Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review

This literature review (2021) explores ketamine’s anti-inflammatory properties and tryptophan-kynurenine (KYN) pathway in patients with unipolar and bipolar depression as well as in animal models of depression. It found that ketamine induces anti-inflammatory effects in at least a proportion of patients with depression and decreased activation of the KYN pathway’s neurotoxic arm.

Abstract

“Background: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its anti-inflammatory properties and subsequent downstream effects on tryptophan (TRP) metabolism have sparked research interest.

Aim: This systematic review examined the effect of ketamine on inflammatory markers and TRP–kynurenine (KYN) pathway metabolites in patients with unipolar and bipolar depression and in animal models of depression.

Methods: MEDLINE, Embase, and PsycINFO databases were searched on October 2020 (1806 to 2020).

Results: Out of 807 initial results, nine human studies and 22 animal studies on rodents met the inclusion criteria. Rodent studies provided strong support for ketamine-induced decreases in pro-inflammatory cytokines, namely in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and indicated anti-inflammatory effects on TRP metabolism, including decreases in the enzyme indoleamine 2,3-dioxygenase (IDO). Clinical evidence was less robust with high heterogeneity between sample characteristics, but most experiments demonstrated decreases in peripheral inflammation including in IL-1β, IL-6, and TNF-α. Preliminary support was also found for reduced activation of the neurotoxic arm of the KYN pathway.

Conclusion: Ketamine appears to induce anti-inflammatory effects in at least a proportion of depressed patients. Suggestions for future research include investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.”

Authors: Emma Kopra, Valeria Mondelli, Carmine Pariante & Naghmeh Nikkheslat

Summary

Introduction

Major depressive disorder (MDD) is among the leading causes of disability worldwide, contributing to high human and societal costs. Antidepressant response rates are low, and bipolar disorder (BD) has fewer available treatment options than in MDD.

Ketamine, a noncompetitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, is a fast acting antidepressant and anti-suicidal medication that can be used to treat both unipolar and bipolar depression. It has been approved as a medication for treatment-resistant MDD in nasal spray form in 2019.

Ketamine’s antidepressant effects are believed to be due to its NMDA receptor antagonist property, but the exact mechanisms are yet to be fully understood. Ketamine has also been shown to have anti-inflammatory properties.

Ketamine is a novel rapid-acting antidepressant.

Ketamine has been shown to have anti-inflammatory effects and may be able to treat depression. This is likely due to the relationship between inflammation and depression being bidirectional, with high inflammation levels increasing the risk of developing depression and vice versa.

Among the main mechanisms of depression, inflammation is suggested to induce depressive symptoms through its effects on the tryptophan – kynurenine (KYN) pathway. The KYN pathway contributes to neurotoxicity through numerous mechanisms, including glutamate excitotoxicity and increased reactive oxygen species. KynA is metabolized by kynurenine aminotransferases in astrocytes and exerts neuroprotective and anti-inflammatory effects, enhances synaptic plasticity, and clears excess glutamate in the brain.

Evidence is rapidly growing that inflammation is associated with KYN pathway abnormalities and dysregulation of KYN metabolites in patients who have committed suicide, however, the data is less robust for the whole MDD population.

Research on ketamine’s potential effect on inflammatory proteins and TRP metabolism in unipolar and bipolar depression, as well as in pre-clinical studies employing animal models of depression, has yielded mixed reports.

Search strategy

Ketamine and inflammation were searched in MEDLINE, APA PsycInfo, and Embase using the keywords Ketamine AND Depress* AND Inflammat/cytokine/interleukin/c-reactive protein/CRP/tumor necrosis factor/TNF/interferon/IFN/kynuren/KYNA/quinolinic/QUIN/QA.

Selection of literature

References were imported into the RefWorks citation manager tool for screening of results. Human studies were required to include in vivo administration of ketamine and comparison of posttreatment biomarkers between ketamine group and a control group with otherwise identical treatment but without administration of an active drug.

Quality assessment

The quality of human studies was evaluated with blinding, absence of adjunct medication, number of outcome measurement points, appropriate statistical analyses, and completeness of data and reporting. Animal studies’ quality was assessed based on depression model.

Study selection

The initial search yielded 848 results, reducing to 807 after limiting results to English language and 581 after deduplication. Nine studies were on humans and 22 on rodents, and all measured protein levels of inflammatory markers and TRP – KYN metabolites.

Six studies included MDD patients, one study included BD patients, and two studies included both. All studies administered a 0.5 mg/kg intravenous dose of ketamine, and all studies included between 2 and 7 post-infusion measurements.

Quality of studies ranged from 4 to 8 out of ten. A few studies did exploratory analyses without adjusting for multiple comparisons, and two studies provided only stratified data according to antidepressant responder status.

Inflammatory markers were measured in 19 and 18 studies, respectively. Ketamine was administered intraperitoneally with doses ranging from 5 to 20 mg/kg, except for one study with a 100 mg/kg dose and one study with an additional 90 mg/kg condition besides a lower-dose group.

Quality scoring of animal studies ranged from four to eight out of a total of eight. Key differences were the depression model used and the clarity of study protocol.

Results of individual studies and evidence synthesis

Human studies found that five out of six inflammatory proteins were decreased in at least one patient, and that two out of three studies found that IL-1 was decreased. Additionally, IL-2, IL-7, IL-10, IL-17A, fractalkine, IL-4, IL-5, and IL-12p70 were increased in one study each.

Most studies found short-term changes in markers, but some studies found long-term changes. In two studies, participants were maintained on their medications, and in one study, BD subjects were allowed mood stabilizers.

Changes in KYN metabolites were observed in two studies; increased KYN, KYNA, and KYN/KynA ratio and reduced IDO and QA/KYN ratio were observed long-term, and increased KYN was observed only in ketamine responders.

No significant ketamine-induced changes were found in KYN and TRP, but there was a trend toward decreased KYN at 2 h (p = 0.067) and KYN/TRP ratio at 24 h (p = 0.054) in responders.

Animal studies found that ketamine reduced one or more pro-inflammatory markers in 18 out of 21 studies. One study observed an unexpected surge in TNF-, and another study observed an increase in anti-inflammatory cytokine IL-10.

Four out of six studies measuring TRP metabolites found decreased inflammation in ketamine-treated mice. However, two studies found no significant differences in any metabolite of the pathway.

Ketamine reduced IL-6 in both serum and CSF, but IL-1 and TNF- in serum only. There was an indication for dose-dependency, with higher doses showing more robust effects.

Discussion

This systematic review examines the effect of ketamine on inflammation and the TRP-KYN pathway in depression in clinical as well as preclinical animal studies.

Ketamine-induced reductions of inflammatory markers were observed most commonly for the cytokines IL-1, IL-6, and TNF-, which have all been consistently found to be implicated in depressive illness. Ketamine also increases BDNF, yet it is unknown to what extent this is induced by ketamine’s anti-inflammatory effects.

In all but one study, IDO activity was found decreased, supporting ketamine’s anti-inflammatory action through decreasing pro-inflammatory cytokines and subsequently downregulating the activity of the enzyme. However, the validity of KYN/TRP ratio as a proxy for IDO activity has been challenged.

Although decreased IDO may lead to reduced synthesis of KYN, our review found no consistent evidence for changes in this metabolite. Instead, increased KYNA and decreased QUIN were found in both clinical and preclinical studies, supporting an anti-inflammatory effect and activation of KAT over KMO.

Studies with significant findings appeared either underpowered or on medicated patients. Ketamine might be less likely to show anti-inflammatory effects in nontreatment-resistant and in medicated subjects, yet many higher-quality studies only observed decreases in one or two inflammatory markers.

Ketamine reduces inflammation only if it is abnormally high, and baseline inflammation levels are likely to be higher than seen in most populations. This could be one reason why preclinical findings have not been replicated as consistently in humans.

There was evidence for dose-dependency across animal studies, and one clinical trial found anti-inflammatory effects only following 0.5 mg/kg ketamine infusion but not 0.2 mg/kg ketamine infusion. Higher ketamine doses may also trigger or augment anti-inflammatory effects in some patients.

The included human studies only measured circulating markers, which might not provide a reflection of levels in the central nervous system. Further studies examining markers in the CSF or in the brain with positron emission tomography are therefore urgently needed.

The current review has some limitations, including the small number of clinical studies and the use of animals to model complex psychiatric conditions. Further research should include more comparable inclusion criteria and methodology, and a placebo group.

Conclusion

In conclusion, the present review supports ketamine’s anti-inflammatory effects in depressed humans and rodents, and further research is needed to understand the specific molecular mechanism behind ketamine’s immunomodulatory effects.