Subgroup Of Major Depressive Disorder Patients Research Articles

What does the immunometabolic status tell us about depression?

AbstractDespite being a clinical identifiable entity, major depressive disorder (MDD) is an heterogenous clinical syndrome, with a variety of clinical presentations which likely reflects different biological underpinnings. The identification of biologically-based depression symptoms profiles would be of great importance to unravel different pathophysiological pathways in MDD and therefore to achieve more precise and personalized therapeutical approaches as well as preventive strategies.Converging evidence from epidemiological and clinical studies, points to the importance of inflammation in MDD, shown by increased levels of pro-inflammatory proteins and increased inflammation-related comorbidities, including metabolic diseases. In fact, there exists a bidirectional relationship between inflammation and metabolic dysfunction that could be linked to multiple factors, including life style, stress and genetic predisposition. MDD patients exhibit several metabolic disturbances such as overweight, insuline resistance and dyslipidemia, among others, which are not always fully explained by life style factors. These findings have led to the formulation of an immunometabolic hypothesis, which could be present in a subgroup of MDD patients, associated to specific symptoms and clinical features.In this presentation, data reflecting the complex relationships and interactions between immune and metabolic disturbances in MDD will be shown. In particular, it will be shown how machine learning approaches can be useful to disentangle the clinical and biological heterogeneity of MDD, using immunometabolic biomarkers.Disclosure of InterestP. Lopez-Garcia Grant / Research support from: Grant from Carlos III Health Institute ref PI15/00204 and FEDER funding from the EU

Basal and LPS-stimulated inflammatory markers and the course of depression and anxiety symptoms

IntroductionMultiple studies show an association between inflammation –characterized by increased blood levels of C-reactive protein (CRP) and pro-inflammatory cytokines– and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. A cross-sectional relationship between low-grade inflammation and anxiety has also been reported, but the potential longitudinal relationship has been less well studied.ObjectivesWe aimed to examine whether basal and lipopolysaccharide (LPS-)induced levels of inflammatory markers are associated with depressive and anxiety symptom severity over the course of nine years. We hypothesized that inflammation is predictive of the severity and the course of a subset of symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise.MethodsWe tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual depressive symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) and anxiety symptoms (measured with the Beck’s Anxiety Inventory; BAI, Fear Questionnaire;FQ and Penn’s State Worry Questionnaire; PSWQ) over a period of up to 9 years using multivariate-adjusted mixed models in 1147 to 2872 Netherlands Study of Depression and Anxiety (NESDA) participants.ResultsAt baseline, participants were on average 42.2 years old, 66.5% were women, and 53.9% had a current mood or anxiety disorder. We found that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow up compared to non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). The associations between inflammation and anxiety symptoms were attenuated by 25%-30% after adjusting for the presence of (comorbid) major depressive disorder (MDD), but remained statistically significant.ConclusionsInflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. With regard to anxiety symptoms, we found that participants with high levels of inflammatory markers have on average high levels of anxiety consisting of physical arousal and agoraphobia, which tended to persist over a period of nine years, albeit with small effect sizes. These associations were partly driven by co-morbid depression. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.Disclosure of InterestNone Declared

C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder

Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA. One hundred and sixty-six participants in the Tulsa 1000 study with a DSM-V diagnosis of MDD completed diffusion tensor imaging and provided a serum sample for the quantification of CRP, KynA, and QA. Correlational tractography was performed using DSI Studio to map the specific white matter pathways that correlated with CRP and KynA/QA. CRP was negatively related to KynA/QA (standardized beta coefficient, SBC = -0.35 with standard error, Std.E = 0.13, p < 0.01) after controlling for nine possible confounders, i.e., age, sex, body mass index (BMI), medication status, lifetime alcohol use, severity of depression, severity of anxiety, length of illness, and smoking status. Higher concentrations of CRP were associated with decreased white matter integrity (fractional anisotropy, FA) of the bilateral cingulum and fornix after controlling for the nine potential confounders (SBC = -0.43, Std.E = 0.13, p = 0.002). Greater serum KynA/QA was associated with increased white matter integrity of the bilateral fornix, bilateral superior thalamic radiations, corpus callosum, and bilateral cingulum bundles after controlling for the same possible confounders (SBC = 0.26, Std.E = 0.09, p = 0.005). The relationship between CRP and FA was not mediated by KynA/QA. Exploratory analyses also showed that KynA/QA but not CRP was associated with self-reported positive affect, attentiveness, and fatigue measured with the PANASX (SBCs = 0.17–0.23). Taken together, these results are consistent with the hypothesis that within a subgroup of MDD patients, a higher level of systemic inflammation alters the balance of KP metabolism but also raise the possibility that CRP and neuroactive KP metabolites represent independent molecular mechanisms underlying white matter alterations in MDD.

Trajectories of somatic drug utilization patterns in Major Depressive Disorder: A Study protocol for a Danish nationwide register study using Latent Class Analysis

Background: Major Depressive disorder (MDD) is a heterogeneous, multi-etiological disorder that is associated with chronic medical conditions and a high somatic treatment burden. A better understanding of the somatic diseases and treatment burden in MDD can be provided through a mapping of the somatic drug utilization patterns over time. The objective of this study is therefore to characterize the somatic drug profiles and their transitions over time (i.e. trajectories) among MDD patients.    Methods: This descriptive study will be a nationwide register-based study including all Danish patients with an incident MDD diagnosis between 2011 and 2015. Using Latent Class Analysis, we will identify homogenous MDD patient subgroups according to somatic drug utilization (i.e. drug profiles). The development in somatic drug profiles will be depicted in four different time intervals from three years prior to the MDD diagnosis to three years after the diagnosis. Patients will be assigned to the latent class (drug profile) to which they have the highest probability of belonging using modal assignment. The treatment trajectories will be performed by cross tabulating these assignments.  Discussion: Profiles and trajectories of somatic drug use will provide a new perspective on patterns of somatic drug burden in MDD patients. Moreover, identifying homogenous subgroups of MDD patients regarding somatic drug use can contribute to a deeper understanding of MDD etiology. In the future, this knowledge could help optimizing MDD treatment by studying if different antidepressants will show different efficacy and safety depending on the profiles and trajectories of somatic diseases.

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

Multiple studies show an association between inflammatory markers and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. We hypothesized that inflammation is predictive of the severity and the course of a subset of MDD symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise. We tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual MDD symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) over a period of up to 9 years using multivariate-adjusted mixed models in 1147–2872 Netherlands Study of Depression and Anxiety (NESDA) participants. At baseline, participants were on average 42.2 years old, 66.5% were women and 53.9% had a current mood or anxiety disorder. We found that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow-up compared with non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). Inflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.

The preclinical discovery and development of agomelatine for the treatment of depression

ABSTRACT Introduction Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. Areas covered The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine’s effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug. Expert opinion There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD.

Distinct Expression Pattern of Epigenetic Machinery Genes in Blood Leucocytes and Brain Cortex of Depressive Patients

In major depressive disorder (MDD), altered gene expression in brain cortex and blood leucocytes may be due to aberrant expression of epigenetic machinery coding genes. Here, we explore the expression of these genes both at the central and peripheral levels. Using real-time quantitative PCR technique, we first measured expression levels of genes encoding DNA and histone modifying enzymes in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) of MDD patients (n = 24) and healthy controls (n = 12). For each brain structure, transcripts levels were compared between subject groups. In an exploratory analysis, we then compared the candidate gene expressions between a subgroup of MDD patients with psychotic characteristics (n = 13) and the group of healthy subjects (n = 12). Finally, we compared transcript levels of the candidate genes in blood leucocytes between separate samples of MDD patients (n = 17) and healthy controls (n = 16). In brain and blood leucocytes of MDD patients, we identified an overexpression of genes encoding enzymes which transfer repressive transcriptional marks: HDAC4-5-6-8 and DNMT3B in the DLPFC, HDAC2 in the CC and blood leucocytes. In the DLPFC of patients with psychotic characteristics, two genes (KAT2A and UBE2A) were additionally overexpressed suggesting a shift to a more transcriptionally permissive conformation of chromatin. Aberrant activation of epigenetic repressive systems may be involved in MDD pathogenesis both in brain tissue and blood leucocytes.

Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy.

Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30–50%. Historically, the monoamine depletion hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants. Stimuli like inflammation and infection can trigger the activation of microglia to release pro-inflammatory cytokines, acting on two main pathways: (1) activation of the hypothalamic–pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits; (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels and the production of quinolinic acid. If this hypothesis is proven true, the subgroup of MDD patients with increased levels of pro-inflammatory cytokines, mainly IL-6, TNF-α and IL-1β, might benefit from an anti-inflammatory intervention. Here, we discuss the pre-clinical and clinical studies that have provided support for treatment with non-steroidal anti-inflammatory drugs in depressed patients with inflammatory comorbidities or an elevated immune profile, as well as evidences for anti-inflammatory properties of standard antidepressants.

A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder

BackgroundHypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. AimThe aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. MethodsTCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. Results: The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 („difficulty in concentration, poor memory“), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. LimitationsCross-sectional design and heterogenous treatment of depressed patients. ConclusionsReduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms.

Peripheral blood gene expression analysis implicates B lymphocyte proliferation and ribosomal S26 transcripts in cognitive dysfunction in people with remitted Major Depression

Residual impairments in cognitive domains including attention, memory, executive function, and social perception occur in about 40% of patients with Major Depressive Disorder (MDD) following remission from acute episodes (Conradi et al., 2011), and are associated with reductions in pre-morbid functioning and higher unemployment rates (Baune et al., 2010; Evans et al., 2014). Cognitive impairment in MDD may represent a trait marker, trait-byillness interaction marker, or endophenotype of MDD that is independent of the acute depressive state and particularly active in a subgroup of MDD patients (Hasler et al., 2004; Iverson et al., 2011). We explored the potential molecular underpinnings of such a ‘cognitive’ MDD phenotype in a well-matched pilot sample of remitted MDD patients with poorer versus better performance on cognitive testing. Because the phenotype is likely highly complex, polygenic, and heterogeneous, we performed weighted gene coexpression network analysis (WGCNA), a hypothesis-free systems biology approach that identifies ‘modules’ of co-regulated – and therefore functionally related – genes in transcriptomic datasets. After constructing a gene co-expression network from samples of all patients, we determined whether modules were correlated with poorer versus better cognitive performance. We additionally explored whether modules were also correlated with a continuous measure of cognitive performance in both groups. We utilized whole blood transcriptomic data from remitted MDD patients from the Adelaide Cognitive Function and Mood Study (CoFaMS, HREC RAH protocol no. 111230g) matched for race, gender, age, Hamilton Depression Scale score, presence of psychotic features during any depressive episode, educational status, annual household income, current drugand alcohol use, and

Interpersonal profiles in major depressive disorder

Although patients with mood disorders report interpersonal difficulties in addition to depression or anxiety, few studies have examined interpersonal patterns in those patients. Here the authors' goals were to (a) identify the interpersonal pattern in patients with major depressive disorder (MDD), (b) determine interpersonal differences between subgroups of MDD patients, and (c) examine the interpersonal patterns of comorbid MDD patients. One- hundred forty-one MDD adults participated in an ongoing randomized clinical trial of treatments for depression. Interpersonal profiles revealed that MDD patients were significantly more distressed by interpersonal problems than normative samples. Furthermore, MDD patients with depressive personality disorder reported more interpersonal distress than MDD-only patients report and were more likely to have interpersonal problems related to dominance and control than submissiveness.