Kynurenine pathway metabolism and the neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy

Allen, Andrew P.; Naughton, Marie; Dowling, Joshua L.; Walsh, Annabel; O'Shea, Robert; Shorten, George; Scott, Lucinda V.; McLoughlin, Declan M.; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.

doi:10.1016/j.jpsychires.2018.02.011

Cited by 40 publications

(65 citation statements)

References 57 publications

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“…In this study, circulating levels of Trp, Kyn, and the Kyn/Trp ratio were examined based on responder status at 230 min and day 1 and Kyn and Kyn/Trp ratio were lower among responders. This difference was maintained up to day 1 for the Kyn/Trp ratio ( p = 0.035), similar to previous reports where they also found lower Kyn concentrations in responders (Allen et al 2018). Based on these results, the study was expanded to examine the metabolites of Kyn and their relation to response to ketamine treatment.…”

Section: Kynurenine Pathwaysupporting

confidence: 91%

“…This is similar to the observation seen in a mouse model of neuroinflammation-induced depression, where an increase in the Kyn/Trp ratio was observed and was abated by the addition of an IDO inhibitor (Dobos et al 2012). Other studies have shown mixed results concerning the metabolites from the Kyn pathway, with some having reported higher circulating Kyn levels in MDD patients (Sublette et al 2011, Allen et al 2018), while others reported no difference between controls and depressed patients for Trp, Kyn or the Kyn/Trp ratio (Sorgdrager et al 2017). In this study, circulating levels of Trp, Kyn, and the Kyn/Trp ratio were examined based on responder status at 230 min and day 1 and Kyn and Kyn/Trp ratio were lower among responders.…”

Section: Kynurenine Pathwaymentioning

confidence: 98%

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Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects

et al. 2018

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(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine’s rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine’s effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment.

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Section: Kynurenine Pathwaysupporting

confidence: 91%

Section: Kynurenine Pathwaymentioning

confidence: 98%

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects

et al. 2018

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“…Ketamine treatment was shown to acutely decrease circulating KYN and the KYN/TRP ratio with a greater magnitude of reduction in treatment responders versus non-responders 169 . Partially consistent with this result, a non-significant reduction in KYN and KYN/TRP also was reported in ketamine responders versus non-responders at two hours and 24 hours post initial infusion 53 . While these two studies did not report significant ketamine-induced changes in downstream KP metabolites, in another study, ketamine was shown to increase KynA concentrations from 24 hours after the first infusion until at least two weeks post initiation of treatment 170 .…”

Section: Therapeutic Implicationssupporting

confidence: 79%

The kynurenine pathway: a finger in every pie

2019

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The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogues of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.

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“…Of the two remaining studies, one collected samples for cortisol analysis in the afternoon (50) and the other did so in the evening (47). Nine studies specifically mentioned a rest period of 15 to 45 min prior to the collection of samples used for quantification of cortisol (20–22, 23, 29, 35, 41, 44, 50). The remaining studies did not comment on this subject.…”

Section: Resultsmentioning

confidence: 99%

“…Seven studies reported C-reactive protein (CRP) levels (20, 37, 44, 45, 47, 49, 50), one study reported eosinophil cationic protein (ECP) levels (27), one study reported eosinophil chemotactic protein-2 (EOTAXIN-2) levels (27), five studies reported interferon-γ (IFN-γ) levels (22, 27, 36, 39, 43), six studies reported IL-1β levels (23, 31, 38, 40, 43, 46), two studies reported IL-1 receptor antagonist (IL-1RA) levels (31, 47), five studies reported IL-2 levels (23, 24, 26, 30, 39), two studies reported IL-4 levels (25, 39), 23 studies reported IL-6 levels (13, 21, 22, 25, 28, 29, 32–34, 35, 37, 38, 41–49–50), one study reported IL-8 levels (22), three studies reported IL-10 levels (22, 25, 39), one study reported monocyte chemoattractant protein-1 (MCP-1) levels (25), one study reported regulated on activation, normal T cell expressed and secreted (RANTES) levels (27), one study reported soluble IL-2 Receptor (sIL-2R) levels (41), 15 studies reported TNF-α levels (24, 25, 27, 28, 32–36, 37, 39, 44, 46, 48, 50), and one study reported vascular endothelial growth factor (VEGF) levels (25).…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis

et al. 2019

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Background: Glucocorticoid resistance—reduced function of the glucocorticoid receptor (GR)—is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. Purpose: We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), GR expression levels, and the results of in vitro assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. Results: After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [ d = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [ d = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine—plasma ( d = 1.04; 95% CI, 0.57–1.50) versus in vitro ( d = 0.24; 95% CI, −0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53–2.18). Combining our analyses of studies that reported DST results with those that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls ( d = 1.02; 95% CI, 0.55–1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Conclusions: Our work provides some support for a model conceptualizing glucocorticoid resistance...

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Kynurenine pathway metabolism and the neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy

Cited by 40 publications

References 57 publications

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects

The kynurenine pathway: a finger in every pie

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis

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