Editorial: Advances in Biological Approaches to Treating Resistant/Refractory Obsessive-Compulsive and Related Disorders.

Obsessive-compulsive disorder (OCD) is a severe and debilitating neuropsychiatric condition that has an estimated lifetime prevalence of 2.5–3.0% of the general population (1). Approximately 40% of patients treated for OCD do not respond to standard and second-line augmentation treatments (2). Treatment-refractory OCD tends to have a chronic and disabling course. Although psychological interventions, namely exposure and response prevention (ERP), have been shown to be effective in treating OCD and as an augmentation strategy for poor response to selective serotonin reuptake inhibitors (SSRIs) (3), many patients cannot engage in exposure therapy or do not respond to such treatments. Some patients with OCD also have adverse reactions to SSRIs and this makes alternative biological options for treating OCD more attractive. With increasing interest in biological therapies for OCD such as deep brain stimulation (DBS), it is important that advances in biological approaches to treating treatment resistant OCD are evaluated

Confirmatory Factor Analysis of the Nepean Dysphoria Scale in a Clinical Sample

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The construct of dysphoria has been described inconsistently across a broad range of psychopathology. The term has been used to refer to an irritable state of discontent, but is also thought to incorporate anger, resentment and nonspecific symptoms associated with anxiety and depression, such as tension and unhappiness. The Nepean Dysphoria Scale has been developed to allow assessment of dysphoria, but its factor structure has not yet been investigated in clinical samples. We aimed to determine the latent structure of dysphoria as reflected by the Nepean Dysphoria Scale, using a clinical sample. Adults (N = 206) seeking treatment at a range of mental health services were administered the Nepean Dysphoria Scale. Four putative factor structures were investigated using confirmatory factor analysis: a single-factor model, a hierarchical model, a bifactor model and a four-factor model as identified in previous studies. No model fit the data except for a four-factor model when a revised 22-item version of the original 24-item scale was investigated. A four-factor structure similar to that identified in non-clinical samples was supported, albeit following the removal of two items. The Nepean Dysphoria Scale appears to have utility for the assessment of dysphoria in routine clinical settings

The structure and intensity of self-reported autonomic arousal symptoms across anxiety disorders and obsessive-compulsive disorder

© 2016 Elsevier B.V. All rights reserved. Background Heightened autonomic arousal symptoms (AAS) are assumed to be a central feature of anxiety disorders. However, it is unclear whether the magnitude and profile of AAS vary across anxiety disorders and whether heightened AAS characterises obsessive-compulsive disorder (OCD). Aims We sought to determine whether the intensity and structure of AAS varied across anxiety disorders and OCD. Method A sample of 459 individuals with a primary anxiety disorder or OCD were administered the Symptom Checklist-90R. Nine items referring to prototypic AAS were included in a latent class analysis. Results A 2-class solution (high and low AAS classes) best fitted the data. Participants comprising the high AAS class scored uniformly high across all assessed AAS symptoms. Older age and the presence of panic disorder, social anxiety disorder and generalized anxiety disorder predicted membership in the high AAS class. No OCD symptom dimension was significantly associated with membership in the high AAS class. Limitation AAS were assessed using a self-report measure and replication is needed using other methodologies. Conclusions These findings suggest that OCD may be sufficiently distinct from anxiety disorders and do not support subtyping of anxiety disorders on the basis of the predominant type of AAS. Therapeutic approaches that target AAS might best be applied in the treatment of panic disorder, social anxiety disorder and generalized anxiety disorder

Does emotional reasoning change during cognitive behavioural therapy for anxiety?

© 2015 Swedish Association for Behaviour Therapy. Abstract: Emotional reasoning refers to the use of subjective emotions, rather than objective evidence, to form conclusions about oneself and the world. It is a key interpretative bias in cognitive models of anxiety disorders and appears to be especially evident in individuals with anxiety disorders. However, the amenability of emotional reasoning to change during treatment has not yet been investigated. We sought to determine whether emotional reasoning tendencies change during a course of routine cognitive-behavioural therapy (CBT). Emotional reasoning tendencies were assessed in 36 individuals with a primary anxiety disorder who were seeking treatment at an outpatient clinic. Changes in anxiety and depressive symptoms as well as emotional reasoning tendencies after 12 sessions of CBT were examined in 25 individuals for whom there was complete data. Emotional reasoning tendencies were evident at pretreatment assessment. Although anxiety and depressive symptoms decreased during CBT, only one of six emotional reasoning interpretative styles (pertaining to conclusions that one is incompetent) changed significantly during the course of therapy. Attrition rates were high and there was not enough information regarding the extent to which therapy specifically focused on addressing emotional reasoning tendencies. Individuals seeking treatment for anxiety disorders appear to engage in emotional reasoning, however routine individual CBT does not appear to result in changes in emotional reasoning tendencies

Use of benzodiazepines in obsessive-compulsive disorder

© 2015 Wolters Kluwer Health, Inc. This study aimed to determine the frequency of benzodiazepine (BDZ) use in a large sample of patients with obsessive-compulsive disorder (OCD) and ascertain the type of BDZ used and the correlates and predictors of BDZ use in OCD. The sample consisted of 955 patients with OCD from a comprehensive, cross-sectional, multicentre study conducted by the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders between 2003 and 2009. The rate of BDZ use over time in this OCD sample was 38.4%. Of individuals taking BDZs, 96.7% used them in combination with other medications, usually serotonin reuptake inhibitors. The most commonly used BDZ was clonazepam. Current age, current level of anxiety and number of additional medications for OCD taken over time significantly predicted BDZ use. This is the first study to comprehensively examine BDZ use in OCD patients, demonstrating that it is relatively common, despite recommendations from treatment guidelines. Use of BDZs in combination with several other medications over time and in patients with marked anxiety suggests that OCD patients taking BDZs may be more complex and more difficult to manage. This calls for further research and clarification of the role of BDZs in the treatment of OCD

In Defence of Modest Doxasticism About Delusions

Here I reply to the main points raised by the commentators on the arguments put forward in my Delusions and Other Irrational Beliefs (OUP, 2009). My response is aimed at defending a modest doxastic account of clinical delusions, and is articulated in three sections. First, I consider the view that delusions are in-between perceptual and doxastic states, defended by Jacob Hohwy and Vivek Rajan, and the view that delusions are failed attempts at believing or not-quite-beliefs, proposed by Eric Schwitzgebel and Maura Tumulty. Then, I address the relationship between the doxastic account of delusions and the role, nature, and prospects of folk psychology, which is discussed by Dominic Murphy, Keith Frankish, and Maura Tumulty in their contributions. In the final remarks, I turn to the continuity thesis and suggest that, although there are important differences between clinical delusions and non-pathological beliefs, these differences cannot be characterised satisfactorily in epistemic terms. \u

Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites

A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB

Structural motifs recurring in different folds recognize the same ligand fragments

<p>Abstract</p> <p>Background</p> <p>The structural analysis of protein ligand binding sites can provide information relevant for assigning functions to unknown proteins, to guide the drug discovery process and to infer relations among distant protein folds. Previous approaches to the comparative analysis of binding pockets have usually been focused either on the ligand or the protein component. Even though several useful observations have been made with these approaches they both have limitations. In the former case the analysis is restricted to binding pockets interacting with similar ligands, while in the latter it is difficult to systematically check whether the observed structural similarities have a functional significance.</p> <p>Results</p> <p>Here we propose a novel methodology that takes into account the structure of both the binding pocket and the ligand. We first look for local similarities in a set of binding pockets and then check whether the bound ligands, even if completely different, share a common fragment that can account for the presence of the structural motif. Thanks to this method we can identify structural motifs whose functional significance is explained by the presence of shared features in the interacting ligands.</p> <p>Conclusion</p> <p>The application of this method to a large dataset of binding pockets allows the identification of recurring protein motifs that bind specific ligand fragments, even in the context of molecules with a different overall structure. In addition some of these motifs are present in a high number of evolutionarily unrelated proteins.</p

New Structural and Functional Contexts of the Dx[DN]xDG Linear Motif: Insights into Evolution of Calcium-Binding Proteins

Binding of calcium ions (Ca2+) to proteins can have profound effects on their structure and function. Common roles of calcium binding include structure stabilization and regulation of activity. It is known that diverse families – EF-hands being one of at least twelve – use a Dx[DN]xDG linear motif to bind calcium in near-identical fashion. Here, four novel structural contexts for the motif are described. Existing experimental data for one of them, a thermophilic archaeal subtilisin, demonstrate for the first time a role for Dx[DN]xDG-bound calcium in protein folding. An integrin-like embedding of the motif in the blade of a β-propeller fold – here named the calcium blade – is discovered in structures of bacterial and fungal proteins. Furthermore, sensitive database searches suggest a common origin for the calcium blade in β-propeller structures of different sizes and a pan-kingdom distribution of these proteins. Factors favouring the multiple convergent evolution of the motif appear to include its general Asp-richness, the regular spacing of the Asp residues and the fact that change of Asp into Gly and vice versa can occur though a single nucleotide change. Among the known structural contexts for the Dx[DN]xDG motif, only the calcium blade and the EF-hand are currently found intracellularly in large numbers, perhaps because the higher extracellular concentration of Ca2+ allows for easier fixing of newly evolved motifs that have acquired useful functions. The analysis presented here will inform ongoing efforts toward prediction of similar calcium-binding motifs from sequence information alone