Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine

Verdonk, Franck; Petit, Anne-Cécile; Abdel-Ahad, Pierre; Vinckier, Fabien; Jouvion, Grégory; Maricourt, Pierre de; Medeiros, Gabriela Ferreira de; Danckært, Anne; Steenwinckel, Juliette Van; Blatzer, Michael; Maignan, Anna; Langeron, Olivier; Sharshar, Tarek; Crinon, Jacques; Launay, Jean‐Marie; Chrétien, Fabrice; Gaillard, Raphaël

doi:10.1016/j.bbi.2019.06.033

Cited by 74 publications

(70 citation statements)

References 67 publications

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“…In a study of a mouse model, chronic restraint stress exposure induced depressive-like behavior that was correlated with the upregulated expression of IL-1β, TNF-α, and IL-6, and the upregulation of these pro-inflammatory cytokines was reversed by ketamine infusions 26 . Other animal studies have revealed that ketamine administration downregulates the levels of IL-1β and IL-6 in the prefrontal cortex and hippocampus 27 and decreases TNF-α and C-reactive protein levels in peripheral blood 28 ; such immunoregulatory effects are primarily observed in microglia and eventually critically reduce quinolinic acid (QUIN) production in lipopolysaccharide-induced depression 29 . Regarding clinical research, our previous study showed that kynurenic acid (KYNA) levels and the KYNA/KYN ratio, which are regulated by inflammatory cytokines, were higher in ketamine responders than in non-responders, which indicates that the KYN pathway may be involved in the rapid antidepressant effect of ketamine 30 .…”

Section: Introductionmentioning

confidence: 99%

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder

et al. 2020

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Increasing evidence has demonstrated that inflammatory cytokines play an important role in major depressive disorder (MDD) and are associated with treatment outcomes. Few studies have explored the trajectories of multiple inflammatory cytokines after repeated ketamine infusions in MDD. In this study, we conducted a secondary analysis to investigate the impact of ketamine on the modulation of the inflammatory pathway in depression and whether this pathway contributes to the antidepressant properties of ketamine. A total of 60 patients with depression received six ketamine infusions (0.5 mg/kg) during a 12-day period. The Montgomery-Asberg Scale (MADRS) was administered, and blood samples were collected at baseline and 24 h and 14 days after the sixth infusion (days 0, 13, and 26). Plasma levels of the 19 cytokines were measured using the Luminex assay. At baseline, inflammatory cytokines were associated with the severity of depression. The concentrations of pro-and anti-inflammatory factors, including granulocyte macrophage colony-stimulating factor (GM-CSF), fractalkine, interferon gamma (IFN-γ), interleukin (IL)-10, IL-12p70, IL-17A, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, and tumor necrosis factor alpha (TNF-α), were downregulated after repeated ketamine administration (all p < 0.05). In addition, alterations in the levels of IL-17A (r = −0.259, p = 0.046) and IL-6 (r = −0.262, p = 0.043) were correlated with symptom improvement. A lower level of interferon-inducible T cell alpha chemoattractant (ITAC) at baseline was predictive of ketamine treatment response on day 13 according to a stepwise linear regression analysis (β = −0.296, p = 0.040). Our results suggest that the inflammatory pathway may be involved in the antidepressant effects of ketamine, which may be conducive to future treatment strategy optimization.

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Section: Introductionmentioning

confidence: 99%

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder

et al. 2020

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“…There is mounting evidence for the beneficial effect of ketamine on synaptogenesis and neuroplasticity; such long-term effects are particularly interesting, considering the neuroprogressive nature of BD. [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]121 There is some evidence for the modifying effects of ketamine on epigenetic processes present in BD, [64][65][66][67][68][69][70] as well as its ability to regulate inflammation. [62][63][64][65][66][67][68][69] Ketamine may also have favorable effects on gut microbiota, which have been shown to be disturbed in patients with BD.…”

Section: Discussionmentioning

confidence: 99%

“…Neuropsychiatric Disease and Treatment 2020:16 2708 on microglia. 40 As suggested by studies investigating the antisuicidal effect of clozapine in patients with schizophrenia, suicidality may constitute a separate symptom dimension. It is, therefore, possible that ketamine also has an antisuicidal effect which is independent of its antidepressive effect.…”

Section: Dovepressmentioning

confidence: 99%

<p>Ketamine in Bipolar Disorder: A Review</p>

Wilkowska¹,

Szałach²,

Cubała³

2020

NDT

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Bipolar disorder (BD) is a psychiatric illness associated with high morbidity, mortality and suicide rate. It has neuroprogressive course and a high rate of treatment resistance. Hence, there is an unquestionable need for new BD treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Since most of the available studies concern unipolar depression, here we present a novel insight arguing that ketamine might be a promising treatment for bipolar disorder.

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“…Ketamine could modulate the microglial reactivity and decrease QUIN production. It was reported that KYNA‐to‐QUIN ratio was a predictor of ketamine response in treatment‐resistant depressed patients, while the reduction in QUIN after treated by ketamine was a predictor to the reduction in MADRS score 129 . Ketamine regulates functions of astrocytes and microcytes to maintain synaptic complement.…”

Section: Synaptic Plasticitymentioning

confidence: 99%

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

Peng

Fan

et al. 2020

Cell Proliferation

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Major depressive disorder takes at least 3 weeks for clinical anti-depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one-third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment-resistant depression patients. The rapid and strong anti-depressant-like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti-depressant-like effects. However, mechanisms about the rapid anti-depressant-like effects remain unclear. Elucidating the mechanisms of rapid anti-depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti-depressant-like effects based on the pre-clinical and clinical evidence, trying to provide new insight into future therapy.

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Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine

Cited by 74 publications

References 67 publications

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder

<p>Ketamine in Bipolar Disorder: A Review</p>

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

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