Targets For Major Depressive Disorder Research Articles

Exploration of microbiota targets for major depressive disorder and mood related traits

Growing evidence suggests the link between gut microbiota and mood regulation. The current study aimed to identify microbiota targets for major depressive disorder (MDD) and mood-related traits in Taiwanese samples, while taking into account the influence of dietary patterns. We recruited 36 MDD patients and 37 healthy controls for 16S rRNA gene sequencing. We assessed nutrient content using food frequency questionnaire, and mood related phenotypes, including depressive severity, anxiety, and perceived stress. Analysis of composition of microbiomes (ANCOM) models were performed to evaluate microbiota compositions between patients and controls, while adjusted for fat intake% and sequencing platforms. We found 23 taxa (4 phyla, 7 families and 12 genera) to be associated with depression and beta diversity was differed between groups. Phylum Actinobacteria and Firmicutes were overrepresented in MDD patients. At genus level, Bifidobacterium (7%) and Blautia (8%) had relatively high abundance among MDD patients, while Prevotella (16%) had high abundance in controls. Holdemania exhibited moderate correlation with anxiety (r = 0.65) and perceived stress level (r = 0.49) mainly in MDD patients but not controls. Pathway analyses revealed that pentose phosphate and starch and sucrose metabolism processes were important pathways for depression via microbiota functions. In conclusion, our results revealed microbiota targets for depression that are independent of fat intake. It is worthwhile to conduct further studies to replicate the current findings and to integrate with biochemistry and metabolomics data to better understand the functions of identified targets.

SU42 - DISCOVERY AND REPLICATION STUDIES FOR MICROBIOTA SIGNATURES IN MAJOR DEPRESSIVE DISORDER

Background Growing evidence suggests the link between gut microbiota and mood regulation. While previous studies reported several microbiota targets for Major Depressive Disorder (MDD), the influence of dietary patterns is not considered. The current study aims to identify microbiota targets for MDD depression in two independent Taiwanese datasets while taking nutrient elements into consideration. Methods We separately analyzed fecal samples from two independent datasets. The discovery set consisted of 9 MDD patients and 11 healthy controls while replication set comprised of 15 MDD patients and 25 healthy controls. Illumina Miniseq or Miseq platform were applied for 16 s rRNA sequencing. We further assessed food frequency questionnaires and Beck depression inventory to obtain the information of nutrients and depressive status. We applied linear discriminant analysis effect size (LEfSe) to test associations between depression and microbiota and adjusted for nutrient status. Results In the discovery data, the microbiota exhibited significant group differences in genus level, including increased abundance of Bilophila and Gillisia, and decreased abundance of Clostridium. The results remained significant after adjusted levels of carbohydrates, protein and fat intake. The replication study is underway. Discussion Our results revealed novel targets to be associated with depression and are independent of dietary influences. These results awaiting replication and further validation for depression.

Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors

BackgroundMajor depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. MethodsWe used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. ResultsThe results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress–induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. ConclusionsOur results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.

Therapeutic role of long non-coding RNA TCONS_00019174 in depressive disorders is dependent on Wnt/β-catenin signaling pathway.

Chronic stress is one of the major causes that lead to major depressive disorder, which is a prevalent mood disorder worldwide. Many patients with major depressive disorder do not benefit from available medication due to the complex etiology of the condition. Recently, long non-coding RNAs, molecular switches of downstream genes expression, have been reported to be involved in the pathogenesis of major depressive disorder. The long non-coding RNA TCONS_00019174 has been implicated in major depressive disorder risk and antidepressant effects, However, the effect of long non-coding RNA TCONS_00019174 on antidepressant responses has not been investigated. This study is designed to determine whether altered expression of long non-coding RNA TCONS_00019174 contributes to depression-like behaviors associated with chronic stress. We found that mice exposed to chronic ultra-mild stress displayed apparent depression-like behaviors and decreased expression of long non-coding RNA TCONS_00019174 in hippocampus. Both changed behaviors and long non-coding RNA TCONS_00019174 expression level were rescued by chronic treatment with imipramine. Viral-mediated long non-coding RNA TCONS_00019174 over expression in hippocampal neurons improved the behaviors of mice exposed to chronic ultra-mild stress. Further, it was found long non-coding RNA TCONS_00019174 over expression upregulated phosphorylated-GSK3β (p-GSK3β) protein and β-catenin in the hippocampus. These findings suggest that long non-coding RNA TCONS_00019174 exerts antidepressant-like effect in mice by activating a Wnt/β-catenin pathway, and that long non-coding RNA may serve as a potential therapeutic target for major depressive disorder in clinical application.

Longitudinal effects of cognitive behavioral therapy for depression on the neural correlates of emotion regulation

Cognitive behavioral therapy (CBT) is effective for a substantial minority of patients suffering from major depressive disorder (MDD), but its mechanism of action at the neural level is not known. As core techniques of CBT seek to enhance emotion regulation, we scanned 31 MDD participants prior to 14 sessions of CBT using functional magnetic resonance imaging (fMRI) and a task in which participants engaged in a voluntary emotion regulation strategy while recalling negative autobiographical memories. Eighteen healthy controls were also scanned. Twenty-three MDD participants completed post-treatment fMRI scanning, and 12 healthy volunteers completed repeat scanning without intervention. Better treatment outcome was associated with longitudinal enhancement of the emotion regulation-dependent BOLD contrast within subgenual anterior cingulate, medial prefrontal cortex, and lingual gyrus. Baseline emotion regulation-dependent BOLD contrast did not predict treatment outcome or differ between MDD and control groups. CBT response may be mediated by enhanced downregulation of neural activity during emotion regulation; brain regions identified overlap with those found using a similar task in a normative sample, and include regions related to self-referential and emotion processing. Future studies should seek to determine specificity of this downregulation to CBT, and evaluate it as a treatment target in MDD.

Cognitive impairment as measured by the THINC-integrated tool (THINC-it): Association with psychosocial function in major depressive disorder

BackgroundPsychosocial impairment represents an important treatment target in major depressive disorder (MDD). The majority of patients with MDD do not regain premorbid levels of psychosocial functioning despite the resolution of core depressive symptoms. This study aimed to investigate the respective effects of cognitive function and depression severity on impaired psychosocial function in MDD. MethodsAdults aged 18–65 with moderate-to-severe MDD (n = 100) and age-, sex-, and education-matched healthy controls participated in a cross-sectional study validating the THINC-integrated tool (THINC-it), a cognitive screening tool comprised of objective and subjective measures of cognitive function. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and psychosocial function was assessed using the Sheehan Disability Scale (SDS). ResultsSubjects with MDD reported greater impairment in psychosocial function than healthy controls, with significant differences in SDS total and domain scores (ps < .01) after controlling for age, sex, and education. Generalized linear models indicated that subjective cognitive function was most strongly associated with SDS total score (RR = .14, p = .01) and SDS domains of work/school (RR = .15, p = .03), family and home responsibilities (RR = .15, p = .02), and economic days lost (RR = .18, p =.03). Depression severity was most strongly associated with SDS social life (RR = .08, p < .01) and economic days underproductive (RR = .07, p < .01). Objective cognitive function was not significantly associated with any SDS outcomes. LimitationsThe cross-sectional, observational study design limits temporal inferences. The self-report nature of measures included may have influenced associations observed. Potential medication effects are not noted. ConclusionsCognitive deficits, as measured by the THINC-it, are associated with significant psychosocial impairment in MDD. These results provide empirical support for the assessment of both subjective and objective measures of cognition, as they are not associated with each other and have differential effects on functional trajectory.

Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression

Background/Aims: Major depressive disorder (MDD) is highly recurrent. This may be due to increased stress sensitivity after remission. Both inflammatory and psychosocial stressors are implicated in the pathogenesis of MDD, but the additive or differential effect is unclear. Methods: We conducted a single-blind placebo-controlled study to investigate the effects of inflammatory stress (i.e., typhoid vaccination), psychosocial stress (i.e., Trier Social Stress Test [TSST]), or a combination of both in women (25-45 years old) with (partially) remitted recurrent MDD (n = 21) and healthy female controls (n = 18). We evaluated the effect on mood measured by the Profile of Mood States, markers of the hypothalamic-pituitary-adrenal (HPA) axis activity, and inflammatory system activation. The study was performed during 2 testing days, separated by a washout of 7-14 days. In a crossover design, subjects received one of the interventions on one day and placebo on the other. Results: A lowering of mood was seen in patients (β [95% CI] = -4.79 [-6.82 to -2.75], p < 0.001) only after vaccination, but not after the TSST or the combination; this effect was not observed in controls. Controls experienced a significantly different response on adrenocorticotropic hormone (ACTH) after vaccination, with a general rise in ACTH not observed in patients. In both groups, the TSST activated the HPA axis and suppressed the inflammatory parameters. Conclusions: There is a differential effect of inflammatory and psychosocial stress on mood and HPA axis activation in patients with remitted recurrent MDD. This may be an interesting treatment target in MDD.

Treating to target in major depressive disorder: response to remission to functional recovery.

Treating to target in chronic diseases [e.g. Major Depressive Disorder (MDD)] fosters precision, consistency, and appropriateness of treatment selection and sequencing. Therapeutic target definitions/endpoints in MDD should satisfy patient-, provider-, and societal expectations. Functional recovery in depression and return to both physical and mental health are the overarching therapeutic objectives. Treating to target in MDD implies multidimensional symptomatic remission, with a particular emphasis on cognitive function and aspects of positive mental health. Several atypical antipsychotic agents (i.e. brexpiprazole, aripiprazole, quetiapine) are FDA-approved as augmentation agents in MDD. Vortioxetine, duloxetine, and psychostimulants have evidence of independent, direct, and robust effects on cognitive function in MDD. Vortioxetine is the only agent that demonstrates efficacy across multiple cognitive domains in MDD associated with functional recovery. Measurement-based care, health information technology/systems, and integrated care models (e.g. medical homes) provide requisite tools and health environments for optimal health outcomes in MDD. Achieving remission in MDD does not equate to health. Return to positive mental health as well as full functioning provide the impetus to pivot away from traditional provider-defined outcomes toward an inclusive perspective involving patient- and society-defined outcomes (i.e. optimization of human capital). As in other chronic diseases, treating to target (e.g. cognitive function) further increases the probability of achieving optimal health outcomes.

Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [¹¹C]ABP688.

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders and is a potential treatment target in major depressive disorder (MDD). This study compared brain mGluR5 binding in elderly patients suffering from MDD with that in elderly healthy volunteers using positron emission tomography (PET) and [11C]ABP688. Twenty elderly (mean age: 63.0±6.3) subjects with MDD and twenty-two healthy volunteers in the same age range (mean age: 66.4±7.3) were examined with PET after a single bolus injection of [11C]ABP688, with many receiving arterial sampling. PET images were analyzed on a region of interest and a voxel level to compare mGluR5 binding in the brain between the two groups. Differences in [11C]ABP688 binding between patients with early- and late-onset depression were also assessed. In contrast to a previously published report in a younger cohort, no significant difference in [11C]ABP688 binding was observed between elderly subjects with MDD and healthy volunteers. [11C]ABP688 binding was also similar between subgroups with early- or late-onset depression. We believe this is the first study to examine mGluR5 expression in depression in the elderly. Although future work is required, results suggest potential differences in the pathophysiology of elderly depression versus depression earlier in life.

Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation.

Background:Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.Methods:In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.Results:LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.Conclusions:The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.

NLRP3 Inflammasome: A New Target in Major Depressive Disorder

Inflammasome has emerged recently as an unexpected sensor for metabolic danger and stress. Indeed, it has been implicated in the development of major diseases such as gout, type 2 diabetes, and obesity-induced insulin resistance and is increasingly suspected of playing a major role in other human pathologies such as cancer, asbestosis, and Alzheimer’s disease [1]. The inflammasome is a protein complex that comprises an intracellular sensor, typically a Nod-like receptor (NLR), the precursor procaspase-1, and the adaptor ASC. Inflammasome activation leads to the maturation of caspase-1 and the processing of its substrates, IL-1b, and IL-18 [2]. Of all the NLRs, NLRP3 is activated by the most diverse array of danger signals. Recently, it has been hypothesized the implication of inflammasome in depression and related comorbid systemic illnesses [3], however, was necessary to demonstrate the activation of NLRP3 inflammasome in depressive patients. This event was intuited because IL-1b, one of the two known cytokines activated by the inflammasome complex, has been implicated in stress, depression, and central nervous system (CNS) dysregulation [3]. A recent paper published in CNS Neuroscience and Therapeutics by Zhang et al. [4] have showed in first time that the NLRP3 inflammasome is involved in lipopolysaccharideinduced mice depressive-like behaviors. In parallel, the authors of the present paper have showed in first time the activation of NLRP3 inflammasome in blood mononuclear cells from depressive patients with a high correlation between IL-1b and IL-18 with Beck Depression Inventory scores of depressive patients [5]. These are two papers demonstrating in an animal model and patients, the hypothesis of Iwata et al. These findings provide new insight into the pathogenesis of major depressive disorder. Now, we must deepen about this and study several point involved in the pathogenesis of this disease. The Mechanism of Disease

ATP-binding cassette sub-family F member 1 (ABCF1) is identified as a putative therapeutic target of escitalopram in the inflammatory cytokine pathway

The inflammatory cytokine pathway may be a potential therapeutic target for major depressive disorder (MDD). Previous reports suggest that antidepressants have anti-inflammatory properties and can cause a reduction in proinflammatory cytokines. Recent evidence suggests this might be mediated at the level of the transcriptome. The current study investigated the transcription of 86 genes in the inflammatory cytokine pathway both at baseline and after eight weeks of escitalopram treatment in MDD patients who were either clinical responders (n=25) or non-responders (n=21), using a subset of samples in the Genome-Based Therapeutic Drugs for Depression project (GENDEP). Changes in expression between baseline and eight weeks of treatment were assessed using two-tailed t-tests. To establish if any significant expression changes related to clinical response, the magnitude of the relative expression change between baseline and eight weeks of treatment was established and binary logistic regressions were used to compare differences between responders and non-responders. ATP-binding cassette sub-family F member 1 (ABCF1), a translational regulator of the inflammatory cytokine pathway showed a significant increase in expression after escitalopram treatment which was significantly greater in responders compared to non-responders, suggesting that ABCF1 may play a role in mediating antidepressant response.

Reduced platelet G protein-coupled receptor kinase 2 in major depressive disorder: Antidepressant treatment-induced upregulation of GRK2 protein discriminates between responder and non-responder patients

The homologous regulation of neurotransmitter receptors by G protein-coupled receptor kinases (GRKs) is important in the pathogenesis and treatment of major depressive disorder (MDD). Previous studies have reported that the basal status of GRK2 is different in brains (upregulation) and platelets (downregulation) of subjects with MDD. The principal aim of this study was to re-examine the status of platelet membrane GRK2 protein in patients with MDD, along with GRK3 (a close kinase homolog) and GRK5 (a kinase with different properties), before and after treatment with serotonin-selective reuptake inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) antidepressants. The main findings indicated that platelet GRK2 and p-Ser670 GRK2 were reduced (36–41%) in unmedicated MDD subjects, and that GRK2 content correlated inversely with the severity of depression ( r = − 0.51). Effective antidepressant treatments normalized platelet GRK2, and, notably, GRK2 upregulation discriminated between responder and non-responder patients. Other findings revealed a modest reduction of platelet GRK3 (23%) and no alteration of platelet GRK5 content. In untreated subjects with MDD, lymphocyte GRK2 and GRK5 mRNAs were unaltered but antidepressant treatment-induced upregulation of GRK2 mRNA expression. The reduced content of platelet GRK2 protein is a relevant target in MDD. Although this peripheral GRK2 defect does not mirror the canonical regulation of brain GRK2 in depressed suicides, it could well represent a disease state marker as well as a surrogate of response to effective antidepressant treatment.

The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder

Ample evidence indicates that glutamate homeostasis and neurotransmission are disrupted in major depressive disorder; but the nature of this disruption and the mechanisms by which it contributes to the syndrome are unclear. Likewise, the effect of existing antidepressants on glutamate is unclear, as is the potential of drugs directly targeting glutamatergic neurotransmission to act as novel antidepressant medications. These are areas of active research. Here we review current knowledge of the contribution of the NMDA receptor, one of the several types of glutamate receptor, to depression and its treatment. Several lines of evidence, in humans and in animal models, support the contention that neurotransmission via the NMDA receptor is dysregulated in depression. Drugs that target the NMDA receptor have shown antidepressant properties in both clinical and preclinical studies. Nevertheless, other effects of such medications, including both cognitive side effects and their psychotomimetic properties, complicate such an application and represent a challenge to the development of clinically useful agents.