The role of the kynurenine pathway in suicidality in adolescent major depressive disorder

Abstract

The neuroimmunological kynurenine pathway (KP) has been implicated in major depressive disorder (MDD) in adults and adolescents, most recently in suicidality in adults. The KP is initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN) en route to neurotoxins. Here, we examined the KP in 20 suicidal depressed adolescents—composed of past attempters and those who expressed active suicidal intent—30 non-suicidal depressed youth, and 22 healthy controls (HC). Plasma levels of TRP, KYN, 3-hydroxyanthranilic acid, and KYN/TRP (index of IDO) were assessed. Suicidal adolescents showed decreased TRP and elevated KYN/TRP compared to both non-suicidal depressed adolescents and HC. Findings became more significantly pronounced when excluding medicated participants, wherein there was also a significant positive correlation between KYN/TRP and suicidality. Finally, although depressed adolescents with a history of suicide attempt differed from acutely suicidal adolescents with respect to disease severity, anhedonia, and suicidality, the groups did not differ in KP measures. Our findings suggest a possible specific role of the KP in suicidality in depressed adolescents, while illustrating the clinical phenomenon that depressed adolescents with a history of suicide attempt are similar to acutely suicidal youth and are at increased risk for completion of suicide.

Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

“…For instance, Sublette et al [22] found no relation between serum concentrations of TRY and suicidal behavior but did find lower levels of KYN among suicidal versus nonsuicidal subjects, whereas Bryleva and Brundin [4] found lower levels of serum TRY among suicidal depressed patients. Another study found lower circulating concentrations of TRY, but also increased KYN and a lower ratio of TRY/KYN among suicidal depressed adolescents [23]. We, instead, found higher plasma concentrations of TRY and a much lower ratio of TRY/KYN with unipolar and bipolar major depression.…”

“…Findings of less circulating TRY and more KYN have been proposed as evidence of the decreased production of serotonin in association with depression [2,7,21,23]. This hypothesized greater efficiency of converting TRY to KYN might, in turn, reflect increased activity of the KYN-synthesizing enzyme indoleamine-2,3-dioxygenase, perhaps through the influence of increased production of glucocorticoids, cytokines, and other inflammatory peptides that can occur with major depression [34].…”

“…Notably, serum concentrations of such metabolites were significantly increased (QA), decreased (KA and picolinic acid), or showed no differences (3-hydroxyanthranilic acid) in subjects who had recently attempted suicide when compared to nonsuicidal but depressed controls [4,5,23].…”

Functional domains as correlates of suicidality among psychiatric inpatients

“…However, when entered together into a regression model, our analyses confirmed independent roles only for anhedonia and entrapment. Past studies have also documented associations between anhedonia and suicidal behaviors in adults and youth with diverse psychiatric conditions (Bradley et al, 2015; Fawcett et al, 1990; Kollias et al, 2008; Nock and Kazdin, 2002; Spijker et al, 2010; Winer et al, 2014). Similarly, imaging studies report abnormalities within the reward circuitry in suicide behavior (Gifuni et al, 2015; Kim et al, 2015; Wagner et al, 2011).…”

“…Addressing this challenge, the Research Domain Criteria (RDoC) project was launched where systems based on cognitive, behavioral and neuronal mechanisms are the focus of investigation rather than a DSM classified psychiatric disorder (Cuthbert, 2015). Relatedly, several suicide studies from our laboratory and others have examined specific symptoms that reflect corresponding disturbances in functional domains, such as anhedonia (Bradley et al, 2015; Fawcett et al, 1990; Gabbay et al, 2015; Kollias et al, 2008; Nock and Kazdin, 2002; Spijker et al, 2010; Winer et al, 2014), anxiety/entrapment (Goldston et al, 1996; Goldston et al, 2006; Hendin et al, 2010; O’Connor et al, 2013; Ohring et al, 1996; Panagioti et al, 2012; Sareen et al, 2005a; Sareen et al, 2005b; Yaseen et al, 2012; Yaseen et al, 2014), and attachment disturbances (Adam et al, 1996; Grunebaum et al, 2010; Lessard and Moretti, 1998; Lizardi et al, 2011; Palitsky et al, 2013). In particular, anhedonia reflects disturbance in reward processing including reward motivation (Auerbach et al, 2015; Gold et al, 2013), attainment (Liu et al, 2016), and learning (Pizzagalli et al, 2008; Pizzagalli et al, 2005); entrapment reflects response to acute threat in the context of frustrative nonreward (Gilbert and Allan, 1998); state and trait anxiety reflect acute sensitivity to and chronic vigilance for threat, respectively (Bishop, 2009; Jusyte et al, 2015); finally, fearful attachment represents disturbance in the social systems involved in affiliation (Safran, 1990; Yaseen et al, 2016).…”