The interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression

Abstract

Background and aims: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested. Methods: We analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients ( n = 18 minocycline; n = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time. Results: At baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman’s ρ = 0.35, p = 0.02) and IL-10, (ρ = 0.41, p = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP ( U = 143.000, p = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18). Conclusion: Increased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Kynurenine pathway and suicidal ideation in treatment-resistant depression

“…In the unlikely event that [Trp] was not decreased in the study patients, other explanations should be sought, for example, whether KAT or kynureninase was inhibited to elevate Kyn levels. The finding by Nettis et al (2023) that QA levels are increased strongly suggests that a raised [Kyn] coupled with activation of KMO and subsequently of kynureninase occur in suicidal ideation patients. The authors found that kynurenic acid (KA) was below the limit of detection.…”

“…Nettis et al (2023) reported that patients with treatment-resistant depression who exhibit suicidal ideation show a higher plasma ratio of kynurenine (Kyn) to tryptophan (Trp), which correlates with immune activation parameters. The study is clearly of interest and the authors should be commended for having measured a range of Kyn metabolites, but they have not taken advantage of the available information that could have enhanced interpretation of their findings and provided important conclusions regarding Kyn pathway (KP) dysfunction in this particular group of patients.…”

“…An increase in the [Kyn]/[Trp] ratio occurs if [Kyn] is increased, [Trp] is decreased or both. As the ratio components Kyn and Trp have been measured by Nettis et al (2023), inclusion of their levels can inform whether the KP is activated, in which case a decrease in [Trp] can be expected. As the authors state that many previous studies of MDD have demonstrated an increase in [Kyn] and a decrease in [Trp], inclusion of the authors’ Kyn and Trp data could have been confirmatory and should be provided in their response to this Letter.…”

“…Although the undetectable anthranilic acid could also imply kynureninase inhibition, the human kynureninase is far more active towards 3-hydroxykynurenine than towards kynurenine, with a ratio of 28:1 (Badawy, 2017). With the undetectable levels of KA, Nettis et al (2023) have not stated the obvious: that the QA/KA ratio will have weighed dramatically in favour of QA, glutamatergic activation and neuronal toxicity.…”

“…In conclusion, a detailed assessment of KP metabolite changes, rather than simple reliance on metabolite ratios is more likely to inform on the KP status in MDD. Nettis et al (2023) have demonstrated that the KP dysfunction in treatment-resistant depression with suicidal ideation involves enhanced conversion of Kyn to neurotoxic QA at the expense of impaired formation of the neuroprotective KA. I suggest that KMO is likely to be activated and that its inhibition should be a therapeutic target in this subgroup of MDD patients, as has indeed been suggested for the entire MDD population (Badawy et al, 2023; Dawood et al, 2022).…”