A trans-diagnostic perspective on obsessive-compulsive disorder

© Cambridge University Press 2017. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Progress in understanding the underlying neurobiology of obsessive-compulsive disorder (OCD) has stalled in part because of the considerable problem of heterogeneity within this diagnostic category, and homogeneity across other putatively discrete, diagnostic categories. As psychiatry begins to recognize the shortcomings of a purely symptom-based psychiatric nosology, new data-driven approaches have begun to be utilized with the goal of solving these problems: specifically, identifying trans-diagnostic aspects of clinical phenomenology based on their association with neurobiological processes. In this review, we describe key methodological approaches to understanding OCD from this perspective and highlight the candidate traits that have already been identified as a result of these early endeavours. We discuss how important inferences can be made from pre-existing case-control studies as well as showcasing newer methods that rely on large general population datasets to refine and validate psychiatric phenotypes. As exemplars, we take 'compulsivity' and 'anxiety', putatively trans-diagnostic symptom dimensions that are linked to well-defined neurobiological mechanisms, goal-directed learning and error-related negativity, respectively. We argue that the identification of biologically valid, more homogeneous, dimensions such as these provides renewed optimism for identifying reliable genetic contributions to OCD and other disorders, improving animal models and critically, provides a path towards a future of more targeted psychiatric treatments.Peer reviewedFinal Published versio

Myosin II filament dynamics in actin networks revealed with interferometric scattering microscopy

The plasma membrane and the underlying cytoskeletal cortex constitute active platforms for a variety of cellular processes. Recent work has shown that the remodeling acto-myosin network modifies local membrane organization, but the molecular details are only partly understood due to difficulties with experimentally accessing the relevant time and length scales. Here, we use interferometric scattering (iSCAT) microscopy to investigate a minimal acto-myosin network linked to a supported lipid bilayer membrane. Using the magnitude of the interferometric contrast, which is proportional to molecular mass, and fast acquisition rates, we detect, and image individual membrane attached actin filaments diffusing within the acto-myosin network and follow individual myosin II filament dynamics. We quantify myosin II filament dwell times and processivity as functions of ATP concentration, providing experimental evidence for the predicted ensemble behavior of myosin head domains. Our results show how decreasing ATP concentrations lead to both increasing dwell times of individual myosin II filaments and a global change from a remodeling to a contractile state of the acto-myosin network

Effects of nebulised iloprost on pulmonary function and gas exchange in severe pulmonary hypertension

SummaryNebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140μg iloprost/24h via an ultrasonic nebuliser.Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423±98 to 415±98) and percutaneous oxygen saturation increased in mean by 0.7% (90±6 to 91±5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction.Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV1, FVC, TLC, residual volume nor in diffusions capacity, SO2 at rest and during 6min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6min walking distance (6 MWD) after 3 months (246±113 to 294±115m, P<0.05).In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients

Habit reversal therapy in obsessive compulsive related disorders : A systematic review of the evidence and consort evaluation of randomized controlled trials

Background: Habit Reversal Therapy (HRT) has long been used in the treatment of Tourette Syndrome and Tic Disorders. It has more recently been used to treat Trichotillomania and skin picking behaviors, both considered as Obsessive Compulsive Related Disorders (OCRD). Objectives: This literature review sought to establish and quality assess the existing randomized controlled trial evidence supporting the use of HRT in the DSM-5 family of OCRDs. Search Methods: EMBASE, PsycINFO, PubMed, and Cochrane databases were searched for key terms relating to each OCRD (as classified in the DSM-5), and HRT. Selection Criteria: Titles and abstracts were screened, and any literature matching pre-specified criteria were then selected to be reviewed further. Of these, 8 Randomized Controlled Trials (RCT) relating to Trichotillomania, and 2 RCTs relating to Excoriation Disorder, were extracted and reviewed against the 2010 Consolidating Standards of Reporting Trials (CONSORT) statement. Results: The review identified 10 RCTs of HRT, but these were limited to patients with a primary diagnosis of Trichotillomania or “excoriation behavior,” only. There were some reports of the use of HRT in Tourette Syndrome or Tic Disorder with secondary OCD, but the OCD symptoms were not reliably reported on. Conclusion: There is a gap in the current literature regarding the use of HRT in the DSM-5 OCRDs. In those RCTs that have been reported, the quality of study methodology was questionable as evaluated by CONSORT criteria. The implications of these findings are discussed, and suggestions are made for future research.Peer reviewe

Meta-analysis of cognitive behaviour therapy and selective serotonin reuptake inhibitors for the treatment of hypochondriasis: Implications for trial design

Background: Classification of hypochondriasis as an obsessive-compulsive and related disorder in the International Classification of Diseases 11th Revision (ICD-11) has generated new heuristics for treatment of this common, chronic and disabling disorder. Standard treatment involves cognitive behaviour therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs), but no meta-analysis has so far considered hypochondriasis as a structured diagnosis or assessed the role of medication. A clearer understanding of the relative effectiveness of these interventions and identification of clinically relevant factors moderating the treatment response is needed for clinical guideline development. Methods: The current systematic review and meta-analysis of interventions for hypochondriasis was preregistered on PROSPERO (CRD42020185768) and follows PRISMA guidelines. We searched MEDLINE, PsycINFO, and Cochrane Library databases until July 2021 for randomized controlled trials (RCTs) of interventions for patients diagnosed with hypochondriasis (or historical diagnostic equivalents). We assessed aspects of study quality using: the CONSORT Checklist for evaluation of RCTs, the Cochrane Risk of Bias 2 tool, researcher allegiance and treatment fidelity. The primary outcome was improvement in hypochondriasis symptoms, comparing intervention and control groups at trial endpoint. Moderator variables were assessed using subgroup and meta-regression analyses. Results: Searches identified 13 randomised controlled trials (RCTs) (N = 1405); 12 included CBT (N = 1212) and three included SSRI (N = 193) arms as the experimental intervention. Random effects meta-analysis yielded a moderate-to-large effect size for CBT versus all controls (g = −0.70 [95% CI -0.99 to −0.41], k = 18, I2 = 81.1%). Funnel plot asymmetry indicated possible publication bias and two potentially missing trials, reducing the effect size (g = −0.60 [95% CI -0.88 to −0.32]). Subgroup analysis showed that choice of control significantly moderated effect size, with those in CBT vs. wait-list (g = −1.32 [95% CI -1.75 to −0.90], k = 7, I2 = 0%) being double those of CBT vs. psychological or pharmacological placebo controls (g = −0.58 [95% CI -0.95 to −0.22], k = 7, I2 = 82%). Analysis of studies directly comparing CBT and SSRIs found a numerical, but not statistical advantage for SSRIs (g = 0.21 [95% CI -0.46 to 0.87], k = 2, I2 = 58.34%) and a modest effect size emerged for SSRIs vs. pill placebo (g = −0.29 [95% CI -0.57 to −0.01], k = 3, I2 = 0%). Most studies (11/13) were rated as high on potential researcher allegiance bias in favour of CBT. Meta-regressions revealed that effect sizes were larger in younger participants, and smaller in better quality and more recent RCTs and those with greater CBT fidelity. Conclusion: CBT and SSRIs are effective in the acute treatment of hypochondriasis, with some indication that intervention at a younger age produces better outcomes for CBT. In the case of CBT, effect sizes appear to have been significantly inflated by the use of wait list controls, and researcher allegiance bias. We recommend that a definitive, adequately controlled trial, designed with respect to the methodological issues raised in this meta-analysis, is needed to determine the magnitude effects for CBT and SSRIs with confidence and the long-term effect of treatments, to inform mental health service provision for this overlooked patient group

Phase-Field Model of Mode III Dynamic Fracture

We introduce a phenomenological continuum model for mode III dynamic fracture that is based on the phase-field methodology used extensively to model interfacial pattern formation. We couple a scalar field, which distinguishes between ``broken'' and ``unbroken'' states of the system, to the displacement field in a way that consistently includes both macroscopic elasticity and a simple rotationally invariant short scale description of breaking. We report two-dimensional simulations that yield steady-state crack motion in a strip geometry above the Griffith threshold.Comment: submitted to PR

Computational modelling reveals contrasting effects on reinforcement learning and cognitive flexibility in stimulant use disorder and obsessive-compulsive disorder: remediating effects of dopaminergic D2/3 receptor agents

Abstract: Rationale: Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms. Objectives: This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses. Methods: We applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood. Results: Stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects. Conclusions: We provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects

Repetitive transcranial magnetic stimulation (r-TMS) and selective serotonin reuptake inhibitor-resistance in obsessive-compulsive disorder: A meta-analysis and clinical implications

Introduction: Despite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. Methods: We conducted a pre-registered (PROSPERO ID: 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 = not treatment resistant, 2 = one SSRI trial failed, 3 = two SSRI trials failed, 4 = two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. Results: Twenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedge's g: -0.47; 95%CI: - 0.67 to −0.27) with moderate heterogeneity (I2 = 39.8%). Assessment of publication bias using Trim and Fill analysis suggested a reduced effect size that remained significant (g: -0.29; 95%CI: −0.51 to −0.07). Subgroup analysis found that those studies including patients non-resistant to SSRI (stage 1) (g: -0.65; 95%CI: −1.05 to −0.25, k = 7) or with low SSRI-resistance (stage 2) (g:-0.47; 95%CI: −0.86 to −0.09, k = 6) produced statistically significant results with low heterogeneity, while studies including more highly resistant patients at stage 3 (g: −0.39; 95%CI: −0.90 to 0.11, k = 4) and stage 4 (g: -0.36; 95%CI: −0.75 to 0.03, k = 8) did not. Intriguingly, the only significant moderator of the effect size found by meta-regression was the severity of baseline depressive symptoms. All trials showed evidence of researcher allegiance in favour of the intervention and therefore caution is required in interpreting the reported effect sizes. Conclusion: This meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn

Applying Market Shaping Approaches to Increase Access to Assistive Technology: Summary of the Wheelchair Product Narrative

To accelerate access to assistive technology (AT), we need to leverage the capabilities and resources of the public, private, and non-profit sectors to harness innovation and break down barriers to access. Market shaping interventions can play a role in enhancing market efficiencies, coordinating and incentivizing the number of stakeholders involved in demand and supply-side activities. Across health sectors, market shaping has demonstrated its potential to enhance national governments’ or donors’ value-for-money, diversify the supply base, and increase reliability – ultimately increasing product and service delivery access for end users. These market shaping successes in other health areas have led practitioners to hypothesize that market shaping could also be applied to assistive technology markets. ATscale, the Global Partnership for AT, aims to mobilise global stakeholders to shape markets in line with a unified strategy. To inform this strategy, it is critical to identify specific interventions required to shape markets and overcome barriers. The first product undergoing analysis by ATscale is wheelchairs. The market for appropriate wheelchairs in low-and middle income countries (LMICs) is highly fragmented and characterized by limited government interest, investment, and a low willingness-to-pay. Moreover, the market is dominated by cheaper, low quality wheelchairs which fail to meet the needs of end-users. Non-profit organizations have attempted to fill the need for context-appropriate wheelchairs, but market uptake is limited. These initial findings led ATscale to believe that market shaping could support increased access to appropriate wheelchairs. This paper outlines what market shaping is, and how it can be applied to assistive technology at large -- using the aforementioned wheelchair product narrative as an illustrative case study and presents the proposed market shaping strategy for wheelchairs. ATscale will develop a framework to evaluate short-term interventions identified to achieve a healthy market and increase access. This paper provides an opportunity to obtain feedback from interested stakeholders on the market shaping strategy for wheelchairs, as well as the product narrative process to be undertaken for other priority AT

The Classification of Obsessive–Compulsive and Related Disorders in the ICD-11

Background To present the rationale for the new Obsessive–Compulsive and Related Disorders (OCRD) grouping in the Mental and Behavioural Disorders chapter of the Eleventh Revision of the World Health Organization’s International Classification of Diseases and Related Health Problems (ICD-11), including the conceptualization and essential features of disorders in this grouping. Methods Review of the recommendations of the ICD-11 Working Group on the Classification for OCRD. These sought to maximize clinical utility, global applicability, and scientific validity. Results The rationale for the grouping is based on common clinical features of included disorders including repetitive unwanted thoughts and associated behaviours, and is supported by emerging evidence from imaging, neurochemical, and genetic studies. The proposed grouping includes obsessive–compulsive disorder, body dysmorphic disorder, hypochondriasis, olfactory reference disorder, and hoarding disorder. Body-focused repetitive behaviour disorders, including trichotillomania and excoriation disorder are also included. Tourette disorder, a neurological disorder in ICD-11, and personality disorder with anankastic features, a personality disorder in ICD-11, are recommended for cross-referencing. Limitations Alternative nosological conceptualizations have been described in the literature and have some merit and empirical basis. Further work is needed to determine whether the proposed ICD-11 OCRD grouping and diagnostic guidelines are mostly likely to achieve the goals of maximizing clinical utility and global applicability. Conclusion It is anticipated that creation of an OCRD grouping will contribute to accurate identification and appropriate treatment of affected patients as well as research efforts aimed at improving our understanding of the prevalence, assessment, and management of its constituent disorders