Evanthia C. Wommack

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.

Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy

Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted.

What does plasma CRP tell us about peripheral and central inflammation in depression

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma ( n  = 89) and CSF ( n  = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p  < 0.05), and a strong correlation was found between plasma and CSF CRP ( r  = 0.855, p  < 0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p  < 0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM ( r  = 0.236, p  = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia ( r  = 0.301, p  = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder

BACKGROUND One third of patients with major depressive disorder (MDD) fail to respond to currently available antidepressant medications. Inflammation may contribute to treatment non-response through effects on neurotransmitter systems relevant to antidepressant efficacy. In post-hoc analyses, increased concentrations of inflammatory markers prior to treatment predict poor antidepressant response. However, limited data exists on whether depressed patients with multiple failed treatment trials in their current episode of depression exhibit increased inflammation. METHODS Plasma concentrations of inflammatory markers were measured in unmedicated, medically stable patients with MDD (n = 98) and varying numbers of adequate antidepressant treatment trials in the current depressive episode as measured by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. Covariates including age, sex, race, education, body mass index (BMI) and severity of depression were included in statistical models where indicated. RESULTS A significant relationship was found between number of failed treatment trials and tumor necrosis factor (TNF), soluble TNF receptor 2 (sTNF-R2) and interleukin (IL)-6 (all p < 0.05 in multivariate analyses). Post hoc pairwise comparisons with correction for multiple testing revealed that patients with 3 or more failed trials in the current episode had significantly higher plasma TNF, sTNF-R2 and IL-6 compared to individuals with 0 or 1 trial (all p < 0.05). High sensitivity c-reactive protein was also associated with a greater number of treatment failures, but only in models with BMI excluded. CONCLUSIONS Measuring inflammatory markers and targeting inflammation or its downstream mediators may be relevant for depressed patients with multiple failed antidepressant treatment trials in their current depressive episode.

Differential regulation of NF-kB and IRF target genes as they relate to fatigue in patients with head and neck cancer

Previous studies have linked plasma inflammatory markers to elevated fatigue in patients with head and neck cancer (HNC). To identify the molecular mechanisms underlying this association, we conducted promoter-based bioinformatics analyses to determine the relationship between fatigue and specific gene expression profiles associated with inflammation in human papillomavirus (HPV)-related and -unrelated HNC patients undergoing treatment. Patients with newly diagnosed HNC without distant metastasis were assessed at baseline (pre-radiotherapy) and one-month post-radiotherapy. Fatigue was measured by the Multidimensional Fatigue Inventory. Genome-wide gene expression profiles were collected from peripheral blood mononuclear cells (PBMC). Promoter-based bioinformatics analyses were employed to identify transcription control pathways underlying transcriptomic correlates of fatigue in the sample as a whole and in HPV-related and HPV-unrelated HNC patients separately. In transcriptome profiling analyses of PBMC from 44 patients, TELiS bioinformatics analyses linked fatigue to increased nuclear factor-kappa B (NF-kB) transcriptional activity and decreased interferon regulatory factor family (IRF) transcription factor activity. Patients with HPV-related HNC showed lower levels of fatigue-related gene expression profile compared to HPV-unrelated HNC. Fatigue in HNC patients undergoing treatment is associated with gene expression profiles consistent with the conserved transcriptional response to adversity (CTRA) characterized by increased proinflammatory and decreased anti-antiviral transcriptional activity. Interestingly, this CTRA response was mitigated in patients with HPV-related HNC and may explain the lower level of fatigue they experience relative to HPV-unrelated HNC.

HPV status is associated with fatigue and inflammation in patients with squamous cell carcinoma of the Head and Neck from pre to up to 3 Months Post IMRT

This longitudinal study examined associations among HPV, inflammation and fatigue in head and neck cancer (HNC) patients receiving intensity-modulated radiation therapy (IMRT). Consented patients were followed pre-, one-month and three-month post-IMRT. Fatigue was assessed by the Multidimensional Fatigue Inventory-20. Plasma interleukin-1receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor2 (sTNFR2) were determined using Magnetic Luminex Screening Assay; acute phase proteins (CRP) were determined using a standard turbidimetric assay. Mixed effect modeling and path analysis were used to examine the associations. Ninety-four patients with newly diagnosed, locally advanced non- metastatic HNC were enrolled from 2012 to 2015; majority received concurrent chemoradiotherapy (CRT). Fifty-three percent of them were HPV+. HPV+ patients were more likely to be male, have no history of tobacco use, have higher BMI, be diagnosed with oropharyngeal cancer, and receive CRT. HPV+ patients had significant lower fatigue, and lower inflammation as represented by CRP (p