Discussion
ideation, suicidal ideation, peripheral inflammation, inflammation, immune-related depression, MDD suicidal ideation, neurotoxic, depressed, MDD, depression, suicidality
INFLAMMATION, SECONDARY
Our study showed that individuals with suicidal ideation have a higher KYN/TRP ratio than those without suicidal ideation and that higher levels of pro-inflammatory markers are associated with an activation of the neurotoxic branch of KP. Compared with placebo, in the minocycline group, the proportion of patients with suicidal ideation halved from baseline to week 4 (showing trend levels of significance, Our findings of an association between increased KP activation and suicidal ideation are consistent with previous studies conducted in MDD. Several biological mechanisms have been suggested to link the KP to suicidal ideation. One hypothesis is that KP mediates the communication between peripheral and central inflammation, which has been suggested to play a role in the development of MDD suicidal ideation and has been observed in patients with suicidal history (Moreover, the KP dysregulation induced by inflammatory processes leads to a depletion of serotonin and melatonin (Consistent with some of the above-mentioned studies, we found an association between KP metabolites ratios indicating a neurotoxic diversion of the KP and inflammatory markers in our sample of patients at baseline. This is a further confirmation of the role of KP in linking inflammation to depression and suggests that a subpopulation of patients with immune-related depression who are non-responsive to standard antidepressants might benefit from KP-targeted investigations and treatment. This is also in line with previous clinical evidence of a correlation between increased peripheral inflammation and increased KP activation in depressed individuals. In particular, TNF and CRP have been found to be the inflammatory markers most closely associated with plasma concentrations of KYN and KYN/TRP (We noted that in patients with baseline suicidal ideation, KYN/TRP tended to decrease over time (although not significantly) in the minocycline group. Furthermore, by week 4, the minocycline group showed a reduction in the proportion of participants with suicidal ideation, compared with the placebo group (although this was also at trend levels). However, we could not find a significant effect of minocycline in affecting the KP metabolites, either in those with or in those without suicidal ideation. This could be due to the short duration of this trial (4 weeks). Indeed, our study did not detect robust changes in inflammatory markers from baseline to week 4 (Indeed, CRP levels ⩾ 3 mg/dL have been associated with no-response to standard antidepressants in patients with MDD (This study was limited by the small sample size. However, the secondary aims analyses were designed as explorative. Another limitation is that the levels of some KP metabolites (e.g., KynA) were below detectable threshold for most participants, so we could not include them in the analyses, even though we were able to identify important findings with the metabolites that were available. Finally, we excluded from the trial people with active and concerning suicidal ideation. This means that severely suicidal patients were not included, and that our subset of participants with suicidal ideation mainly had suicidal thoughts, without clear plans to act on them. This also means that our findings might reflect an association of increased KT ratio with the severity of depression, directly linked to suicidality, more than with suicidality per se. Unfortunately, we could not further explore this possibility in our sample, but future studies could attempt to clarify this. Indeed, it is possible that including participants with more severe suicidal ideation could lead to the identification of a stronger role of both KP and minocycline in suicidality. Finally, future studies might use more detailed questionnaires such as the Columbia Suicide Severity Rating Scale (CSSR-S) to capture different aspects of suicidality and its association with the KP.