Pharmacological interventions for challenging behaviour in children with intellectual disabilities: a systematic review and meta-analysis

Background Psychotropic medications are frequently used to treat challenging behaviour in children with intellectual disabilities, despite a lack of evidence for their efficacy. This systematic review and meta-analysis aimed to determine the safety and efficacy of pharmacological interventions for challenging behaviour among children with intellectual disabilities. Methods Electronic databases were searched and supplemented with a hand search of reference lists and trial registries. Randomised controlled trials of pharmacological interventions for challenging behaviour among children with intellectual disabilities were included. Data were analysed using meta-analysis or described narratively if meta-analysis was not possible. For quality assessment, the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were used. Results Fourteen studies including 912 participants met inclusion criteria. Antipsychotic medication reduced challenging behaviour among children with intellectual disabilities in the short-term (SMD = −1.09, p < 0.001 for risperidone; SMD = −0.64, p <0.001 for aripiprazole). However, there were significant side-effects including elevated prolactin levels (SMD = 3.22, p < 0.001) and weight gain (SMD = 0.82, p < 0.001). Evidence was inconclusive regarding the effectiveness of anticonvulsants and antioxidants for reducing challenging behaviour. The quality of all evidence was low and there were no long term follow up studies. Conclusions Antipsychotic medications appear to be effective for reducing challenging behaviour in the short-term among children with intellectual disabilities, but they carry a risk of significant side effects. Findings from this review must be interpreted with caution as studies were typically of low quality and most outcomes were based on a small number of studies. Further long-term, high-quality research is needed to determine the effectiveness and safety of psychotropic medication for reducing challenging behaviour

Psychological therapies for depression and cardiovascular risk: evidence from national healthcare records in England

Aims: People with depression are up to 72% more at risk to develop cardiovascular disease (CVD) in their lifetime. Evidence-based psychotherapies are first-line interventions for the treatment of depression and are delivered nationally in England through the National Health Service via the Improving Access to Psychological Therapy (IAPT) primary care programme. It is currently unknown whether positive therapy outcomes may be associated with cardiovascular risk reduction. This study aimed to examine the association between psychotherapy outcomes for depression and incident CVD. Methods and results: A cohort of 636 955 individuals who have completed a course of psychotherapy was built from linked electronic healthcare record databases of national coverage in England: the national IAPT database, the Hospital Episode Statistics (HES) database, and the HES–ONS (Office of National Statistics) mortality database. Multivariable Cox models adjusting for clinical and demographic covariates were run to estimate the association between reliable improvement from depression and the risk of subsequent incidence of cardiovascular events. After a median follow-up of 3.1 years, reliable improvement from depression symptoms was associated with a lower risk of new onset of any CVD [hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.86, 0.89], coronary heart disease (HR: 0.89, 95% CI: 0.86, 0.92), stroke (HR: 0.88, 95% CI: 0.83, 0.94), and all-cause mortality (HR: 0.81, 95% CI: 0.78, 0.84). This association was stronger in the under 60 compared with the over 60 for all outcomes. Results were confirmed in sensitivity analyses. Conclusion: Management of depression through psychological interventions may be associated with reduced risk of CVD. More research is needed to understand the causality of these associations

Current state of the evidence on community treatments for people with complex emotional needs:a scoping review

BACKGROUND: Improving the quality of care in community settings for people with 'Complex Emotional Needs' (CEN-our preferred working term for services for people with a "personality disorder" diagnosis or comparable needs) is recognised internationally as a priority. Plans to improve care should be rooted as far as possible in evidence. We aimed to take stock of the current state of such evidence, and identify significant gaps through a scoping review of published investigations of outcomes of community-based psychosocial interventions designed for CEN. METHODS: We conducted a scoping review with systematic searches. We searched six bibliographic databases, including forward and backward citation searching, and reference searching of relevant systematic reviews. We included studies using quantitative methods to test for effects on any clinical, social, and functioning outcomes from community-based interventions for people with CEN. The final search was conducted in November 2020. RESULTS: We included 226 papers in all (210 studies). Little relevant literature was published before 2000. Since then, publications per year and sample sizes have gradually increased, but most studies are relatively small, including many pilot or uncontrolled studies. Most studies focus on symptom and self-harm outcomes of various forms of specialist psychotherapy: most result in outcomes better than from inactive controls and similar to other specialist psychotherapies. We found large evidence gaps. Adaptation and testing of therapies for significant groups (e.g. people with comorbid psychosis, bipolar disorder, post-traumatic stress disorder, or substance misuse; older and younger groups; parents) have for the most part only reached a feasibility testing stage. We found little evidence regarding interventions to improve social aspects of people's lives, peer support, or ways of designing effective services. CONCLUSIONS: Compared with other longer term mental health problems that significantly impair functioning, the evidence base on how to provide high quality care for people with CEN is very limited. There is good evidence that people with CEN can be helped when specialist therapies are available and when they are able to engage with them. However, a much more methodologically robust and substantial literature addressing a much wider range of research questions is urgently needed to optimise treatment and support across this group

Mental health problems in people with learning disabilities: prevention, assessment and management

This guideline covers preventing, assessing and managing mental health problems in people with learning disabilities in all settings (including health, social care, education, and forensic and criminal justice). It aims to improve assessment and support for mental health conditions, and help people with learning disabilities and their families and carers to be involved in their care

Delivering stepped care: an analysis of implementation in routine practice

addresses: Mood Disorders Centre, University of Exeter, Exeter, EX4 4QG, UK. [email protected]: PMCID: PMC3283464types: Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't© 2012 Richards et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.In the United Kingdom, clinical guidelines recommend that services for depression and anxiety should be structured around a stepped care model, where patients receive treatment at different 'steps,' with the intensity of treatment (i.e., the amount and type) increasing at each step if they fail to benefit at previous steps. There are very limited data available on the implementation of this model, particularly on the intensity of psychological treatment at each step. Our objective was to describe patient pathways through stepped care services and the impact of this on patient flow and management

Kailo: a systemic approach to addressing the social determinants of young people’s mental health and wellbeing at the local level [version 1; peer review: awaiting peer review]

The mental health and wellbeing of children and young people is deteriorating. It is increasingly recognised that mental health is a systemic issue, with a wide range of contributing and interacting factors. However, the vast majority of attention and resources are focused on the identification and treatment of mental health disorders, with relatively scant attention on the social determinants of mental health and wellbeing and investment in preventative approaches. Furthermore, there is little attention on how the social determinants manifest or may be influenced at the local level, impeding the design of contextually nuanced preventative approaches. This paper describes a major research and design initiative called Kailo that aims to support the design and implementation of local and contextually nuanced preventative strategies to improve children's and young people’s mental health and wellbeing. The Kailo Framework involves structured engagement with a wide range of local partners and stakeholders - including young people, community partners, practitioners and local system leaders - to better understand local systemic influences and support programmes of youth-centred and evidence-informed co-design, prototyping and testing. It is hypothesised that integrating different sources of knowledge, experience, insight and evidence will result in better embedded, more sustainable and more impactful strategies that address the social determinants of young people’s mental health and wellbeing at the local level

Impact on mental health care and on mental health service users of the COVID-19 pandemic: a mixed methods survey of UK mental health care staff

PURPOSE: The COVID-19 pandemic has potential to disrupt and burden the mental health care system, and to magnify inequalities experienced by mental health service users. METHODS: We investigated staff reports regarding the impact of the COVID-19 pandemic in its early weeks on mental health care and mental health service users in the UK using a mixed methods online survey. Recruitment channels included professional associations and networks, charities, and social media. Quantitative findings were reported with descriptive statistics, and content analysis conducted for qualitative data. RESULTS: 2,180 staff from a range of sectors, professions, and specialties participated. Immediate infection control concerns were highly salient for inpatient staff, new ways of working for community staff. Multiple rapid adaptations and innovations in response to the crisis were described, especially remote working. This was cautiously welcomed but found successful in only some clinical situations. Staff had specific concerns about many groups of service users, including people whose conditions are exacerbated by pandemic anxieties and social disruptions; people experiencing loneliness, domestic abuse and family conflict; those unable to understand and follow social distancing requirements; and those who cannot engage with remote care. CONCLUSION: This overview of staff concerns and experiences in the early COVID-19 pandemic suggests directions for further research and service development: we suggest that how to combine infection control and a therapeutic environment in hospital, and how to achieve effective and targeted tele-health implementation in the community, should be priorities. The limitations of our convenience sample must be noted

Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals

This is the final version. Available on open access from Impact Journals via the DOI in this recordDNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p&lt;0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension