Loneliness in Posttraumatic Stress Disorder: A Neglected Factor in Accelerated Aging?

Prior research suggests that people with Posttraumatic Stress Disorder (PTSD) may experience a form of accelerated biological aging. In other populations, loneliness has been shown to elevate risk for many of the same components of accelerated biological aging, and other deleterious outcomes, as seen in people with PTSD. Although standard diagnostic criteria for PTSD include "feelings of detachment or estrangement from others", the relationship of such feelings to the concept of loneliness remains uncertain, in par potentially due to a failure to distinguish between loneliness versus objective social isolation. In order to catalyze wider research attention to loneliness in PTSD, and the potential contribution to accelerated biological aging, the present paper provides three components: (1) a conceptual overview of the relevant constructs and potential interrelationships, (2) a review of the limited extant empirical literature, and (3) suggested directions for future research. The existing empirical literature is too small to support many definitive conclusions, but there is evidence of an association between loneliness and symptoms of PTSD. The nature of this association may be complex, and the causal direction(s) uncertain. Guided by the conceptual overview and review of existing literature, we also highlight key areas for further research. The ultimate goal of this line of work is to elucidate mechanisms underlying any link between loneliness and accelerated aging in PTSD, and to develop, validate, and refine prevention and treatment efforts.

Increased Prevalence of Metabolic Syndrome in Veterans with PTSD Untreated with Antipsychotic Medications.

Post-Traumatic Stress Disorder (PTSD) is not solely a psychiatric disorder; it also includes significant medical morbidity. Although there is evidence of increased risk of metabolic syndrome (MetS) in PTSD, the interpretation of previous studies is confounded by inclusion of people on antipsychotic medications, which independently cause increased MetS. In this study we investigated whether Veterans with PTSD not treated with antipsychotic medications (n=115) demonstrate increased MetS compared to an age-comparable group of people from the U.S. National Health and Nutrition Examination Survey (NHNES; n=1005). Using standardized criteria (abnormal values in 3 out of the 5 domains of obesity, hypertension, high density lipoprotein, triglyceride and fasting glucose concentrations) we compared the prevalence of MetS across groups. Relative to the NHNES group, a significantly higher proportion of the Veteran PTSD group met criteria for MetS (26.9% vs. 41.7%) with a higher proportion of abnormal values in four out of five MetS domains (excepting glucose). Our results suggest that the elevation of MetS associated with PTSD cannot be fully explained by iatrogenic effects of antipsychotic medication. We suggest that extra attention be devoted to the clinical management of metabolic risk factors for morbidity in patients with PTSD.

Allostatic load and the cannabinoid system: implications for the treatment of physiological abnormalities in post-traumatic stress disorder (PTSD).

It is becoming clear that post-traumatic stress disorder (PTSD) is not simply a psychiatric disorder, but one that involves pervasive physiological impairments as well. These physiological disturbances deserve attention in any attempt at integrative treatment of PTSD that requires a focus beyond the PTSD symptoms themselves. The physiological disturbances in PTSD range over many systems, but a common thread thought to underlie them is that the chronic effects of PTSD involve problems with allostatic control mechanisms that result in an excess in what has been termed "allostatic load" (AL). A pharmacological approach to reducing AL would be valuable, but, because of the large range of physiological issues involved - including metabolic, inflammatory, and cardiovascular systems - it is unclear whether there exists a simple comprehensive way to address the AL landscape. In this paper, we propose that the cannabinoid system may offer just such an approach, and we outline evidence for the potential utility of cannabinoids in reducing many of the chronic physiological abnormalities seen in PTSD which are thought to be related to excess AL.

The Potential for Renal Injury Elicited by Physical Work in the Heat.

An epidemic of chronic kidney disease (CKD) is occurring in laborers who undertake physical work in hot conditions. Rodent data indicate that heat exposure causes kidney injury, and when this injury is regularly repeated it can elicit CKD. Studies in humans demonstrate that a single bout of exercise in the heat increases biomarkers of acute kidney injury (AKI). Elevations in AKI biomarkers in this context likely reflect an increased susceptibility of the kidneys to AKI. Data largely derived from animal models indicate that the mechanism(s) by which exercise in the heat may increase the risk of AKI is multifactorial. For instance, heat-related reductions in renal blood flow may provoke heterogenous intrarenal blood flow. This can promote localized ischemia, hypoxemia and ATP depletion in renal tubular cells, which could be exacerbated by increased sodium reabsorption. Heightened fructokinase pathway activity likely exacerbates ATP depletion occurring secondary to intrarenal fructose production and hyperuricemia. Collectively, these responses can promote inflammation and oxidative stress, thereby increasing the risk of AKI. Equivalent mechanistic evidence in humans is lacking. Such an understanding could inform the development of countermeasures to safeguard the renal health of laborers who regularly engage in physical work in hot environments.

The nature of bradykinesia in schizophrenia treated with antipsychotics.

Recognizing drug-induced parkinsonian bradykinesia in psychosis patients can be challenging due to overlapping presentation with psychomotor slowing associated with depression, negative symptoms, or cognitive disturbances. In this study, we apply prior findings on the pathophysiology of bradykinesia in Parkinson's disease to gain an understanding of motor slowing in psychosis patients. Handwriting movements from 57 healthy participants and 70 psychosis patients were recorded on a digitizing tablet. Temporal and kinematic features were extracted from handwritten loops and circles. An independent objective measure based on peak velocity for circles written at maximum speed was used to classify patients as bradykinetic. Using a statistical cut-point derived from normative data, 64% of the patients met criterion for bradykinesia compared with 46% using a conventional observer-based severity rating scale. Bradykinetic patients produced handwriting movements with longer stroke durations, smaller amplitudes and lower peak velocities compared with non-bradykinetic patients. Thirty-six percent of the pen strokes produced by the bradykinetic patients were non-ballistic compare with 20% for the non-bradykinetic patients. The proportion of nonballistic movements observed in handwriting was unrelated to current antipsychotic dose, severity of negative psychosis or depression. The ease-of-use and standardization of a tablet-based approach to quantifying parkinsonian bradykinesia can aid in diagnosing parkinsonian bradykinesia in patients treated with antipsychotics.

Aging and Trauma: Post Traumatic Stress Disorder Among Korean War Veterans.

Having experienced posttraumatic stress disorder 30 years prior to its recognition as a formal disorder, Korean War veterans are now an aging population that requires unique clinical management.

A randomized controlled trial of ganaxolone in posttraumatic stress disorder.

Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3ß-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.

Progression of kidney disease in elderly stage 3 and 4 chronic kidney disease patients.

PURPOSE: The prevalence of chronic kidney disease (CKD) has been rising steadily in the elderly population. We studied the rate of progression of CKD in this population and the factors associated with progression of CKD to better identify patients who are likely to progress to ESRD. METHODS: This was an observational study including 4562 patients older than 65 years with two outpatient estimated glomerular filtration rates (eGFRs) of <60 ml/min/1.73 m2, at least 90 days apart with no intervening eGFR >60 ml/min/1.73 m2 (March 1, 2001, and March 31, 2008) at VA healthcare facilities. Patients with eGFR <15 ml/min/1.73 m2 were excluded. Annual rate of decline of eGFR was studied and categorized as <1 ml/min/1.73 m2, 1-4 ml/min/1.73 m2, and >4 ml/min/1.73 m2. RESULTS: Mean age of the study participants was 77.2 years. 24.3% were diabetics. 4.3% had proteinuria. In univariate comparison of different rates of progression, 54.2% patients had an annual rate of progression of <1 ml/min/1.73 m2. Multivariable mixed model analyses revealed that increasing age, body mass index, presence of cardiovascular disease, diabetes mellitus, and proteinuria were associated with significantly increased rate of progression of CKD. Serum albumin and hemoglobin level were inversely associated with progression of CKD. CONCLUSIONS: CKD progresses at a slower rate in the elderly population. We have identified risk factors associated with an increased risk of progression of CKD in the elderly. This may help to improve health care planning and resource utilization.

VA eScreening program: Technology to improve care for post-9/11 veterans.

The Veterans Health Administration (VHA) provides health care services to a growing number of veterans. There is ample support for the use of technology-based self-screening to support health care delivery. We developed the VA eScreening program for veterans to directly provide self-report mental and physical health information through a veteran-facing portal that communicates with the electronic medical records system. A total of 1,372 newly enrolling veterans in 2 cohorts participated in a study to assess veteran satisfaction, determine accessibility and clinical processes, measure screening differences, and examine connection to care between eScreening and paper screening. Veterans who completed eScreening were slightly more satisfied with screening than those who completed paper screening. Accessibility, rate of screening completion, and clinical processes were significantly better with eScreening than paper screening. Except for higher alcohol use in the paper-based cohort, veterans who completed paper and eScreening were similar in the rates of positive health screens. Connection to VA services, rate and speed of vesting in the health care system, and time to document required suicide risk assessments were better with the VA eScreening program than paper screening. The VA eScreening program is a unique and promising tool that may leverage limited resources to improve screening and care for veterans. (PsycINFO Database Record

Prevalence of chronic kidney disease in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

BACKGROUND: The incidence and prevalence of chronic kidney disease (CKD) continue to rise worldwide. Increasing age, diabetes, hypertension, and cigarette smoking are well-recognized risk factors for CKD. Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation leading to airway obstruction and parenchymal lung destruction. Due to some of the common pathogenic mechanisms, COPD has been associated with increased prevalence of CKD. METHODS: Systematic review of medical literature reporting the incidence and prevalence of CKD in patients with COPD using the Cochrane Collaboration Methodology, and conduct meta-analysis to study the cumulative effect of the eligible studies. We searched Medline via Ovid, PubMed, EMBASE and ISI Web of Science databases from 1950 through May, 2016. We included prospective and retrospective observational studies that reported the prevalence of CKD in patients with COPD. RESULTS: Our search resulted in 19 eligible studies of which 9 have been included in the meta-analysis. The definition of CKD was uniform across all the studies included in analysis. COPD was found to be associated with CKD in the included epidemiological studies conducted in many countries. Our meta-analysis showed that COPD was found to be associated with a significantly increased prevalence of CKD (Odds Ratio [OR] = 2.20; 95% Confidence Interval [CI] 1.83, 2.65). STUDY LIMITATIONS: Studies included are observational studies. However, given the nature of our research question there is no possibility to perform a randomized control trial. CONCLUSIONS: Patients with COPD have increased odds of developing CKD. Future research should investigate the pathophysiological mechanism behind this association, which may lead to better outcomes.

Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.

BACKGROUND: Acute interstitial nephritis secondary to proton pump inhibitors (PPIs) frequently goes undiagnosed due to its subacute clinical presentation, which may later present as chronic kidney disease (CKD). We investigated the association of PPI use with the development of CKD and death. METHODS: Two separate retrospective case-control study designs were employed with a prospective logistic regression analysis of data to evaluate the association of development of CKD and death with PPI use. The population included 99,269 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of the CKD outcome, 22,807 with preexisting CKD at the first observation in Veterans Affairs Health Care Upstate New York (VISN2) network data system were excluded. Data obtained included use of PPI (Yes/No), demographics, laboratory data, pre-PPI comorbidity variables. RESULTS: A total of 19,311/76,462 patients developed CKD. Of those who developed CKD 24.4 % were on PPI. Patients receiving PPI were less likely to have vascular disease, COPD, cancer and diabetes. Of the total of 99,269 patients analyzed for mortality outcome, 11,758 died. A prospective logistic analysis of case-control data showed higher odds for development of CKD (OR 1.10 95 % CI 1.05-1.16) and mortality (OR 1.76, 95 % CI 1.67-1.84) among patients taking PPIs versus those not on PPIs. CONCLUSIONS: Use of proton pump inhibitors is associated with increased risk of development of CKD and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications.

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury.

We report findings from a 12-week randomized double-blinded placebo-controlled trial of methylphenidate or galantamine to treat emotional and cognitive complaints in individuals (n=32) with a history of PTSD, TBI, or both conditions. In this small pilot study, methylphenidate treatment was associated with clinically meaningful and statistically significant improvement compared with placebo on the primary outcome, a measure of cognitive complaints (Ruff Neurobehavioral Inventory-Postmorbid Cognitive Scale), as well as on the secondary outcomes reflecting post-concussive (Rivermead Post Concussive Symptom Questionnaire) and post-traumatic stress symptoms (Posttraumatic Stress Disorder Checklist). Treatment was well tolerated. These results suggest the need for a larger RCT to replicate and confirm these findings. Design considerations for such a trial should include the need for multiple sites to facilitate adequate recruitment and extension of the treatment and follow-up periods.

Prevalence of various comorbidities among veterans with chronic kidney disease and its comparison with other datasets.

Chronic kidney disease (CKD) has a complicated interrelationship with various comorbidities. The purpose of this study was to describe the prevalence of various comorbidities among veterans with CKD and compare it with other datasets like Kidney Early Evaluation Program (KEEP), National Health and Nutrition Examination Survey (NHANES) and Medicare. Patients who had at least one outpatient visit in year 2007 (1 January 2007 to 31 December 2007) were included in the study (n = 75,787). Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease (MDRD) study equation. CKD prevalence was calculated based on one or two serum creatinine values at least 3 months apart. Demographic data were obtained including age, gender, race, weight, height and body mass index (BMI). The prevalence of various comorbidities was also collected based on ICD 9 codes from the problem list. The prevalence of CKD among veterans was 47.3%, much higher than estimated in the US population. Patients with CKD were more likely to have any vascular disease (36.89% vs. 14.87%), diabetes (34.18% vs. 17.83%), hypertension (86.65% vs. 57.56%), and cancer (18.69% vs. 9.23%). Irrespective of age, the prevalence of vascular disease was much higher among veterans with CKD. The prevalence of coronary artery disease, peripheral vascular disease, and cancer was much higher among elderly veterans with CKD as compared to other datasets. CKD is a growing endemic associated with a high frequency of concomitant chronic illnesses. Public health resources should be applied for early recognition and risk modification of CKD.

Renin-Angiotensin-Aldosterone System Blockers in Elderly Adults with Chronic Kidney Disease without Diabetes Mellitus or Proteinuria.

OBJECTIVES: To compare the effect of renin-angiotensin-aldosterone system (RAAS) blockers with that of other antihypertensive agents on outcomes in a cohort of elderly veterans with incident chronic kidney disease (CKD) without diabetes mellitus or proteinuria. DESIGN: Retrospective cohort study. SETTING: Veterans Affairs (VA) Upstate New York Healthcare System. PARTICIPANTS: All participants were seen in primary care clinic in Veterans Integrated Service Network 2, which comprises five VA medical centers and 29 community-based outpatient clinics, from April 2001 to April 2008. Veterans with incident CKD who were taking antihypertensive medications and did not have proteinuria or diabetes mellitus on the date of onset of CKD were selected from this population. MEASUREMENTS: The outcome variables studied were progression of kidney disease (doubling of serum creatinine level or Stage 5 CKD (estimated glomerular filtration rate <15 mL/min per 1.73 m2 )), all-cause mortality, and combined outcome. RESULTS: Analysis included 2,474 participants, 47.9% of whom were taking RAAS blockers at baseline and the rest other antihypertensives. Time-varying Cox proportional hazards analyses did not reveal a statistically significant difference in primary combined outcome in participants taking RAAS blockers and those taking other antihypertensives (hazard ratio = 1.09, 95% confidence interval = 0.93-1.27). There was also no significant effect on individual outcomes (death or progression of kidney disease). CONCLUSION: Use of RAAS blockers was not associated with less hazard of combined and individual outcomes (doubling of serum creatinine, Stage 5 CKD, death) in elderly veterans with incident CKD without diabetes mellitus or proteinuria.

The clinical challenges of akathisia.

Akathisia is one of the most vexing problems in neuropsychiatry. Although it is one of the most common side effects of antipsychotic medications, it is often difficult to describe by patients, and is difficult to diagnose and treat by practitioners. Akathisia is usually grouped with extrapyramidal movement disorders (ie, movement disorders that originate outside the pyramidal or corticospinal tracts and generally involve the basal ganglia). Yet, it can present as a purely subjective clinical complaint, without overt movement abnormalities. It has been subtyped into acute, subacute, chronic, tardive, withdrawal-related, and "pseudo" forms, although the distinction between many of these is unclear. It is therefore not surprising that akathisia is generally either underdiagnosed or misdiagnosed, which is a serious problem because it can lead to such adverse outcomes as poor adherence to medications, exacerbation of psychiatric symptoms, and, in some cases, aggression, violence, and suicide. In this article, we will attempt to address some of the confusion surrounding the condition, its relationship to other disorders, and differential diagnosis, as well as treatment alternatives.

Is Post-Traumatic Stress Disorder Associated with Premature Senescence? A Review of the Literature.

OBJECTIVE: Post-traumatic stress disorder (PTSD) has major public health significance. Evidence that PTSD may be associated with premature senescence (early or accelerated aging) would have major implications for quality of life and healthcare policy. We conducted a comprehensive review of published empirical studies relevant to early aging in PTSD. METHOD: Our search included the PubMed, PsycINFO, and PILOTS databases for empirical reports published since the year 2000 relevant to early senescence and PTSD, including: 1) biomarkers of senescence (leukocyte telomere length [LTL] and pro-inflammatory markers), 2) prevalence of senescence-associated medical conditions, and 3) mortality rates. RESULTS: All six studies examining LTL indicated reduced LTL in PTSD (pooled Cohen's d = 0.76). We also found consistent evidence of increased pro-inflammatory markers in PTSD (mean Cohen's ds), including C-reactive protein = 0.18, Interleukin-1 beta = 0.44, Interleukin-6 = 0.78, and tumor necrosis factor alpha = 0.81. The majority of reviewed studies also indicated increased medical comorbidity among several targeted conditions known to be associated with normal aging, including cardiovascular disease, type 2 diabetes mellitus, gastrointestinal ulcer disease, and dementia. We also found seven of 10 studies indicated PTSD to be associated with earlier mortality (average hazard ratio: 1.29). CONCLUSION: In short, evidence from multiple lines of investigation suggests that PTSD may be associated with a phenotype of accelerated senescence. Further research is critical to understand the nature of this association. There may be a need to re-conceptualize PTSD beyond the boundaries of mental illness, and instead as a full systemic disorder.

Differential impact of combat on postdeployment symptoms in female and male veterans of iraq and afghanistan.

OBJECTIVES: We aimed to describe differences in combat experience for male and female veterans and characterize differential effects on postdeployment physical and mental health symptoms, including aggression. METHODS: Retrospective cross-sectional health screening data from 554 Operation Enduring Freedom and Operation Iraqi Freedom veterans who enrolled for Veterans Affairs health care in San Diego were examined including measures of combat experience, pain intensity, traumatic brain injury symptoms, military sexual trauma, post-traumatic stress disorder, depression, alcohol use, and aggression. RESULTS: Although male veterans (n = 458) experienced significantly higher rates of combat than female veterans (n = 96), both experienced similar levels of postdeployment post-traumatic stress disorder and depression symptoms as well self-reported aggressive behavior compared to male veterans. Female veterans had higher rates of military sexual trauma and lower alcohol consumption than male veterans. CONCLUSIONS: All Operation Enduring Freedom and Operation Iraqi Freedom veterans returning from deployment may benefit from broad-based screening of physical and mental health symptoms, beyond those currently mandated by Veterans Affairs, including anger and aggression.

A quantitative measure of handwriting dysfluency for assessing tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder commonly associated with chronic exposure to antidopaminergic medications, which may be in some cases disfiguring and socially disabling. The consensus from a growing body of research on the incidence and prevalence of TD in the modern era of antipsychotics indicates that this disorder has not disappeared continues to challenge the effective management of psychotic symptoms in patients with schizophrenia. A fundamental component in an effective strategy for managing TD is its reliable and accurate assessment. In the present study, we examined the clinical utility of a brief handwriting dysfluency measure for quantifying TD. Digitized samples of handwritten circles and loops were obtained from 62 psychosis patients with or without TD and from 50 healthy subjects. Two measures of dysfluent pen movements were extracted from each vertical pen stroke, including normalized jerk and the number of acceleration peaks. Tardive dyskinesia patients exhibited significantly higher dysfluency scores than non-TD patients and controls. Severity of handwriting movement dysfluency was correlated with Abnormal Involuntary Movement Scale severity ratings for some tasks. The procedure yielded high degrees of test-retest reliability. These results suggest that measures of handwriting movement dysfluency may be particularly useful for objectively evaluating the efficacy of pharmacotherapeutic strategies for treating TD.

Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: A pilot study.

The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.