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

Highlights

• Plasma KYN/TRP (IDO) is increased in suicidal adolescents with MDD.

• Plasma TRP is decreased in suicidal adolescents with MDD.

• KYN/TRP (IDO) differences were enhanced when medicated adolescents were excluded.

• TRP and KYN/TRP (IDO) were similar in acutely and previously suicidal adolescents.

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 (3-HAA), 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.

Introduction

Suicide is among the most serious health problems for children and adolescents in the United States. According to a recent report by the Centers for Disease Control and Prevention (CDC), suicide has become the second leading cause of death among children aged 12–17 years after non-intentional injuries and ahead of homicides and malignancies (Perou et al., 2013). The two most prominent risk factors for completed suicide in youth are a past suicide attempt and a diagnosis of a depressive episode, each independently representing a 10–30 fold increased risk for completed suicide (Shaffer et al., 1996). Consequently, depressed adolescents with a past suicide attempt are at high risk for completion of suicide (Brent et al., 1993).

There has been sparse research into the neurobiology of suicide. Clinical and postmortem work has mainly focused on the monoamine system, documenting serotonin (5-HT) and dopamine deficiency with limited progress on the contributory biology. Over the past decade there has been a shift in research from the monoamine system to complex mechanisms that induce neuroplasticity impairment, such as inflammation and glutamatergic excitotoxicity. The neuroimmunological kynurenine pathway (KP) is hypothesized to play a key role in such processes, linking peripheral inflammation and glutamate disturbances (Laugeray et al., 2010). The KP (illustrated in Fig. 1) is activated by the enzyme indoleamine 2,3-dioxygenase (IDO), which is induced by pro-inflammatory cytokines and is the rate-limiting enzyme of the pathway. IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby reducing TRP availability for 5-HT synthesis. KYN by itself is not neuroactive, but crosses the blood brain barrier to generate free-radical-producing 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) or the glutamatergically active kynurenine metabolite quinolinic acid (QUIN). Conversely, KYN can also be metabolized into kynurenic acid (KA), which is a glutamate receptor antagonist, constituting the neurotrophic branch of the KP. Converging evidence dating back to the 1970s has implicated the KP neurotoxic branch with major depressive disorder (MDD) (Curzon and Bridges, 1970, Heyes et al., 1992, Laugeray et al., 2010). Work from our laboratory documented relationships between KP activation and anhedonia (Gabbay et al., 2010a, Gabbay et al., 2012) in adolescents with MDD. More recently, the KP has been associated specifically with suicidality in adults (Sublette et al., 2011, Erhardt et al., 2013, Bay-Richter et al., 2015). Findings included elevated cerebrospinal fluid (CSF) QUIN levels in suicide attempters across psychiatric disorders compared to healthy control adults (Erhardt et al., 2013, Bay-Richter et al., 2015). However, these studies did not include a non-suicidal psychiatric group and thus, findings may be related to the psychiatric condition rather than the suicidal behavior. In a separate study, plasma KYN, TRP, and IDO (indexed by KYN/TRP) were examined, with only KYN levels elevated in depressed patients with a history of suicide attempt compared to those who had never attempted suicide (Sublette et al., 2011). However, there was no acutely suicidal subgroup.

Based on the above observations, we sought to examine the KP in depressed suicidal adolescents, composed of both past attempters and those who expressed active suicidal intent, compared to non-suicidal depressed adolescents and healthy controls (HC). Hypotheses were that depressed suicidal adolescents would exhibit increased KP activation, indexed by increased IDO (quantified by KYN/TRP), KYN and 3-HAA, and decreased TRP. Since psychotropic medications are known to have anti-inflammatory effects (Kostadinov et al., 2014, Liu et al., 2014, Obuchowicz et al., 2014), analyses were repeated while excluding medicated participants. Finally, we explored whether KP metabolites differed between subgroups of depressed adolescents who were actively suicidal and those with prior attempts, both of which were included in the suicidal group.