Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

Sulheim, Dag; Fagermoen, Even; Winger, Anette; Andersen, Anders; Godang, Kristin; Müller, Fredrik; Rowe, Peter C.; Saul, J. Philip; Skovlund, Eva; Øie, Merete Glenne; Wyller, Vegard Bruun

doi:10.1001/jamapediatrics.2013.4647

Cited by 66 publications

(144 citation statements)

References 47 publications

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“…Real-time polymerase chain reaction assays for the detection of enteroviruses (including coxsackievirus and echovirus), adenovirus, human Parvovirus B19, Epstein-Barr virus, cytomegalovirus, and human herpes virus 6 were performed as described elsewhere [18].…”

Section: Viral Genome Detectionmentioning

confidence: 99%

Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure

Broch

Andreassen

Ueland

et al. 2015

International Journal of Cardiology

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Section: Viral Genome Detectionmentioning

confidence: 99%

Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure

Broch

Andreassen

Ueland

et al. 2015

International Journal of Cardiology

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“…A diagnosis of CFS was based upon a standardized set of investigations (pediatric specialist assessment, comprehensive hematology and biochemistry analyses, chest x-ray, abdominal ultrasound, and brain MRI) carried out by the referring unit, as well as independent clinical assessment by two of the authors (EF and DS). In agreement with recent clinical guidelines [2,18] and previous studies from our group [7,9-11,19], we applied a ‘broad’ case definition of CFS, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset. We did not require that patients meet any other accompanying symptom criteria.…”

Section: Methodsmentioning

confidence: 97%

“…Details of NorCAPITAL are described elsewhere [19]. Data were collected in the period March 2010 until October 2012.…”

Section: Methodsmentioning

confidence: 99%

“…Details of the HUT protocol have been described elsewhere [10]. The feasibility of this protocol for studying adolescent CFS patients has been demonstrated in several previous studies [9,10,19]. In particular, the low tilt angle (20°) does not normally precipitate syncope, which is otherwise a common problem among adolescents being subjected to stronger orthostatic challenges.…”

Section: Methodsmentioning

confidence: 99%

“…The Autonomic Symptom Profile (ASP) [23], which is a validated inventory for the assessment of autonomic symptoms, was slightly modified in order to fit our age group and distributed together with several other inventories, as described elsewhere [19]. For this study, a composite score reflecting symptoms of orthostatic intolerance was constructed from 7 single items from the ASP that address experiences of dizziness in specific situations.…”

Section: Methodsmentioning

confidence: 99%

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Orthostatic responses in adolescent chronic fatigue syndrome: contributions from expectancies as well as gravity

Wyller

Fagermoen

Sulheim

et al. 2014

BioPsychoSocial Med

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BackgroundOrthostatic intolerance is common in chronic fatigue syndrome (CFS), and several studies have documented an abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli. The aim of this study was to explore whether the expectancies towards standing are contributors to autonomic responses in addition to the gravitational stimulus itself.MethodsA total of 30 CFS patients (12–18 years of age) and 39 healthy controls underwent 20° head-up tilt test and a motor imagery protocol of standing upright. Beat-to-beat cardiovascular variables were recorded.ResultsAt supine rest, CFS patients had significantly higher heart rate, diastolic blood pressure, and mean arterial blood pressure, and lower stroke index and heart rate variability (HRV) indices. The response to 20° head-up tilt was identical in the two groups. The response to imaginary upright position was characterized by a stronger increase of HRV indices of sympathetic predominance (power in the low-frequency range as well as the ratio low-frequency: high-frequency power) among CFS patients.ConclusionsThese results suggest that in CFS patients expectancies towards orthostatic challenge might be additional determinants of autonomic cardiovascular modulation along with the gravitational stimulus per se.

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Drug‐Placebo Additivity in Randomized Clinical Trials

Hall

Loscalzo

2019

Clin Pharma and Therapeutics

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In randomized clinical trials (RCTs), it is assumed that nonspecific effects beyond action of pharmacological agents are roughly equivalent in drug and placebo treatment groups. Hence, since the inception of RCTs, drug efficacy is determined by comparing outcomes in active to those in placebo control arms. However, quantitation of efficacy is based on an unproven assumption, that drug and placebo responses are always additive. Response to treatment in RCTs can be differentially influenced by the perturbing effects of patient expectations, side effects, and pharmacogenomic interactions in both drug and placebo arms. Ability to control for these effects requires understanding of when and where they arise, how to mitigate, analyze, and even leverage their impact. Here, we examine three factors that influence additivity: expectation, side effects, and pharmacogenomics. Furthermore, to provide novel insights into nonadditivity and solutions for managing it, we introduce systems pharmacogenomics, a network approach to integrating and analyzing the effects of the numerous interacting perturbations to which a patient is exposed in RCTs.In randomized placebo controlled clinical trials (RCTs), the placebo treatment arm is designed to capture and control for the nonspecific variables that can influence clinical outcomes. These include regression to the mean, spontaneous remission, changes due to the natural course of the disease, and placebo effects. Placebo effects refer to clinical improvement derived from the patient's interactions with the clinician, the information they receive with regard to their condition and treatment, and the therapeutic ritual performed in the clinical setting. 1 Hence, factors that influence clinical outcomes in RCTs derive from the "players" engaged in the therapeutic encounter and their emergent properties. From the patient's characteristics, the physician's appearance and manner, and the information communicated, to the mise-en-scène, and the pharmacological agent's properties, this complexity of factors can make predicting that there will be a statistically significant drug-placebo difference difficult. It is this complexity that placebo controls, along with randomization and double-blinding, were designed to reduce, allowing us to use simple arithmetic to subtract the nonspecific effects captured in the placebo control arm to reveal the efficacy of the drug. Hence, determination of drug efficacy relies on the assumption that the placebo and drug responses are additive (i.e., drug efficacy = drug response -placebo response).For drugs like antimicrobials or chemotherapeutics that target well-defined exogenous pathogens or cellular processes not under the influence of placebo effects, the additivity assumption seems to hold, allowing us to establish successfully the efficacy of numerous medications. [2][3][4] In contrast, treatments for conditions such as pain, anxiety, and depression, and a wide variety of functional and central sensitization disorders defined less by pathophysiology and more...

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Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

Abstract: clinicaltrials.gov Identifier: NCT01040429.

Cited by 66 publications

References 47 publications

Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure

Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure

Orthostatic responses in adolescent chronic fatigue syndrome: contributions from expectancies as well as gravity

Drug‐Placebo Additivity in Randomized Clinical Trials

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