Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression

Zhou, Yanling; Zheng, Wei; Liu, Weijian; Wang, Chengyu; Zhan, Yongle; Li, Hanqiu; Chen, Lijian; Li, Mingding; Ning, Yuping

doi:10.1016/j.bbi.2018.09.007

Cited by 68 publications

(48 citation statements)

References 29 publications

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“…MDD subjects received a thrice-weekly ketamine infusion regimen for two weeks. The detailed methods have been described in our previous studies 12,23,24 . Following an overnight fast, patients received a subanesthetic dose (0.5 mg/kg) of ketamine diluted in saline administered over 40 min via IV intravenous pump continuous infusion.…”

Section: Methodsmentioning

confidence: 99%

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Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

Zhou

Liu

et al. 2020

Transl Psychiatry

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Abnormal subcortical structures have been associated with major depressive disorder (MDD) and could be reversed by antidepressant treatment. To date no study has examined the relationship between subcortical volumes and repeated ketamine treatment. The current study investigated volume changes in specific subcortical structures and hippocampal subfields after six ketamine infusions. Forty-four patients with MDD received six subanesthetic dose infusions of ketamine. Depressive symptoms were assessed and magnetic resonance imaging scans were performed before and after six ketamine infusions. FreeSurfer software was used to process the T1 images and analyze the volumes of the subcortical regions and hippocampal subfields. After six ketamine infusions, increases were observed in the volumes of the left amygdala; the right hippocampus; the cornu ammonis 4 body, granule cell and molecular layer of the dentate gyrus body in the left hippocampus; and the cornu ammonis 4 head and molecular layer head in the right hippocampus. Positive correlations were found between symptom improvement and the pretreatment volumes of the right thalamus (r = 0.501; P = 0.001) and left subiculum head of the hippocampus (r = 0.471; P = 0.002), and changes in the volumes of the left amygdala (r = −0.452; P = 0.003) and the left cornu ammonis 4 body (r = −0.537; P < 0.001). Our findings provided evidence for critical roles of the amygdala and specific hippocampal subfields in the antidepressant effect of repeated ketamine treatment. Relatively larger volumes in right thalamus and left subiculum head in the hippocampus can predict a superior clinical outcome of ketamine treatment in MDD patients.

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Section: Methodsmentioning

confidence: 99%

“…The data were obtained from a clinical trial (clinical trial number: ChiCTR-OOC-17012239) that examined the antidepressant effects of repeat ketamine treatment in depressed individuals 12,23,24 . This project started in September 2016 and is ongoing.…”

Section: Participantsmentioning

confidence: 99%

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

Zhou

Liu

et al. 2020

Transl Psychiatry

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“…Previously reported studies have shown that higher peripheral levels of Shank3 and IL-6 as well as lower levels of adiponectin at baseline could predict antidepressant efficacy after administration of a single ketamine dose 32,57,58 . Our previous study showed that changes in KYN pathway metabolite levels were correlated with the treatment response after repeated infusions 30 . In this study, we first found that lower baseline levels of ITAC were predictive of symptom improvement following six ketamine administrations.…”

Section: Predictors Of Treatment Responsementioning

confidence: 95%

“…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 . In addition, a recent study demonstrated that a single ketamine infusion in patients with TRD could decrease the level of TNF-α, which was correlated with the antidepressant efficacy 31 .…”

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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“…Plus récemment, des études ont montré que l’augmentation de QUIN était corrélée aux manifestations dépressives chez les souris et que le traitement préalable par kétamine était en mesure d’empêcher l’apparition de l’état dépressif [61] . Chez des patients déprimés répondeurs à la kétamine, l’augmentation des concentrations de KYNA 24 h après la première perfusion étaient corrélées à l’amélioration des symptômes dépressifs à la fin de la cure [62] . Enfin, dans une approche translationnelle, il a été montré que les cellules microgliales, qui sont activées suite à l’injection de LPS chez la souris, présentent des modifications morphologiques et métaboliques suite à l’administration de kétamine, avec une baisse de la production d’IL6 et une augmentation du ratio KYNA/QUIN.…”

Section: Quels Mécanismes ?unclassified

Psychotropes du futur : de l’imipramine à la kétamine

Carrillo

Petit

Gaillard

et al. 2020

Bulletin de l'Académie Nationale de Médecine

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Depuis les années 1950, l’arsenal thérapeutique permettant de lutter contre la dépression s’est considérablement enrichi. De la découverte des inhibiteurs de la monoamine oxydase (IMAO) à celle de la kétamine, ces percées pharmacologiques ont marqué l’histoire de la psychiatrie et guidé la recherche sur la physiopathologie de la dépression, cette pathologie dévastatrice affectant entre 10 et 20 % de la population mondiale. Nous proposons dans cet article une courte revue historique des différentes options thérapeutiques développées au cours du siècle passé et des conséquences qu’ont eu ces innovations. Nous réalisons ensuite un état des lieux de la plus récente de ces découvertes, celle des effets antidépresseurs de la kétamine (et de son énantiomère S, l’eskétamine), spectaculaires de par leur délai d’apparition et leur efficacité même dans les formes les plus résistantes de dépression. De même que la découverte des IMAO et des tricycliques a permis de concevoir une théorie monoaminergique de la dépression, l’étude des mécanismes d’actions de la kétamine pourrait permettre de comprendre le rôle de la transmission glutamatergique ou de la neuro-inflammation dans la neurobiologie de cette pathologie, d’affiner nos connaissances sur sa physiopathologie cognitive ou encore de transformer en profondeur les représentations des cliniciens sur cette maladie.

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Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression

Cited by 68 publications

References 29 publications

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

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

Psychotropes du futur : de l’imipramine à la kétamine

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