Publications by authors named "Andrew H Miller"

179 Publications

Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 18. Epub 2021 Apr 18.

Emory University School of Nursing.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to <0.001). A non-linear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (when BMI<35,p=0.04) or increased BMI (when BMI≥35,p=0.01), was linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio (HR)=1.11,95% CI=[1.03,1.18],p=0.004; HR=1.10,95% CI=[1.01,1.19], p=0.02, for EAA at 6-months and 12-months post-treatment, respectively), PFS (HR=1.10, 95% CI=[1.02,1.19], p=0.02; HR=1.14, 95% CI=[1.06,1.23], p<0.001; HR=1.08,95% CI=[1.02,1.14], p=0.01, for EAA before, end, and 6-months post-radiotherapy, respectively), and QOL over time (β=-0.61,p=0.001). An average of 3.25-3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrences compared to those who did not (all p<0.001).

Conclusion: Compared to demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
April 2021

Point of care ultrasound facilitated diagnosis of right ventricular mass as the etiology of syncope; A case report of intravenous leiomyomatosis.

Radiol Case Rep 2021 Jun 28;16(6):1288-1293. Epub 2021 Mar 28.

Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida Morsani College of Medicine, Lehigh Valley Campus, Cedar Crest Boulevard & I-78, Allentown PA 18103, USA.

Syncope is a common emergency department (ED) chief complaint. Rarely, syncope can be the result of right ventricular outflow obstruction from an intracardiac tumor, such as an intracardiac extension of intravenous leiomyomatosis (IVL). Typically, this type of tumor is confined to the pelvic veins, but in very rare cases, it can extend through the inferior vena cava into the right atrium. Point-of-care ultrasound (POCUS) can be a crucial tool in the ED for identifying intracardiac tumors presenting as syncope and expediting clinical management. We present the case of a 39-year-old female with no prior medical history that presented to the ED having experienced dyspnea on exertion and two syncopal episodes prior to ED admission. POCUS use in the ED elucidated the presence of a right atrial mass and further imaging showed a mass on the patient's uterus. After surgical removal of a portion of the atrial mass, a subsequent biopsy revealed it had leiomyoma-like features; as such, the patient was diagnosed with IVL. This case illustrates the importance of using POCUS in the ED to help determine the etiology of syncope. Although intracardiac extensions of IVL are rare, it is important for emergency physicians to keep this diagnosis in the differential in patients with symptoms or risk factors suggestive of IVL with intracardiac extension.
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http://dx.doi.org/10.1016/j.radcr.2021.02.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026911PMC
June 2021

Remembering Bruce S. McEwen - A tribute from psychoneuroimmunology.

Brain Behav Immun 2021 May 29;94:11-14. Epub 2021 Jan 29.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States.

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http://dx.doi.org/10.1016/j.bbi.2021.01.018DOI Listing
May 2021

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV.

J Neurovirol 2021 Feb 6;27(1):160-167. Epub 2021 Jan 6.

Department of Psychiatry, University of California, La Jolla, San Diego, CA, USA.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II > 22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.
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http://dx.doi.org/10.1007/s13365-020-00925-1DOI Listing
February 2021

Prognostic implications of depression and inflammation in patients with metastatic lung cancer.

Future Oncol 2021 Jan 11;17(2):183-196. Epub 2020 Dec 11.

Department of Psychiatry & Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Lung cancer-related inflammation is associated with depression. Both elevated inflammation and depression are associated with worse survival. However, outcomes of patients with concomitant depression and elevated inflammation are not known. Patients with metastatic lung cancer (n = 123) were evaluated for depression and inflammation. Kaplan-Meier plots and Cox proportional hazard models provided survival estimations. Estimated survival was 515 days for the cohort and 323 days for patients with depression (hazard ratio: 1.12; 95% CI: 1.05-1.179), 356 days for patients with elevated inflammation (hazard ratio: 2.85, 95% CI: 1.856-4.388), and 307 days with both (χ = 12.546; p < 0.001]). Depression and inflammation are independently associated with inferior survival. Survival worsened by inflammation is mediated by depression-a treatable risk factor.
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http://dx.doi.org/10.2217/fon-2020-0632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857340PMC
January 2021

Physician-directed smoking cessation using patient "opt-out" approach in the emergency department: A pilot program.

J Am Coll Emerg Physicians Open 2020 Oct 6;1(5):782-789. Epub 2020 Jul 6.

Department of Medicine Lehigh Valley Hospital and Health Network/University of South Florida Morsani College of Medicine Lehigh Valley Campus Allentown Pennsylvania USA.

Objective: Using a physician-directed, patient "opt-out" approach to prescriptive smoking cessation in the emergency department (ED) setting, we set out to describe patient actions as they related to smoking cessation behaviors.

Methods: A convenience sample of smokers at 2 Pennsylvania hospital EDs who met inclusion/exclusion criteria were approached to participate in a brief intervention known as screening, treatment initiation, and referral (STIR) counseling that included phone follow-up. Demographic information, current smoking status, and specific physician prescription and follow-up recommendations were collected. Approximately 3 months later, patients were contacted to determine current smoking status and actions taken since their ED visit.

Results: One hundred six patients were approached and 7 (6.6%) opted out of the intervention. Patients who did not opt out were evaluated for appropriate use of smoking cessation-related medications; 35 (35.4%) opted out of the prescription(s) and 6 (6.1%) were not indicated. Twenty-one (21.2%) patients opted out of ambulatory referral follow-ups with primary care and/or tobacco treatment program; one (1.0%) was not indicated for referral. Nineteen (32.8%) patients who received prescription(s) for smoking cessation-related medications initially also followed the prescription(s). Seventeen (22.1%) patients participated in referral follow-up.

Conclusion: In this small ED pilot, using the STIR concepts in an opt-out method, few smokers opted out of the smoking cessation intervention. About one-third of the patients declined prescriptions for smoking cessation-related medications and less than one-quarter declined ambulatory referrals for follow-up. These findings support a willingness of patients to participate in STIR and the benefits of intervention in this setting.
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http://dx.doi.org/10.1002/emp2.12176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593453PMC
October 2020

Exercise and Cognitive Training Intervention Improves Self-Care, Quality of Life and Functional Capacity in Persons With Heart Failure.

J Appl Gerontol 2020 Oct 13:733464820964338. Epub 2020 Oct 13.

Emory University, Atlanta, GA, USA.

This study evaluated a 12-week, home-based combined aerobic exercise (walking) and computerized cognitive training (EX/CCT) program on heart failure (HF) self-care behaviors (Self-care of HF Index [SCHFI]), disease specific quality of life (Kansas City Cardiomyopathy Questionnaire [KCCQ]), and functional capacity (6-minute walk distance) compared to exercise only (EX) or a usual care attention control (AC) stretching and flexibility program. Participants ( = 69) were older, predominately female (54%) and African American (55%). There was significant improvement in self-care management, (2, 13) = 5.7, < .016; KCCQ physical limitation subscale, (2, 52) = 3.4, < .039; and functional capacity (336 ± 18 vs 388 ± 20 m, < .05) among the EX/CCT participants. The underlying mechanisms that EX and CCT targets and the optimal dose that leads to improved outcomes are needed to design effective interventions for this rapidly growing population.
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http://dx.doi.org/10.1177/0733464820964338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041896PMC
October 2020

A Longitudinal Analysis of Inflammation and Depression in Patients With Metastatic Lung Cancer: Associations With Survival.

Biol Res Nurs 2020 Sep 22:1099800420959721. Epub 2020 Sep 22.

Department of Psychiatry and Behavioral Sciences, 423828Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Depression and inflammation are concomitantly elevated in patients with lung cancer and may have collective survival implications. However, the longitudinal relationship between depression and inflammation in patients with metastatic lung cancer is not fully appreciated. We hypothesized that longitudinal changes in inflammation and depression would be concordant; that longitudinally elevated inflammation would lead to greater depression over time; and that depression with inflammation would be more persistent than depression without inflammation.

Methods: Patients with metastatic lung cancer (n = 68) were assessed for clinically significant depression (Hospital Anxiety and Depression Scale ≥ 8) and inflammation (C-Reactive Protein ≥ 1 mg/L) along with demographic variables. Survival estimations were made using Cox Proportional Hazard Model and Kaplan-Meier plot analyses.

Results: At baseline (T1), 15% had depression and 35% had increased inflammation followed by 18% with depression and 38% with increased inflammation 4.7 months later (T2). The odds ratio of depression in the presence of clinically significant inflammation was 4.8 at T1 and 5.3 at T2. Between time points, inflammation difference correlated with depression difference (r = -.26, = .03). Significant depression at was associated with a 4 fold risk of inferior survival while significant inflammation at was associated with >3 fold risk of inferior survival.

Conclusions: Depression and inflammation track together over time and have variable implications on survival. Persistent depression is particularly detrimental but incidental inflammation is more sensitive to predicting poor survival. These findings have implications for treating depression early in the lung cancer trajectory.
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http://dx.doi.org/10.1177/1099800420959721DOI Listing
September 2020

Trial failures of anti-inflammatory drugs in depression.

Lancet Psychiatry 2020 10;7(10):837

Centre for Affective Disorders, Stress, Psychiatry and Immunology Laboratory and Section of Perinatal Psychiatry, National Institute for Health Research, and Maudsley Biomedical Research Centre, King's College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(20)30357-6DOI Listing
October 2020

Gut Microbiome Associated with the Psychoneurological Symptom Cluster in Patients with Head and Neck Cancers.

Cancers (Basel) 2020 Sep 6;12(9). Epub 2020 Sep 6.

School of Nursing, Yale University, New Haven, CT 06477, USA.

Cancer patients experience a cluster of co-occurring psychoneurological symptoms (PNS) related to cancer treatments. The gut microbiome may affect severity of the PNS via neural, immune, and endocrine signaling pathways. However, the link between the gut microbiome and PNS has not been well investigated in cancer patients, including those with head and neck cancers (HNCs). This pilot study enrolled 13 patients with HNCs, who reported PNS using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (CTCAEs). Stool specimens were collected to analyze patients' gut microbiome. All data were collected pre- and post-radiation therapy (RT). Associations between the bacterial abundances and the PNS clusters were analyzed using the linear discriminant analysis effect size; functional pathway analyses of 16S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The high PNS cluster had a greater decrease in microbial evenness than the low PNS cluster from pre- to post-RT. The high and low PNS clusters showed significant differences using weighted UniFrac distance. Those individuals with the high PNS cluster were more likely to have higher abundances in phylum , order , class , and four genera (, and ), while the low PNS cluster had higher abundances in family and three genera (, and ). Both glycan metabolism (Lipopolysaccharide biosynthesis) and vitamin metabolism (folate biosynthesis and lipoic acid metabolism) were significantly different between the high and low PNS clusters pre- and post-RT. Our preliminary data suggest that the diversity and abundance of the gut microbiome play a potential role in developing PNS among cancer patients.
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http://dx.doi.org/10.3390/cancers12092531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563252PMC
September 2020

Early childhood adversity in adult patients with metastatic lung cancer: Cross-sectional analysis of symptom burden and inflammation.

Brain Behav Immun 2020 11 11;90:167-173. Epub 2020 Aug 11.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States.

Objective: Psychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation.

Methods: Patients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation.

Results: ECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression.

Conclusion: ECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.
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http://dx.doi.org/10.1016/j.bbi.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544656PMC
November 2020

Identifying Immunophenotypes of Inflammation in Depression: Dismantling the Monolith.

Biol Psychiatry 2020 07;88(2):136-138

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.04.024DOI Listing
July 2020

Association Among Glucocorticoid Receptor Sensitivity, Fatigue, and Inflammation in Patients With Head and Neck Cancer.

Psychosom Med 2020 06;82(5):508-516

From the School of Nursing (Xiao, Knobf), Yale University, Orange, Connecticut; and School of Nursing (Eldridge, Chico, Bruner), School of Medicine (Beitler, Higgins, Saba, Shin), and Department of Psychiatry and Behavioral Sciences, School of Medicine (Felger, Wommack, Miller), Emory University, Atlanta, Gerogia.

Objective: Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment.

Methods: HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used.

Results: In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity.

Conclusions: Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.
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http://dx.doi.org/10.1097/PSY.0000000000000816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905992PMC
June 2020

Depression-free after Interferon-α exposure indicates less incidence of depressive disorder: A longitudinal study in Taiwan.

Brain Behav Immun 2020 08 17;88:125-131. Epub 2020 May 17.

College of Medicine, China Medical University, Taichung, Taiwan; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan.

Background: IFN-α-induced depression in patients undergoing hepatitis C virus (HCV) treatment provides powerful support for the inflammation hypothesis of depression. Most studies have focused on the occurrence of depressive symptoms, but there has been no study yet in depression-free HCV patients receiving IFN-α. We hypothesized that HCV patients who did not develop depression after IFN-α exposure might have a lower incidence of depressive disorders after the IFN-α treatment.

Methods: We conducted a twelve-year population-based cohort study of chronic HCV patients who received IFN-α therapy. The data were obtained from the Taiwan National Health Insurance Research Database. The study cohort was patients without any depressive disorder nor antidepressant use before and during IFN-α therapy. They were matched randomly by age, sex income and urbanization at a ratio of 1:4 with the control cohort of HCV patients without IFN-α therapy. The follow-up started after the last administration of IFN-α, and the primary outcome was the incidence of depressive disorders after IFN-α therapy.

Results: A total of 20,468 depression-free subjects were identified from records of HCV patients receiving IFN-α therapy. Patients without IFN-α-induced depression were associated with a significantly lower incidence (per 10,000 person-years) of new-onset depressive disorders (126.8, 95% Confidential Interval [CI] of 118.5-135.6) as compared to the control cohort (145.2, 95% CI of 140.0-150.6) (p < 0.001). After adjusting for age, sex, income, urbanization and comorbid diseases, the crude hazard ratio for the incident depressive disorder was 0.87 (95% CI, 0.80-0.87) and the adjusted hazard ratios was 0.79 (95% CI, 0.72-0.87) for IFN-α-induced depression-free subjects as compared to the controls.

Discussion: Our study indicates that IFN-α treated depression-free patients have a lower risk for depressive disorders. This hypothesized mechanism might derive from an IFN-α-induced resilience factor as yet to be defined.

Conclusions: Our study might suggest a new possibility for a new pharmacological strategy against depression.
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http://dx.doi.org/10.1016/j.bbi.2020.05.044DOI Listing
August 2020

Posttraumatic stress disorder and breast cancer: Risk factors and the role of inflammation and endocrine function.

Cancer 2020 07 6;126(14):3181-3191. Epub 2020 May 6.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.

A breast cancer diagnosis can be a life-changing and stressful experience that can lead to chronic mental health conditions such as posttraumatic stress disorder (PTSD). Greater than one-third of patients initially diagnosed with PTSD after a diagnosis of breast cancer continue to have persistent or worsening PTSD symptoms after 4 years. An emerging body of literature has indicated several key environmental and biological risk factors for PTSD among survivors of breast cancer. Well-recognized risk factors include having a history of childhood trauma, being nonwhite, obesity, younger age at the time of diagnosis, diagnosis with a higher stage of breast cancer, and short time since treatment. Of the emerging risk factors related to fear circuitry in the brain, 2 pathways of particular importance are the stress-driven activation of inflammatory pathways and the long-term effect of antiendocrine therapies. These central and peripheral responses during and after stress exposure are important because increased fear and anxiety can lead to the maintenance of PTSD and worse patient outcomes. Given the poor outcomes associated with PTSD and the high prevalence of breast cancer in women, more research to identify those women at heightened risk of PTSD after breast cancer is warranted to reduce the number of diagnoses and lessen the negative impact of this chronic mental health condition.
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http://dx.doi.org/10.1002/cncr.32934DOI Listing
July 2020

Depression and Inflammation in Patients With Lung Cancer: A Comparative Analysis of Acute Phase Reactant Inflammatory Markers.

Psychosomatics 2020 Sep - Oct;61(5):527-537. Epub 2020 Apr 2.

Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: Depression and inflammation are intertwined, which is particularly relevant for patients with lung cancer who have an abundance of inflammation and experience depression. Acute phase reactants (APRs), albumin and C-reactive protein (CRP), are easily interpretable indirect markers of inflammation that have never been concomitantly compared with depression. Inflammation increases CRP (positive APR) and decreases albumin (negative APR). We hypothesize that albumin will be similarly associated with depression, thereby helping to inform the diagnosis of inflammatory depression.

Objective: Compares the relationship between depression and representative positive and negative acute phase reactants in patients with metastatic lung cancer.

Methods: Patients (n = 109) with metastatic lung cancer were evaluated for depression using the Hospital Anxiety and Depression Scale. Inflammation as measured by positive (CRP) and negative (albumin) APRs along with demographic and treatment variables were analyzed for associations with depression.

Results: Depression was associated with lower albumin (r = -0.35, P < 0.001), higher CRP (r = 0.47, P < 0.001), and the CRP/albumin ratio (r = 0.45, P < 0.001). Hierarchical linear regression modeling found that albumin was associated with depression when controlling for demographics, disease, and treatment types (β = -0.28, P = 0.01). When both APRs were in the model, only CRP predicted depression (β = 0.31, P = 0.01), and albumin did not moderate CRP and depression. CRP/albumin ratio did not add to understanding depression variability, but patients with both low albumin and high CRP had particularly severe depression.

Conclusion: Albumin is associated with depression but not to a greater extent than CRP. The coupling of lower albumin and higher CRP describes more severe depression. Positive and negative APRs may form a distinct biologic signature to help identify patients with inflammatory depression in the lung cancer setting.
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http://dx.doi.org/10.1016/j.psym.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529727PMC
April 2020

Pilot study of combined aerobic and resistance exercise on fatigue for patients with head and neck cancer: Inflammatory and epigenetic changes.

Brain Behav Immun 2020 08 21;88:184-192. Epub 2020 Apr 21.

School of Nursing, Emory University, 1520 Clifton Road NE, Atlanta 30322, United States.

This pilot study examined whether a combined aerobic resistance exercise program reduced fatigue and the potential inflammatory and epigenetic mechanisms in patients with head and neck cancer (HNC) receiving intensity-modulated radiotherapy. The exercise group (N = 12) received a 3-month supervised aerobic resistance exercise intervention that was initiated before a 6-week radiotherapy regimen; the control group (N = 14) received standard care. Fatigue was measured using Multidimensional Fatigue Inventory-20; physical function measures included a 6-minute walk distance (6MWD), chair stands, bicep curls, and hand grip strength. Inflammatory markers and DNA methylation data were acquired using standardized protocol. Patients were mostly white (93%) and male (81%) with a mean age of 57 years. At the end of the intervention, the exercise group had a marginal decrease in fatigue compared with the control (-5.0 vs. 4.9; P = 0.10). The exercise group had a significantly greater improvement in 6MWD (29.8 vs. -55.5 m; P = 0.04), and a marginally smaller decline in hand grip (-0.3 vs. -5.8 lbs; P = 0.05) at the end of the intervention than the control. No significant difference in inflammatory markers was observed between groups. Lower plasma interleukin (IL) 6, IL1 receptor antagonist, tumor necrosis factor α (TNFα), soluble TNF receptor II and C-reactive protein were significantly associated with increased 6MWD, chair stand, and bicep curl at the end of the intervention (p < 0.05). Among the 1152 differentially methylated sites (DMS) after intervention (p < 0.001), 163 DMS were located in gene promoter regions. Enrichment analysis suggested that the top 10 upstream regulators were associated with tumor (HNF4A, RPP38, HOXA9, SAHM1, CDK7, NDN, RPS15) and inflammation (IRF7, CRKL, ONECUT1). The top 5 diseases or functions annotations of the 62 hypermethylated DMS indicated anti-tumor and anti-inflammatory effects that might be linked to exercise. These findings suggest that exercise may improve physical performance and reduce fatigue, which could be further linked to decreased inflammation, during active radiotherapy for HNC patients. Larger studies are warranted.
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http://dx.doi.org/10.1016/j.bbi.2020.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415514PMC
August 2020

Tumor Mutation Burden and Depression in Lung Cancer: Association With Inflammation.

J Natl Compr Canc Netw 2020 04;18(4):434-442

Department of Psychology, Fordham University, Bronx, New York.

Background: Patients with lung cancer with greater systemic inflammation have higher rates of depression. Tumor mutation burden (TMB) predicts immunotherapy response in patients with lung cancer and is associated with intratumoral inflammation, which may contribute to systemic inflammation and depression. This study evaluated whether higher TMB was associated with increased depression and systemic inflammation in patients with lung cancer.

Patients And Methods: Patients with metastatic lung cancers were evaluated for depression severity using the Hospital Anxiety and Depression Scale. TMB was measured using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Inflammation was evaluated using C-reactive protein (CRP) level and neutrophil-to-lymphocyte ratio (NLR).

Results: A total of 96 patients with adequate TMB testing were evaluated. The average number of mutations (TMB) was 10.8 (SD, 10.9). A total of 19% of patients endorsed clinically significant depression symptoms. TMB was significantly correlated with depression severity (r = 0.34; P=.001) and NLR (r = 0.37; P=.002) but not CRP level (r = 0.19; P=.07). TMB was also higher in patients receiving chemotherapy (mean, 12.0) and immunotherapy (mean, 14.4) versus targeted therapy (mean, 4.8). A multivariate model found that TMB (β = 0.30; P=.01) and CRP level (β = 0.31; P=.01) were independently associated with depression; there was no significant interaction effect of TMB × CRP and depression. A similar multivariate model showed no independent effect for NLR and depression (β = 0.16; P=.17) after accounting for TMB.

Conclusions: These data provide evidence for biologic depression risk in patients with lung cancer who have high levels of TMB. The underlying mechanism of the association is not clearly related to inflammation but warrants further analysis to broadly elucidate the mechanism of biologically derived depression in cancer.
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http://dx.doi.org/10.6004/jnccn.2019.7374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327956PMC
April 2020

Inflammatory markers are associated with psychomotor slowing in patients with schizophrenia compared to healthy controls.

NPJ Schizophr 2020 Apr 1;6(1). Epub 2020 Apr 1.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA.

Patients with schizophrenia exhibit psychomotor deficits that are associated with poor functional outcomes. One pathway that may be associated with psychomotor slowing is inflammation. Inflammatory markers have been shown to be elevated in patients with schizophrenia and are associated with psychomotor deficits in both animal and human studies. Forty-three patients with schizophrenia and 29 healthy controls were recruited and underwent a battery of psychomotor tasks. The following immune measures in peripheral blood were assayed: IL-6, IL-1 beta, IL-10, TNF, MCP-1, IL-6sr, IL-1RA, and TNFR2. Generalized linear models were used to determine which immune markers, in addition to their interaction with diagnosis, were associated with performance on the psychomotor tasks. As expected, patients with schizophrenia demonstrated slower performance compared with healthy controls on the finger tapping test (FTT, tested on dominant and non-dominant hands), trail making test (TMT), and symbol coding test (SC). Interactive effects with diagnosis were found for TNF, IL-10, IL-6sr, and TNFR2 for the FTT (dominant), IL-10 and IL-6sr for FTT (non-dominant), TNF and IL-10 for TMT and TNF, IL-10, IL-6sr, TNFR2, and IL-1RA for SC. The results of this study provide evidence that peripheral inflammatory markers contribute to psychomotor slowing in patients with schizophrenia. These data are consistent with a growing literature, demonstrating that inflammation may target the basal ganglia to contribute to psychomotor deficits as is seen in other psychiatric disorders such as depression. These data also indicate that psychomotor speed may be a relevant construct to target in studies of the immune system in schizophrenia.
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http://dx.doi.org/10.1038/s41537-020-0098-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113262PMC
April 2020

Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia.

Brain Behav Immun 2020 08 18;88:161-165. Epub 2020 Mar 18.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.
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http://dx.doi.org/10.1016/j.bbi.2020.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415632PMC
August 2020

Complication of otitis media leads to opisthotonos in a toddler.

Am J Emerg Med 2020 06 17;38(6):1296.e5-1296.e7. Epub 2020 Jan 17.

Lehigh Valley Health Network, Department of Emergency and Hospital Medicine/USF, Morsani College of Medicine, Cedar Crest Boulevard & I-78, Allentown, PA 18103, USA.

Opisthotonos, extreme involuntary neck and back extension, is rarely seen in modern emergency departments. Vaccines have prevented the most common causes of this clinical presentation. Alternatively, otitis media is one of the most common pediatric infections and is characteristically non-invasive and harmless. In exceedingly rare cases, otitis media can develop complications and progress to invasive pneumococcal diseases including mastoiditis and meningitis. Streptococcus pneumoniae accounts for the majority of otitis media infections, however, since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) otitis media and its complications have decreased significantly. The present case reports of a previously healthy and immunized child presenting to a pediatric emergency department (PED) with opisthotonos, and was found to have pneumococcal meningitis, bacteremia and mastoiditis arising from otitis media.
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http://dx.doi.org/10.1016/j.ajem.2020.01.028DOI Listing
June 2020

Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression.

Neuropsychopharmacology 2020 05 15;45(6):998-1007. Epub 2020 Jan 15.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.
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http://dx.doi.org/10.1038/s41386-020-0607-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162907PMC
May 2020

Beyond depression: the expanding role of inflammation in psychiatric disorders.

Authors:
Andrew H Miller

World Psychiatry 2020 Feb;19(1):108-109

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.

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http://dx.doi.org/10.1002/wps.20723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953590PMC
February 2020

Chronic inflammation in the etiology of disease across the life span.

Nat Med 2019 12 5;25(12):1822-1832. Epub 2019 Dec 5.

Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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http://dx.doi.org/10.1038/s41591-019-0675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147972PMC
December 2019

Full axillary lymph node dissection and increased breast epidermal thickness 1 year after radiation therapy for breast cancer.

J Surg Oncol 2019 Dec 8;120(8):1397-1403. Epub 2019 Nov 8.

Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia.

Background: We previously reported a prospective study showing axillary lymph node dissection (ALND) is associated with increased breast skin thickening during and 6 weeks post-radiation therapy (RT), and now report ALND's long-term impact at 1 year.

Methods: Among 66 women who received whole breast RT after lumpectomy, objective ultrasound measurements of epidermal thickness over four quadrants of the treated breast were measured at five time points: before RT, week 6 of RT, and 6 weeks, 6 months, and 1 year post-RT. Skin thickness ratio (STRA) was generated by normalizing for corresponding measurements of the contralateral breast.

Results: A total of 2,436 ultrasound images were obtained. Among 63 women with evaluable data at 1 year, mean STRA significantly increased at 6 months (absolute mean increase of 65%, SD 0.054), and remained elevated at 1 year post-RT (absolute mean increase of 44%, SD 0.048). In multivariable analysis, ALND compared to sentinel lymph node biopsy, longer interval between surgery and RT, increased baseline STRA, and Caucasian race predicted for more severe changes in STRA at 1 year compared to baseline (all P < .05).

Conclusions: In the setting of whole breast RT, our findings suggest that ALND has long-term repercussions on breast skin thickening.
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http://dx.doi.org/10.1002/jso.25757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015418PMC
December 2019

Complement Activation During Early Pregnancy and Clinical Predictors of Preterm Birth in African American Women.

J Perinat Neonatal Nurs 2019 Oct/Dec;33(4):E15-E26

Emory University, Atlanta, Georgia.

Complement activation is essential for select physiologic processes during pregnancy; however, excess activation has been associated with an increased risk for preterm birth (PTB). African American (AA) women experience disproportionately higher rates of inflammation-associated PTB than other groups of women; thus, the purpose of this study was to explore the relationship between complement activation and perinatal outcomes among AA women. A plasma sample was collected between 8 and 14 weeks' gestation from a cohort of healthy AA women (N = 144) enrolled in a larger PTB cohort study. Medical record review was conducted to collect information on clinical factors (cervical length, health behaviors, gestational age at delivery). Multiple regression analysis was used to explore the relationships between complement marker (C3a/Bb) concentrations and the outcomes of interest after adjusting for baseline characteristics. C3a/Bb concentrations were not significant predictors of the gestational age at delivery, cervical length, or behavioral risk factors for PTB in this sample. Complement markers may not influence pregnancy outcomes among AA women in the same way as in predominantly white populations; however, more studies are needed to define complement dysregulation and the relationship with outcomes among AA women.
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http://dx.doi.org/10.1097/JPN.0000000000000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818745PMC
April 2020

Instruments for determining clinically relevant fatigue in breast cancer patients during radiotherapy.

Breast Cancer 2020 Mar 6;27(2):197-205. Epub 2019 Sep 6.

Department of Radiation Oncology Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: This study aimed to determine radiotherapy (RT)-related changes in cancer-related fatigue (CRF), using Multidimensional Fatigue Inventory-20 (MFI-20), and fatigue-intensity rating (FIR) instruments at three different timepoints and to identify the optimal thresholds of MFI-20 scores which would correlate with moderate-to-severe fatigue warranting an intervention in breast cancer patients treated with RT.

Methods: Eighty-eight breast cancer patients treated with surgery followed by RT were included in the study. CRF was assessed with both FIR and MFI-20 tools at three different timepoints: within the week prior to RT (pre-RT), last week of RT, and 6 weeks after RT completion (post-RT). Changes in measurements, correlations between measurements and optimal cutpoints of MFI-20 scores were analyzed.

Results: While FIR scores significantly changed over time (η: 0.179), changes in MFI-20 scores were relatively small (η: 0.076). Comparisons of the last week of RT versus post-RT scores showed small-to-moderate decrease for MFI-20 and FIR. FIR and MFI-20 scores were correlated at all timepoints and most correlated during and after RT (r = 0.525 95%CI 0.346-0.667, r = 0.791 95%CI 0.692-0.860 and r = 0.716 95%CI 0.589-0.808, respectively). Furthermore, the most correlated MFI-20 subscale with FIR was general fatigue (r = 0.603 95%CI 0.442-0.725, r = 0.821 95%CI 0.734-0.881 and r = 0.754 95%CI 0.641-0.835, respectively). Optimal cutpoints of the MFI-20 total scores corresponding to FIR scores ≥ 4 was 43.5 for all timepoints and the MFI total scores corresponding to FIR score ≥ 7 were 53.5, 52.5 and 60.5, respectively.

Conclusions: MFI-20 and FIR scores are highly correlated measures of CRF among breast cancer patients treated with RT. An MFI-20 score of ≥ 43.5 is suggested as a clinically significant score indicating moderate-to-severe fatigue, while an MFI score of ≥ 52.5 is indicative of severe fatigue.
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http://dx.doi.org/10.1007/s12282-019-01008-8DOI Listing
March 2020

Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.

Brain Behav Immun 2019 08 9;80:657-666. Epub 2019 May 9.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address:

Major depressive disorder is a heterogeneous disease involving widespread disruptions in functional brain networks, the neurobiological mechanisms of which are poorly understood. Amassing evidence supports innate immune activation as one pathophysiologic mechanism contributing to depression in a subgroup of patients with elevated inflammatory markers. Although inflammation is known to alter monoamine and glutamate neurotransmitters, little work has been done to understand its role in network dysfunction in patients with depression. Here we conducted a large-scale network-based analyses of resting-state functional magnetic resonance imaging (rfMRI) data acquired from depressed patients with varying levels of inflammation to develop a comprehensive characterization of network alterations as an effect of inflammation. Complementary approaches of global brain connectivity and parcellation-based network analysis applied to the whole brain revealed that increased plasma C-reactive protein (CRP) was associated with reduced functional connectivity in a widely-distributed network including ventral striatum, parahippocampal gyrus/amygdala, orbitofrontal and insular cortices, and posterior cingulate cortex. These broad alterations were centralized in the ventral medial prefrontal cortex (vmPFC), representing a hub for the effects of inflammation on network function in the whole brain. When feeding the identified multivariate network features into a machine learning algorithm of support vector regression, we achieved high prediction accuracies for depressive symptoms that have been associated with inflammation in previous studies including anhedonia and motor slowing. These findings extend and broaden previous observations from hypothesis-driven studies, providing further support for inflammation as a distinct contributing factor to network dysfunction and symptom severity in depression.
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http://dx.doi.org/10.1016/j.bbi.2019.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660411PMC
August 2019

Depression and inflammation among epidermal growth factor receptor (EGFR) mutant nonsmall cell lung cancer patients.

Psychooncology 2019 07 15;28(7):1461-1469. Epub 2019 May 15.

Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: Depression is highly prevalent in nonsmall cell lung cancer (NSCLC) and is associated with elevated inflammation. However, certain subtypes of driver mutation-associated NSCLC such as epidermal growth factor receptor (EGFR)-mutated NSCLC may be associated with less depression given the differences in their underlying biology and disease trajectories. Biological variables such as inflammation, measured by C-reactive protein (CRP), may provide insight into depression variability in EGFR mutant NSCLC.

Methods: Patients with EGFR mutant and wild-type metastatic NSCLC were evaluated for depression using the Hospital Anxiety and Depression Scale (HADS) on a continuous scale and meeting depression screening criteria (HADS ≥ 8). Inflammation was measured using CRP. A mediation model was created to understand how inflammation mediates EGFR wild-type associated depression.

Results: One hundred out of 120 patients with NSCLC were recruited (83.3% response rate). The 20 participants with EGFR mutant NSCLC had less depression (HADS-D 3.0 versus 5.4) (P < .001), met depression screening criteria less often (P = .047), and exhibited less inflammation (CRP = 0.23 mg/mL versus 2.71 mg/mL) (P < .001) in comparison with EGFR wild-type NSCLC. Multivariate linear regression model revealed that only CRP predicted depression (P = .015) while controlling for age and sex. Mediation analysis found that lower CRP partially mediated less depression in EGFR mutant NSCLC.

Conclusions: EGFR mutant NSCLC is associated with less depression but the relationship is partially mediated by lower CRP-related inflammation, which is a stronger predictor of depression than EGFR status. Depression in lung cancer varies by subtype and is significantly related to inflammation.
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http://dx.doi.org/10.1002/pon.5097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610756PMC
July 2019

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive.

Trends Cogn Sci 2019 05 2;23(5):435-448. Epub 2019 Apr 2.

Department of Psychiatry and Behavioral Sciences and The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.

Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can't) versus preference (won't) for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.
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http://dx.doi.org/10.1016/j.tics.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839942PMC
May 2019