Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Park, Minkyung; Newman, Laura; Gold, Philip W.; Luckenbaugh, David A.; Yuan, Peixiong; Machado‐Vieira, Rodrigo; Zarate, Carlos A.

doi:10.1016/j.jpsychires.2016.09.025

Cited by 75 publications

(60 citation statements)

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“…Moreover, serum levels of the proinflammatory cytokines tumor necrosis factor-a, interferon g, and interleukin 2, 5, and 10 were unaltered following a 40-minute i.v. subanesthetic infusion of ketamine (0.5 mg/kg) in patients suffering from depression, whereas levels of the anti-inflammatory cytokine IL-6 were reported to increase 230 minutes postketamine infusion (Park et al, 2017). However, this effect of ketamine on IL-6 levels was not associated with the antidepressant actions of the drug (Park et al, 2017).…”

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confidence: 99%

“…subanesthetic infusion of ketamine (0.5 mg/kg) in patients suffering from depression, whereas levels of the anti-inflammatory cytokine IL-6 were reported to increase 230 minutes postketamine infusion (Park et al, 2017). However, this effect of ketamine on IL-6 levels was not associated with the antidepressant actions of the drug (Park et al, 2017). It is possible that the infusion itself led to an acute stress-related increase in IL-6 levels, given that this has been observed following saline infusion as well (Cho et al, 2009).…”

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Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

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Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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“…Thus, the rapid anti‐inflammatory actions of ketamine might contribute to its rapid antidepressant effects. Conversely, changes in the IL‐6 levels after ketamine infusion were not associated with the antidepressant response . Furthermore, several pro‐inflammatory cytokines exhibited significant changes in the blood of treatment‐resistant MDD patients after ketamine injection .…”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 89%

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Hashimoto

2019

Psychiatry Clin Neurosci

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Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.

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“…This is similar to findings with ketamine treatment, in which higher levels of IL-6 at baseline were found to predict a more favorable response to ketamine, 34 though this was not replicated in a subsequent study. 35 In contrast, elevated markers of inflammation are associated with an attenuated response to antidepressant medications. 13,14,16,17 Together, these data suggest the possibility that certain treatment interventions for depression may in part be mechanistically dependent on inflammation, or that different subtypes of depression (i.e., inflammatory vs. non-inflammatory) may respond to one treatment approach but not another.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression

Kruse¹,

Congdon²,

Olmstead³

et al. 2018

J. Clin. Psychiatry

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Objective Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6) predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment resistant depression, and to what extent this association differed between men and women. Methods In patients (n=29) with a current major depressive episode diagnosed using DSM-IV-TR criteria, undergoing ECT at an academic referral center, levels of CRP, IL-6, IL-8, tumor necrosis factor (TNF)-α, and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale, MADRS) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between 12/2011 and 12/2014. The primary outcome was end-of-treatment MADRS score. Results In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (p=0.01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (p=0.02) but not men (p=0.1), and CRP emerged as a significant predictor for women (p=0.04) but not men (p=0.66). CRP and IL-6 increased from baseline to the second ECT session (p’s<0.01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. Conclusions Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pre-treatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment resistant depression.

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Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Cited by 75 publications

References 25 publications

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression

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