Introduction
TRD, peripheral inflammation, neuroinflammation, suicidal ideation, depressive disorder, neurotoxicity, DEPression, neurotoxic, MDD, depression, Suicidality, suicidality
OXIDATIVE STRESS
Suicidality is a frequent clinical feature of major depressive disorder (MDD) and a major global health problem. Alongside psychosocial factors, various biological mechanisms have been implicated in increasing the risk of suicide and suicidal behaviour (The KP is an essential pathway in the metabolism of the serotonin precursor, tryptophan, and is strictly regulated by immune activation. Under normal conditions, a proportion of tryptophan is metabolized to kynurenine, which, in turn, is transformed by astrocytic kynurenine aminotransferases into kynurenic acid (KynA). KynA has been suggested to have neuroprotective effects, including anti-inflammatory mechanisms, reduction in glutamate excitotoxicity and enhancement of synaptic plasticity (KP neurotoxic metabolites include 3-hydroxykynurenine (3HK) and quinolinic acid (QUIN). Prior studies have found that 3HK activates neuronal apoptosis and increases the concentration of oxygen reactive species (As an indication of IDO activation and KP dysregulation, previous works have used the increased kynurenine/tryptophan (KYN/TRP) ratio in plasma. Interestingly, an increased KYN/TRP (with increased KYN levels and lower TRP levels) has been found in individuals with MDD and a history of suicidality when compared with those without such history or with healthy controls (Overall, the activation of the KP is believed to be an important mechanism linking peripheral inflammation to the onset of depression, through the production of neurotoxic metabolites, neuroinflammation and oxidative stress (Previous preclinical research suggested that anti-inflammatory medications (such as non-steroidal anti-inflammatory drugs), as well as antidepressants with anti-inflammatory effects (e.g. venlafaxine), may exert an antidepressant effect by decreasing the levels of peripheral inflammation and by inhibiting tryptophan 2,3 dioxygenase (the other enzyme which activates the KP) (The antibiotic minocycline has been shown to inhibit the KP in preclinical studies. For instance, in rats injected with lipopolysaccharide, the administration of minocycline appeared to block IDO indirectly, by attenuating lipopolysaccharide-induced pro-inflammatory response and thus preventing the development of depressive-like behaviours (Interestingly, minocycline showed the ability to pass the blood–brain barrier, which would facilitate neuroprotective properties (With the present work, we aimed to (1) replicate previous evidence on the association between KP and suicidality in a sample of outpatients with TRD selected for increased peripheral inflammation (MINocycline in DEPression (MINDEP) study). We hypothesized that individuals with suicidal ideation would show increased IDO activity, as reflected by increased KYN/TRP ratio and increased levels of neurotoxic metabolites such as QUIN; (2) explore the association between metabolites ratios of the KP, indicating a KP diversion towards neurotoxicity and markers of peripheral inflammation and (3) explore the effect of 4-week treatment with minocycline on suicidality and KP metabolites in the same sample of patients. We hypothesized that minocycline would reduce the number of patients with suicidal ideation from baseline to week 4 of treatment and that this would be mediated by changes in the KP metabolites.