Biomarker Approaches in Major Depressive Disorder Evaluated in the Context of Current Hypotheses

jentsch, Mike; Buel, E. M. van; Bosker, Fokko J.; Gladkevich, Anatoliy V.; Klein, Hans; Voshaar, Richard C. Oude; Ruhé, Eric G; Eisel, Ulrich; Schoevers, Robert A.

doi:10.2217/bmm.14.114

Cited by 58 publications

(60 citation statements)

References 194 publications

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“…Yet, functional imaging and peripheral biomarker measurements in patients with TRD are relatively scarce. By introducing such measurements in the present study we hope to provide additional information regarding the pathophysiological processes involved in TRD including their relation with treatment response [19]. Conversely such information may be useful to verify or falsify our working hypothesis that inflammatory processes and oxidative stress play a pivotal role in this TRD sample.…”

Section: Discussionmentioning

confidence: 96%

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

Yang

Bosker

et al. 2018

BMC Psychiatry

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BackgroundA subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Methods/designA double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included.DiscussionThis is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Trial registrationThe trial protocol has been registered on “ClinicalTrials.gov“with protocol ID “NAC-2015-TJAH” and ClinicalTrials.gov ID “NCT02972398”.

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Section: Discussionmentioning

confidence: 96%

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

Yang

Bosker

et al. 2018

BMC Psychiatry

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“…The most widely investigated neurotrophic factor is BDNF (Wu et al, 2014), which was also investigated in MDD (Jentsch et al, 2015). This neurotrophic factor induces proliferation, survival, and differentiation of existing neurons, and the formation of new synapses.…”

Section: What About the Switch?mentioning

confidence: 99%

“…This neurotrophic factor induces proliferation, survival, and differentiation of existing neurons, and the formation of new synapses. In MDD, there exists a clear relationship between BDNF levels and the depressive state, as well as the success of antidepressant therapy (Jentsch et al, 2015). However, the results in bipolar disorder are far more ambiguous (Wu et al, 2014).…”

Section: What About the Switch?mentioning

confidence: 99%

“…The putative neuroplastic effects of cytokines form the core of the neuro-immune hypothesis of MDD (Loonen and Ivanova, 2016a). Several findings suggest that inflammatory changes, demonstrated by increased levels of proinflammatory cytokines, decreased levels of anti-inflammatory cytokines, and activation of immune cells, are causally related to MDD (Jentsch et al, 2015; Réus et al, 2015). Also, in bipolar disorder, activation of microglia, which results in the production of cytokines, is believed to render the brain in a vulnerable and unstable state that precipitates mood disturbances (Réus et al, 2015; Muneer, 2016).…”

Section: What About the Switch?mentioning

confidence: 99%

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Circuits Regulating Pleasure and Happiness in Bipolar Disorder

Loonen

Kupka

Ivanova

2017

Front. Neural Circuits

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According to our model, the motivation for appetitive-searching vs. distress-avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side to the centromedial amygdala on the other side, control the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). From an evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula-projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward-driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities.

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“…Although modern pharmacological medications such as selective serotonin reuptake inhibitors (SSRIs) and more recently serotoninnorepinephrine reuptakes inhibitors (SNRIs, e.g., duloxetine), has demonstrated efficacy and potential to prevent negative consequences (such as suicidal behavior) associated with MDD (Girardi et al, 2009), the optimal therapies to manage MDD remain unclear, as more than 20% of MDD patients remain resistant to treatments and around 50% of the episodes are recurrent (Kessler, 2003;Möller, 2008). Therefore, there is a need for improvement of MDD patient medical care and identification of reliable biomarkers could help in diagnosis, classification of MDD subtypes, and monitoring of disease progression (Jentsch et al, 2015;Young et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Translational identification of transcriptional signatures of major depression and antidepressant response

Hervé¹,

Bergon²,

Guisquet³

et al. 2017

European Neuropsychopharmacology

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Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD.

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Biomarker Approaches in Major Depressive Disorder Evaluated in the Context of Current Hypotheses

Cited by 58 publications

References 194 publications

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

Circuits Regulating Pleasure and Happiness in Bipolar Disorder

Translational identification of transcriptional signatures of major depression and antidepressant response

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