Theories of Change and Mediators of Psychotherapy Effectiveness in Adolescents With Externalising Behaviours: A Systematic Review

bstract Background Externalising behaviours are becoming a remarkably prevalent problem during adolescence, often precipitating both externalising and internalising disorders in later adulthood. Psychological treatments aim to increase the social functioning of adolescents in order for them to live a more balanced life and prevent these negative trajectories. However, little is known of the intervening variables and mediators involved in these treatments' change mechanisms. We conducted a systematic review, exploring the available evidence on mediators of psychological treatments for externalising behaviours and symptoms amongst adolescents (10 to 19 years old). Methods A systematic search was performed on Medline and PsycINFO databases, which identified studies from inception to February 23, 2020. Eligible studies included randomised controlled trials that enrolled adolescents with externalising symptoms and behaviours as, at least, one of the primary outcomes. A group of 20 reviewers from the COST-Action TREATme (CA16102) were divided into 10 pairs. Each pair independently screened studies for inclusion, extracted information from the included studies, and assessed the methodological quality of the included studies and the requirements for mediators, following Kazdin's criteria. Risk of bias of RCTs was assessed by the Mixed Methods Appraisal Tool. Extracted data from the included studies were reported using a narrative synthesis. Results Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), after removing duplicates, 3,660 articles were screened. Disagreements were resolved by consensus. In a second stage, 965 full-text articles were assessed for eligibility. A total of 14 studies fulfilled all inclusion criteria. The majority were related to systemic psychological treatment approaches. Two types of mediators were identified as potentially being involved in the mechanisms of change for better social improvements of adolescents: to increase healthier parent–adolescent relationships and parental discipline. However, there were significant and non-significant results amongst the same mediators, which led to discussing the results tentatively. Conclusions Family variables were found to be the largest group of investigated mediators, followed by relational, behavioural, and emotional variables. No cognitive or treatment-specific mediators were identified. Both adequate behavioural control of adolescents' peer behaviour and a better positive balance in their relationships with their parents seemed to buffer the effects of externalising behaviours in adolescents. Several methodological limitations concerning mediation testing design, outcome measures, and mediator selection have been identified. Ethics and Dissemination Ethical approval was not required. PROSPERO registration number: CRD42021231835

Mediators of outcome in adolescent psychotherapy and their implications for theories and mechanisms of change: a systematic review.

Psychotherapeutic treatment of adolescents requires age-specific approaches and thus plausibly also involves different change mechanisms than adult psychotherapy. To guide further research and improve therapeutic outcomes for adolescents, we reviewed all RCTs investigating mechanisms of change in the psychological treatment of adolescents to identify the most promising age-, disorder- or treatment-specific mediators. Following the preferred reporting items for systematic reviews (PRISMA), 106 studies were included that reported 252 statistical mediation tests assessed with 181 different measures. Most often studied and significant mediators were cognitive, followed by family-related, and behavioral variables. Several mediators were identified to be promising for future investigations: changes in negative thoughts, dysfunctional beliefs and metacognitive skills; family functioning and parenting skills; as well as successful engagement in therapy activities and increased impulse control. Symptom change during therapy was least often a mediator for other therapeutic changes. Relational and emotional mediators were largely understudied, whereas peer-influence appeared a promising mediator for intervention outcomes. Adolescence-specific mediators were most commonly investigated. Majority of studied mediators were not disorder-specific. There was a tendency to mainly test change mechanisms of specific theoretical models without considering other possible change theories. Further, virtually no studies fulfilled all criteria for rigorously investigating mediation and only nine were classified with an overall good study quality. While bearing in mind the current limitations in study designs, methodological rigor and reporting, there appears to be substantial evidence for transdiagnostic age-specific change models in the psychological treatment of adolescents. For future research, need for consensus on a core set of transdiagnostic and transtheoretical mediators and measures is highlighted. These should address likely core mechanisms of change, as well as take into account age-relevant developmental challenges and biological markers

Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents

Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alphav beta6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery programme. Compounds 33S and 43E1 are pan alphav antagonists having ca 100 nM potency against alphav beta3, alphav beta5, alphav beta6 and alphav beta8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for alphav beta3 and alphav beta5

Mediators and theories of change in psychotherapy with adolescents: a systematic review protocol

Introduction Approximately 75% of mental disorders emerge before the age of 25 years but less than half receive appropriate treatment. Little is known about the mechanisms underlying the therapeutic change of adolescents in psychotherapy. The 'European Network of Individualised Psychotherapy Treatment of Young People with Mental Disorders', funded by the European Cooperation in Science and Technology, will conduct the first systematic review to summarise the existing knowledge on mediators and theories of change in psychotherapy for adolescents. Method A systematic review will be conducted, conforming to the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement recommendations. Electronic databases (PubMed and PsycINFO) have been systematically searched on 23 February 2020, for prospective, longitudinal and case-control designs which examine mediators of change. Participants will be adolescents between 10 and 19 years of age who suffer from a mental disorder or psychological difficulties and receive an intervention that aims at preventing, ameliorating and/or treating psychological problems. Ethics and dissemination Ethical approval is not required for this systematic review as no primary data will be collected. The results will be published in a peer-reviewed journals and at conference presentations and will be shared with stakeholder groups. The whole data set will be offered to other research groups following recommendations of the open science initiative. Databases with the systematic search will be made openly available following open science initiatives. PROSPERO registration number CRD42020177535

Mediators in Psychological Treatments for Anxiety and Depression in Adolescents and Young People: A Protocol of a Systematic Review

Introduction Anxiety and depressive disorders are a significant problem that starts in childhood or adolescence and should be addressed early to avoid chronic mental conditions. There is strong evidence to demonstrate that psychological treatments are effective for these disorders, however, little is known on mediators and mechanisms of change of psychological treatment in adolescents and young adults. Understanding the pathways through which psychological treatments operate will facilitate more effective treatments. Aim We aim to conduct a systematic review, exploring the available evidence on mediators of psychological treatments for anxiety and depression in adolescents and young adults. Methods A systematic search has been performed on PubMed and PsycINFO databases to identify studies from inception to 23rd February 2020. Eligible studies include randomized controlled trials and trials (quasi-experimental) designs that have enrolled adolescents and young adults presenting with depression and/or anxiety and that have examined mediators of psychological treatments. A group of 20 reviewers from the COST-Action TREATme (CA16102) divided into 10 pairs independently screen studies for inclusion, extract information from the included studies, and assess the methodological quality of the included studies and the requirements for mediators. The methodological quality will be assessed by The Mixed Methods Appraisal Tool. Extracted data from the included studies will be collected and presented using a narrative approach. Discussion This systematic review will summarize and provide a comprehensive overview of the current evidence on mediators of psychological treatments for anxiety and depression for adolescents and young adults. Results will allow the identification of strategies to optimize intervention to enhance clinical outcomes. Ethics and dissemination Ethics approval is not required. Findings from this systematic review will be published in a peer-reviewed journal and disseminated at conferences and meetings. PROSPERO registration number: CRD42021234641.This review is based upon work from COST Action European Network on Individualized Psychotherapy Treatment of Young People with Mental Disorders (TREATme; CA16102), supported by COST (European Cooperation in Science and Technology) (www.cost.eu)

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB