Targeting inflammation in depression: Ketamine as an anti-inflammatory antidepressant in psychiatric emergency

Major depressive disorder (MDD) is a common, heterogeneous psychiatric condition with complex, multifactorial aetiology. The Introduction summarises emerging evidence from psychoneuroimmunology that links dysregulated inflammatory processes to MDD and to poorer response to conventional antidepressants. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, impaired glucocorticoid signalling, peripheral immune activation (for example increased neutrophils, monocytes, cytokines and C‑reactive protein), and inflammatory activation of the kynurenine pathway are described as mechanisms that may drive neuroinflammation, reduce serotonin availability and produce neurotoxic metabolites that contribute to depressive symptoms and suicidality. The resulting picture is of an inflammatory subtype of depression that is over-represented among patients with treatment‑resistant depression (TRD) and active suicidal ideation. This review by Nikkheslat sets out to examine ketamine’s rapid antidepressant properties alongside its effects on peripheral and central inflammation, with the goal of better understanding whether ketamine’s anti‑inflammatory actions contribute to its clinical efficacy in psychiatric emergency settings. The author frames the need for rapid‑acting interventions that can address both severe depressive symptoms and inflammation-driven TRD, emphasising the clinical urgency for alternatives to conventional antidepressants in patients with imminent suicide risk.

The extracted text does not present a formal Methods section or an explicit description of search strategy, inclusion criteria, databases, or dates for literature identification. From the prose, the paper appears to be a narrative review synthesising findings from clinical trials, preclinical (animal and in vitro) studies, and prior meta-analyses, and the author refers to "our recent systematic review" and ongoing clinical trials from the research group. Because details of literature selection, risk-of-bias assessment, and analytic approach are not reported in the extracted text, it is not possible to reconstruct a reproducible methods pipeline for evidence retrieval or to evaluate how comprehensive the review was. The review instead summarises key clinical trial results, mechanistic preclinical data, perioperative immunomodulation studies, and biomarker findings relevant to ketamine’s antidepressant and anti‑inflammatory effects.

Antidepressant efficacy and temporal profile: Clinical trials and meta-analytic data summarised in the review indicate that low-dose ketamine produces a rapid antidepressant effect detectable within hours. Early placebo‑controlled trials reported symptom alleviation within 72 hours after a single infusion; subsequent randomised trials found onset as early as 2 hours, peaking around 24 hours, with approximately 35% of patients maintaining benefit for about 1 week after a single infusion. Repeated intravenous infusions produced cumulative and more sustained responses in responders. Ketamine has also demonstrated rapid reductions in suicidal ideation: single infusions reduced suicidal thoughts within about 40 minutes and effects have been reported to persist hours to days, with repeated dosing sustaining benefit for up to 12 days in some reports. Meta-analytic evidence confirms a rapid reduction in suicidal ideation within one day and up to one week after ketamine, in part independent of its antidepressant effect. Mechanistic findings: The review emphasises NMDA receptor antagonism as a central mechanism: ketamine blocks NMDA receptors on GABAergic interneurons, leading to disinhibition of glutamate release, AMPA receptor activation, increased brain-derived neurotrophic factor (BDNF) release, and downstream synaptogenesis via TrkB and mTOR signalling. Preclinical work links ketamine’s synaptogenic and behavioural effects to mTOR activation, and some clinical data exploring mTOR blockade (rapamycin) give mixed results. Ketamine’s rapid antidepressant action is also attributed to de‑suppression of BDNF translation via eukaryotic elongation factor 2 kinase, modulation of multiple neurotransmitter systems (dopaminergic, serotonergic, adrenergic, cholinergic), interaction with opioid signalling, and activity of metabolites such as hydroxynorketamines. The review notes that S‑ketamine (esketamine) is a more potent NMDA antagonist, has received FDA approval for TRD and for MDD with acute suicidal ideation or behaviour, and has demonstrated rapid onset and relapse‑prevention effects when used adjunctively. Adverse effects and limitations of use: Ketamine commonly elicits acute, transient adverse effects including dissociative symptoms, transient blood pressure elevation and tachycardia, perceptual disturbances and potential urological toxicity. A meta-analysis of single subanaesthetic intravenous doses found most adverse symptoms peaked within 1 hour, resolved by 2 hours and none persisted beyond 4 hours in the trials analysed; however, the long‑term safety of repeated or routine clinical use has not been fully established. Concerns about psychotomimetic effects, abuse liability and the need for clinic‑based administration (particularly for intravenous routes) are emphasised as barriers to widespread outpatient use. Animal data suggest R‑ketamine may have a more favourable efficacy and side‑effect profile than S‑ketamine, but clinical confirmation is lacking. Anti‑inflammatory properties: The review compiles perioperative, in vitro, animal and clinical evidence that ketamine modulates immune function. In surgical contexts, intraoperative ketamine reduced early postoperative IL‑6 responses and preserved certain immune functions. In vitro and ex vivo studies show ketamine inhibits lipopolysaccharide (LPS)‑induced production of proinflammatory cytokines (TNF‑α, IL‑6, IL‑1β, IL‑8) in human whole blood, macrophages, microglia and astrocytes. In animal depression models, ketamine reversed stress‑induced increases in hippocampal IL‑1β, IL‑6 and TNF‑α, reduced activated microglia counts, and acted via pathways including TLR4/p38 signalling and down‑regulation of P2X7 receptor to suppress cytokine synthesis and release. Clinical signals linking inflammation to ketamine response include associations between baseline adipokines or IL‑6 and subsequent antidepressant response, and a trial where rapid suppression of TNF‑α correlated with symptom improvement. The review notes a dose‑relationship: anti‑inflammatory effects were observed more clearly at 0.5 mg/kg than at 0.2 mg/kg, whereas antidepressant effects can occur at lower doses, suggesting multiple mechanisms across dose ranges. Kynurenine pathway and neurotoxic metabolites: Ketamine’s interactions with the kynurenine pathway are highlighted as a potential anti‑inflammatory antidepressant mechanism. Clinical and post‑mortem data in suicidal patients show abnormalities in kynurenine metabolites (lower CSF kynurenic acid, higher quinolinic acid) linked to NMDA receptor agonism and neurotoxicity; ketamine has been associated with increases in kynurenic acid and reductions in quinolinic acid activity, and preclinical data suggest ketamine can block quinolinic acid effects at NMDA receptors. These effects provide a mechanistic bridge between inflammation, glutamatergic dysfunction and ketamine’s therapeutic actions. Limitations of the evidence: The review acknowledges heterogeneity in findings and limited clinical data for some mechanistic claims. Some clinical studies report contradictory results for inflammatory markers, and direct causal mediation by inflammatory changes has not been conclusively established.

Nikkheslat and colleagues interpret the assembled evidence to suggest that ketamine’s rapid antidepressant and anti‑suicidal actions are plausibly linked, at least in part, to its anti‑inflammatory and immunomodulatory effects in addition to its glutamatergic and neuroplasticity actions. The author positions these findings within prior literature by noting stronger, more consistent mechanistic support from preclinical models and mixed but promising clinical signals, including biomarker associations and perioperative immunomodulation studies. Key uncertainties and limitations highlighted include the lack of large, long‑term clinical trials specifically designed to test inflammation‑mediated mechanisms, some contradictory clinical biomarker findings, the short durability of single ketamine doses requiring repeated administration, and safety concerns related to psychotomimetic effects and abuse potential. The review also points out that much of the mechanistic detail comes from animal or in vitro work, and that stereoisomer differences observed preclinically (for example apparent advantages of R‑ketamine) have not yet been validated in clinical populations. For future research and clinical translation, the author recommends larger clinical studies that comprehensively measure peripheral inflammatory markers, HPA axis biomarkers, and full kynurenine pathway metabolites to characterise the inflammatory phenotype and to test whether rapid changes in inflammatory markers mediate clinical response. Comparative studies of ketamine stereoisomers, especially clinical investigation of R‑ketamine, are urged. The review further suggests that identifying patients with elevated inflammation who might preferentially benefit from ketamine could support personalised treatment approaches and inform development of next‑generation rapid‑acting antidepressants that combine anti‑inflammatory and antidepressant mechanisms.

The review concludes that ketamine is a promising rapid‑acting antidepressant whose anti‑inflammatory properties may be particularly relevant for treating inflammatory‑related TRD and acute suicidal ideation. The author calls for greater clinical investigation—larger, biomarker‑rich trials and stereoisomer comparisons—to validate preclinical findings, clarify mechanisms, and guide personalised use. Improved characterisation of inflammatory status, HPA axis function and kynurenine metabolites is recommended to determine whether rapid modulation of inflammation mediates ketamine’s therapeutic effects and to inform the development of safer, effective rapid‑acting agents.