Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

Attwells, Sophia; Setiawan, Elaine; Rusjan, Pablo; Xu, Cynthia; Hutton, Celeste; Rafiei, Dorsa; Varughese, Benjamin; Kahn, Alan R.; Kish, Stephen J.; Vasdev, Neil; Houle, Sylvain; Meyer, Jeffrey H.

doi:10.1016/j.biopsych.2020.03.007

Cited by 40 publications

(35 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This TSPO binding pattern was similar to those in patients with MDD, for which a meta-analysis reported increased TSPO expression in ACC, frontal lobe, prefrontal and temporal cortices, insula, and hippocampus when compared to healthy controls [71]. Interestingly, a recent study showed that higher TPSO values in patients with treatmentresistant depression predicted better treatment response to Celecoxib [76]. However, these findings need to be interpreted with caution, as results of TSPO PET studies in neuroinflammatory conditions or states have shown inconsistent results [77], challenging the general assumption that altered TSPO expression or binding unequivocally mirrors neuroinflammation [78,79].…”

Section: Endotoxin-induced Inflammation and Neuroimaging Findingssupporting

confidence: 74%

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression

et al. 2020

View full text Add to dashboard Cite

Depression is one of the global leading causes of disability, but treatments remain limited and classical antidepressants were found to be ineffective in a substantial proportion of patients. Thus, novel effective therapies for the treatment of depression are urgently needed. Given the emerging role of inflammation in the etiology and pathophysiology of affective disorders, we herein illustrate how experimental endotoxemia, a translational model of systemic inflammation, could be used as a tool to develop and test new therapeutic options against depression. Our concept is based on the striking overlap of inflammatory, neural, and affective characteristics in patients with inflammation-associated depression and in endotoxin-challenged healthy subjects. Experimental administration of endotoxin in healthy volunteers is safe, well-tolerated, and without known longterm health risks. It offers a highly standardized translational approach to characterize potential targets of therapies against inflammation-associated depression, as well as to identify characteristics of patients that would benefit from these interventions, and, therefore, could contribute to improve personalization of treatment and to increase the overall rate of responders.

show abstract

Section: Endotoxin-induced Inflammation and Neuroimaging Findingssupporting

confidence: 74%

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In each case, increased Glu in these brain regions was associated with increases in the overall severity of depressive symptoms and symptoms of anhedonia, amotivation, and psychomotor slowing [ 1 – 3 ]. Of note, anhedonia is rapidly emerging as a public health priority [ 4 ]. For instance, anhedonia is not only common in MD (rates of ~70%) but was associated with a ~30% increase in the risk of death and disability among depressed individuals [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression

et al. 2021

View full text Add to dashboard Cite

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

show abstract

“…In each case, increased Glu in these brain regions was associated with increases in the overall severity of depressive symptoms and symptoms of anhedonia, amotivation, and psychomotor slowing [1][2][3] . In addition, greater CRP concentrations in the cerebrospinal fluid (CSF) of MD patients were associated with increases in myo-inositol (mI), a marker of astroglial distress in the BG, suggesting that the effects of inflammation upon Glu may reflect alterations in astrocyte function induced by inflammation and oxidative stress 3,4 .…”

Section: Introduction (4842 Words Formatted)mentioning

confidence: 99%

Kynurenines Increase MRS Metabolites in Basal Ganglia and Decrease Resting State Connectivity in Frontostriatal Reward Circuitry in Depression

Chen

Beltran

Tsygankova

et al. 2021

Preprint

View full text Add to dashboard Cite

Inflammation is associated with depressive symptoms including anhedonia in patients with major depression. Nevertheless, the mechanisms by which peripheral inflammatory signals are communicated to the brain to influence central nervous system (CNS) function has yet to be fully elucidated. Based on laboratory animal studies, molecules of the kynurenine pathway (KP), which is activated by inflammation, can readily enter the brain, and generate metabolites that can alter neuronal and glial function, leading to behavioral changes. We therefore examined the relationship between KP metabolites in the plasma and cerebrospinal fluid (CSF) and brain chemistry and neural network function using multi-modal neuroimaging in 49 unmedicated, depressed subjects. CNS measures included 1) biochemical markers of glial dysfunction including glutamate (Glu) and myo-inositol (mI) in the left basal ganglia (LBG) using magnetic resonance spectroscopy (MRS); 2) local activity coherence (regional homogeneity, ReHo) and functional connectivity using resting-state functional magnetic resonance imaging; and 3) anhedonia from the Inventory for Depressive Symptoms-Self Reported. Plasma quinolinic acid (QA) was associated with increases and kynurenic acid (KYNA) and KYNA/QA with decreases in LBG Glu. Plasma kynurenine/tryptophan and CSF 3-hydroxy kynurenine (3HK) were associated with increases in LBG mI. Plasma and CSF KP were associated with decreases in ReHo in LBG and dorsomedial prefrontal cortex (DMPFC), and impaired functional connectivity between these two brain regions. DMPFC-BG connectivity mediated the effect of plasma and CSF KP metabolites on anhedonia. These findings highlight the contribution of KP metabolites to glial and neuronal dysfunction and ultimately behavior in depression.

show abstract

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

Cited by 40 publications

References 42 publications

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression

Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression

Kynurenines Increase MRS Metabolites in Basal Ganglia and Decrease Resting State Connectivity in Frontostriatal Reward Circuitry in Depression

Contact Info

Product

Resources

About