating scale designed to be particularly sensitive to treatment effects is described, and its capacity to differentiate between responders and non-responders to antidepressant treatment was better than the HRS, indicating greater sensitivity to change.
Abstract: The construction of a depression rating scale designed to be particularly sensitive to treatment effects is described. Ratings of 54 English and 52 Swedish patients on a 65 item comprehensive psychopathology scale were used to identify the 17 most commonly occurring symptoms in primary depressive illness in the combined sample. Ratings on these 17 items for 64 patients participating in studies of four different antidepressant drugs were used to create a depression scale consisting of the 10 items which showed the largest changes with treatment and the highest correlation to overall change. The inner-rater reliability of the new depression scale was high. Scores on the scale correlated significantly with scores on a standard rating scale for depression, the Hamilton Rating Scale (HRS), indicating its validity as a general severity estimate. Its capacity to differentiate between responders and non-responders to antidepressant treatment was better than the HRS, indicating greater sensitivity to change. The practical and ethical implications in terms of smaller sample sizes in clinical trials are discussed.
11,923 citations
TL;DR: This is an account of further work on a rating scale for depressive states, including a detailed discussion on the general problems of comparing successive samples from a ‘population’, the meaning of factor scores, and the other results obtained.
Abstract: This is an account of further work on a rating scale for depressive states, including a detailed discussion on the general problems of comparing successive samples from a ‘population’, the meaning of factor scores, and the other results obtained. The intercorrelation matrix of the items of the scale has been factor-analysed by the method of principal components, which were then given a Varimax rotation. Weights are given for calculating factor scores, both for rotated as well as unrotated factors. The data for 152 men and 120 women having been kept separate, it is possible to compare the two sets of results. The method of using the rating scale is described in detail in relation to the individual items.
7,977 citations
TL;DR: A meta-analysis of studies measuring cytokine concentration in patients with major depression reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects, strengthening evidence that depression is accompanied by activation of the IRS.
3,800 citations
TL;DR: It is shown that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.
1,621 citations