Sleep disturbance and kynurenine metabolism in depression

Abstract

Objective Although the interrelationships between sleep disturbance, inflammation, and depression have been found, molecular mechanisms that link these conditions are largely unknown. Kynurenine metabolism is hypothesized to be a key mechanism that links inflammation and depression. Inflammation activates the kynurenine pathway, leading to increases in 3-hydroxykynurenine (3HK) and quinolinic acid (QA), potentially neurotoxic metabolites, and decreases in kynurenic acid (KynA), a potentially neuroprotective compound. This relative neurotoxic shift in the balance of kynurenine metabolites has been associated with depression, but never been examined regarding sleep disturbance. We tested the association between sleep disturbance and this relative neurotoxic shift in 68 currently depressed, 26 previously depressed, and 66 never depressed subjects. Methods Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Putative neuroprotective indices reflecting the relative activity of neuroprotective and neurotoxic kynurenine metabolites were calculated as KynA/QA and KynA/3HK (primary outcomes). Results Sleep disturbance was associated with reduced KynA/QA in the currently depressed group only (unadjusted beta −0.43, p<0.001). This association remained significant even after controlling for age, sex, analysis batch, body-mass index, and depressive symptoms in currently depressed subjects (adjusted beta −0.30, p=0.02). There was no significant association between sleep disturbance and KynA/3HK in any of the groups. Sleep disturbance was associated with increased C-reactive protein in currently depressed subjects only (unadjusted beta 0.38, p=0.007; adjusted beta 0.33, p=0.02). Conclusion These data support the hypothesis that altered kynurenine metabolism may molecularly link sleep disturbance and depression.

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats

“…Stimulation of the enzymes TDO and/or IDO, by elevations in corticosterone or immunological activation that occurs with stress reactivity respectively 16 , 53 , is thought to activate KP metabolism by promoting the catabolism of tryptophan. These effects could also play a role in enhanced inflammation with sleep-loss 54 , and contribute to misbalance in the KP in health and disease processes 12 , 55 . Importantly, our present data draw additional attention to sex as an important biological variable in KP studies 12 , 13 , 56 , 57 , and introduce a novel interplay between the HPA responses to sleep deprivation and downstream KP metabolism.…”

“…Sleep disturbances in patients with schizophrenia and depression may aggravate the severity of the disorders and often negatively impact the patients’ quality of life 59 . Conceivable hypotheses suggest that cognitive impairments and abnormalities in sleep are connected, and the potential contribution of KYNA in mechanistically mediating a relationship between sleep and cognition in schizophrenia patients remains under investigation 55 , 60 .…”

The key role of insomnia and sleep loss in the dysregulation of multiple systems involved in mood disorders: A proposed model

“…In a recent study conducted in a group of depressed individuals, poor sleep quality was associated with an increase in CRP and with an alteration in kynurenine metabolism. The authors hypothesized that the latter finding may be the molecular link between poor sleep quality and depression (Cho et al., ). These findings are also supported by experimental sleep deprivation studies in humans.…”

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…Schizophrenia, for example, has been linked closely with kynurenic acid concentrations in the CNS (Stone and Darlington ; Cho et al ; Plitman et al ; Erhardt et al 2017; Ogyu et al ; Laumet et al ; Dantzer et al ; Kindler et al ). In schizophrenia, the concentration of kynurenate in the brain is elevated above normal and nucleotide polymorphisms of kynurenine pathway enzymes have been identified (Wonodi and Schwarcz ; Holtze et al ; Stone and Darlington ; Erhardt et al ; Hahn et al ).…”