Hyong Jin Cho1, Jonathan Savitz2, Robert Dantzer3, T Kent Teague4, Wayne C Drevets5, Michael R Irwin6. 1. Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. Electronic address: hjcho@mednet.ucla.edu. 2. Laureate Institute for Brain Research, Tulsa, OK, United States; Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, United States. 3. Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States. 4. Department of Surgery, University of Oklahoma College of Medicine, Tulsa, OK, United States. 5. Janssen Pharmaceuticals of Johnson & Johnson, Titusville, NJ, United States. 6. Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
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.
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 neurotoxickynurenine 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.
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