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Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

ABSTRACT: Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP?5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation.

SUBMITTER: Weinberger JF

PROVIDER: S-EPMC4468009 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Weinberger Jeremy F JF Raison Charles L CL Rye David B DB Montague Amy R AR Woolwine Bobbi J BJ Felger Jennifer C JC Haroon Ebrahim E Miller Andrew H AH

Brain, behavior, and immunity 20141218

Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n ...[more]

PMID: 25529904

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Project description:Background:Listeria monocytogenes is historically a central nervous system pathogen of consideration in the very young, very old, and immune suppressed. Diagnosis of Listeria is based on positive bodily fluid culture or PCR testing. Cerebral edema is nonspecific and can be a manifestation of vasculitis, trauma, anoxia, ischemia, infarction, malignancy, or an infectious process. A main mechanism of immune protection against Listeria is tumor necrosis factor (TNF). Lenalidomide, an immunosuppressant, inhibits TNF. Case Presentation. A 61-year-old female with diabetes mellitus 2 and multiple myeloma treated with stem cell transplant and immunosuppressant (lenalidomide) was found to have cerebral edema after presenting with headache for 3?weeks and new focal neurologic deficits. Vitals signs were stable, with no meningeal exam findings and unremarkable initial serum testing. Blood cultures on days 0 and 2 of hospitalization as well as cerebral spinal fluid cultures were negative for infectious organisms. PCR testing of CSF was also negative for microorganisms. Brain biopsy was scheduled but postponed due to outstanding prion testing. The patient's focal neurologic deficits worsened prompting administration of dexamethasone after extensive negative infectious disease workup. By day 6, gross neurologic function deteriorated prompting transfer to higher level of care where the patient spiked a fever and one set of blood cultures revealed Gram-positive bacillus. Aggressive antimicrobial therapy was initiated, excluding ampicillin; however, this was later added. Blood culture further identified Listeria monocytogenes. By day 17, the patient suffered demise. Autopsy revealed brain microabscess lesions consistent with Listeria. Conclusion:Clinicians should employ prophylactic antimicrobial treatment for Listeria when caring for those patients presenting with cerebral edema who are immune suppressed with TNF inhibition no matter the initial exam findings, serum testing, and/or radiologic interpretation. If initial workup is negative and brain biopsy is needed to determine the next course of action in the patient with cerebral edema, transfer the patient to a higher level of care if unable to complete biopsy at your facility in an expedient fashion.

Project description:Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants.To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response.Double-blind, placebo-controlled, randomized clinical trial.Outpatient infusion center at Emory University in Atlanta, Georgia.A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method.Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial.The 17-item Hamilton Scale for Depression (HAM-D) scores.No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (?50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups.This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.clinicaltrials.gov Identifier: NCT00463580.

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Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Publications

Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

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