Is Cyberchondria a New Transdiagnostic Digital Compulsive Syndrome? A Systematic Review of the Evidence

© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background. Cyberchondria (CYB) has been described relatively recently as a behaviour characterized by excessive online searching for medical information that is associated with increasing levels of health anxiety. Although CYB has received some attention from researchers, there is no consensus about many of its aspects. Aims. We describe one of the first reported cases of a treatment-seeking patient with CYB. We review the published literature on the definition of CYB, its assessment, epidemiology, cost and burden, psychological models and mechanisms associated with CYB, relationships between CYB and mental disorders and prevention and treatment strategies. Methods: Systematic review of all peer-reviewed papers published within the PubMed, PsycINFO, and Cochrane Library databases. Results. 61 articles were selected. Nearly all the studies were descriptive and cross-sectional recruiting sample mainly from the general/university student population and collecting self-report data via online surveys. Data on epidemiology, clinical features, course, comorbidity and therapeutic interventions were scarce. CYB showed a self-reported association with health anxiety, hypochondriasis and obsessive-compulsive disorder (OCD) as well as other forms of problematic usage of the internet (PUI) The psychological mechanisms associated with CYB include low self-esteem, anxiety sensitivity, intolerance of uncertainty, pain catastrophizing and certain meta-cognitive beliefs. Conclusion: A working definition of CYB includes excessive online health searches that are compulsive and may serve the purpose of seeking reassurance, whilst leading to a worsening of anxiety or distress and further negative consequences. CYB represents a clinically relevant transdiagnostic compulsive behavioural syndrome, closely related to PUI and usually presenting in association with health anxiety, hypochondriasis and/or OCD. CYB is clearly in need of further study and we identify key areas for future research.Peer reviewe

Aripiprazole causing false positive urine amphetamine drug screen in an adult patient with bipolar disorder.

There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole.Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications. Keywords: Aripiprazole, False positive, Urine drug scree

Functional Interventions as Augmentation Strategies for Obsessive-Compulsive Disorder (OCD) : Scoping Review and Expert Survey from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS)

© 2021 Taylor & Francis. This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Psychiatry in Clinical Practice on 27/01/2021, available online: https://dx.doi.org/10.1080/13651501.2021.1872646.Background. Patients with obsessive-compulsive disorder (OCD) commonly exhibit a range of functional difficulties, presumed linked to neurocognitive changes. Evidence-based first-line treatments have limited effect on improving these cognitive-functional problems. Candidate interventions could be used to augment evidence-based treatments by the multi-professional mental health team. Methods. A scoping review was performed to identify any intervention with at least one peer-reviewed report of clinical improvement in any of the 13 functional domains of the Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13). Next, an online survey of experts of the International College of Obsessive-Compulsive Spectrum Disorders was conducted.Results. Forty-four studies were identified reporting a positive outcome for 27 different kinds of intervention. Twenty-six experts from 12 different countries, including at least one expert from each continent, completed the opinion survey. Five interventions were identified as ‘highly promising’, none of which was moderated by rater-related factors, suggesting global applicability. Conclusion. Patients with OCD may benefit from a detailed functional assessment, to identify areas of unmet need. A variety of interventions show theoretical promise for treating the complex functional difficulties in OCD as adjuncts to first-line treatments, but the published evidence is weak. Randomised controlled trials are needed to determine the clinical effectiveness of these interventions.Peer reviewe

Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models

Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington's disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine-and temperaturedependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperatureand polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients

siRNA screen identifies QPCT as a druggable target for Huntington's disease.

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development

Functional interventions as augmentation strategies for obsessive-compulsive disorder (OCD): scoping review and expert survey from the international college of obsessive-compulsive spectrum disorders (ICOCS)

BACKGROUND Patients with obsessive-compulsive disorder (OCD) commonly exhibit a range of functional difficulties, presumed linked to neurocognitive changes. Evidence-based first-line treatments have limited effect on improving these cognitive-functional problems. Candidate interventions could be used to augment evidence-based treatments by the multi-professional mental health team. METHODS A scoping review was performed to identify any intervention with at least one peer-reviewed report of clinical improvement in any of the 13 functional domains of the Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13). Next, an online survey of experts of the International College of Obsessive-Compulsive Spectrum Disorders was conducted. RESULTS Forty-four studies were identified reporting a positive outcome for 27 different kinds of intervention. Twenty-six experts from 12 different countries, including at least one expert from each continent, completed the opinion survey. Five interventions were identified as 'highly promising', none of which was moderated by rater-related factors, suggesting global applicability. CONCLUSION Patients with OCD may benefit from a detailed functional assessment, to identify areas of unmet need. A variety of interventions show theoretical promise for treating the complex functional difficulties in OCD as adjuncts to first-line treatments, but the published evidence is weak. Randomised controlled trials are needed to determine the clinical effectiveness of these interventions. Highlights Functional-cognitive problems are common in patients with OCD. First-line evidence-based treatments have limited effect on these functionalcognitive difficulties. In our scoping review we found 44 studies reporting of improved clinical outcomes in any of the 13 functional domains of the Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13). An online survey of experts of the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) was conducted and identified five interventions as "highly promising" candidate treatments for functional-cognitive problems in OCD. Randomised controlled trials are needed to determine the clinical effectiveness of these interventions

Testosterone amplifies excitotoxic damage of cultured oligodendrocytes

An overactivation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage in demyelinating disorders of the CNS. We decided to examine the effect of testosterone on excitotoxic death of oligodendrocytes because a gender difference exists in the incidence and disease course of multiple sclerosis. Short-term pure cultures of oligodendrocytes (4 days in vitro) were exposed to a brief pulse with kainate or AMPA + cyclothiazide for the induction of excitotoxicity. Exposure to testosterone enantate was slightly toxic per se and amplified both AMPA and kainate toxicity. Testosterone treatment induced all gene targets of p53, and amplified the induction of these genes induced by kainate. The effect of testosterone was mediated by the activation of androgen receptors and was resistant to the aromatase inhibitors, dl-aminoglutethimide and 4-hydroxyandrost-4-ene-3,17-dione. Testosterone treatment also potentiated the stimulation of 45Ca2+ influx induced by AMPA + cyclothiazide or kainate without changing the expression of the glutamate receptor (GluR) 1, -2/3, and -4 subunits of AMPA receptors or the GluR6/7 subunits of kainate receptors. We conclude that testosterone amplifies excitotoxic damage of oligodendrocytes acting at an early step of the death cascade triggered by AMPA/kainate receptors

Testosterone amplifies excitotoxic damage of cultured oligodendrocytes.

An overactivation of a-amino-3-hydroxy-5-methylisoxazole- 4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage in demyelinating disorders of the CNS. We decided to examine the effect of testosterone on excitotoxic death of oligodendrocytes because a gender difference exists in the incidence and disease course of multiple sclerosis. Short-term pure cultures of oligodendrocytes (4 days in vitro) were exposed to a brief pulse with kainate or AMPA + cyclothiazide for the induction of excitotoxicity. Exposure to testosterone enantate was slightly toxic per se and amplified both AMPA and kainate toxicity. Testosterone treatment induced all gene targets of p53, and amplified the induction of these genes induced by kainate. The effect of testosterone was mediated by the activation of androgen receptors and was resistant to the aromatase inhibitors, DL-aminoglutethimide and 4-hydroxyandrost-4-ene-3,17-dione. Testosterone treatment also potentiated the stimulation of 45Ca2+ influx induced by AMPA + cyclothiazide or kainate without changing the expression of the glutamate receptor (GluR) 1, -2/3, and -4 subunits of AMPA receptors or the GluR6/7 subunits of kainate receptors. We conclude that testosterone amplifies excitotoxic damage of oligodendrocytes acting at an early step of the death cascade triggered by AMPA/kainate receptors

Polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy.

BACKGROUND:In Huntington's disease, expansion of a CAG triplet repeat occurs in exon 1 of the huntingtin gene (HTT), resulting in a protein bearing>35 polyglutamine residues whose N-terminal fragments display a high propensity to misfold and aggregate. Recent data demonstrate that polyglutamine expansion results in conformational changes in the huntingtin protein (HTT), which likely influence its biological and biophysical properties. Developing assays to characterize and measure these conformational changes in isolated proteins and biological samples would advance the testing of novel therapeutic approaches aimed at correcting mutant HTT misfolding. Time-resolved Förster energy transfer (TR-FRET)-based assays represent high-throughput, homogeneous, sensitive immunoassays widely employed for the quantification of proteins of interest. TR-FRET is extremely sensitive to small distances and can therefore provide conformational information based on detection of exposure and relative position of epitopes present on the target protein as recognized by selective antibodies. We have previously reported TR-FRET assays to quantify HTT proteins based on the use of antibodies specific for different amino-terminal HTT epitopes. Here, we investigate the possibility of interrogating HTT protein conformation using these assays. METHODOLOGY/PRINCIPAL FINDINGS:By performing TR-FRET measurements on the same samples (purified recombinant proteins or lysates from cells expressing HTT fragments or full length protein) at different temperatures, we have discovered a temperature-dependent, reversible, polyglutamine-dependent conformational change of wild type and expanded mutant HTT proteins. Circular dichroism spectroscopy confirms the temperature and polyglutamine-dependent change in HTT structure, revealing an effect of polyglutamine length and of temperature on the alpha-helical content of the protein. CONCLUSIONS/SIGNIFICANCE:The temperature- and polyglutamine-dependent effects observed with TR-FRET on HTT proteins represent a simple, scalable, quantitative and sensitive assay to identify genetic and pharmacological modulators of mutant HTT conformation, and potentially to assess the relevance of conformational changes during onset and progression of Huntington's disease