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A Realist Evaluation of Social Care Practitioners' Experiences With and Understanding of Applied Healthcare Research.
Social care practitioners are often under-represented in research activity and output. Evidence-based practice enables social care practitioners to develop/engage the skills to evaluate evidence and be more actively involved in research. REalist Synthesis Of non-pharmacologicaL interVEntions for antipsychotic-induced weight gain (RESOLVE) is a NIHR-funded study where realist synthesis is used to understand and explain how, why, for whom, and in what contexts non-pharmacological interventions help service users, with severe mental illness, to manage antipsychotic-induced weight gain. Social care practitioners are a key part of the team providing care for people living with severe mental illness and therefore supporting antipsychotic-induced weight gain. The current study, RESOLVE 2, uses realist evaluation and RESOLVE as an illustrative example to help understand why and how social care practitioners engage (or not) with research. Semi-structured, audio-recorded interviews will be undertaken with a purposive sample of approximately 20 social care practitioners working with people who have severe mental illness, are treated with antipsychotics, and have experienced weight gain. Participants will be recruited from NHS Trusts and recruitment avenues such as social media and personal networks. Topics discussed during interviews will include barriers and facilitators to engagement in research, current, and past engagement as well as recommendations for researchers and other practitioners. Interview recordings will be transcribed verbatim and analyzed using realist evaluation which will allow in-depth causal explanations for research engagement. Better understanding of research engagement by social care practitioners will allow for evidence-based practice and better patient outcomes within these settings.
Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030.
Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.
Topiramate and Metformin Are Effective Add-On Treatments in Controlling Antipsychotic-Induced Weight Gain: A Systematic Review and Network Meta-Analysis.
Background: Antipsychotic drugs may lead to side effects such as obesity, diabetes, dyslipidemia, and cardiovascular disease. The current systematic review and network meta-analysis analyzes and provides an update on the clinical performance of these add-ons in comparison to placebo on body weight and body mass index (BMI) reductions. Methods: A comprehensive literature search was performed on electronic databases: PubMed (1946-), Embase (1974-), Cochrane library (1992-), and OpenGrey (2000-) until 31 July 2018. Network meta-analyses, comparing the body weight change, BMI change and withdrawn due to adverse events of different pharmacological add-ons, was performed using a multivariate meta-regression model with random-effects, adopting a frequentist approach. To rank the prognosis for all add-ons, we used surface under the cumulative ranking (SUCRA) values. Outcomes: From 614 potential studies identified, 27 eligible studies (n = 1,349 subjects) were included. All the studies demonstrated low to moderate risk of bias. For the analysis of body weight change, all add-ons except Ranitidine showed significant weight reductions comparing to placebo. The effectiveness rank based on SUCRA results from highest to lowest was Sibutramine, Topiramate, Metformin, Reboxetine, Ranitidine, and placebo. A similar pattern was seen for BMI change. The analysis of safety outcome did not detect significantly increased withdrawn number from the add-ons. Current evidence showed relatively good tolerance and safety of using the pharmacological add-ons. Interpretation: Topiramate and Metformin are effective add-on treatments in controlling antipsychotic-induced weight gain, comparing to placebo. They are well tolerated in short-term period. Although Sibutramine has the highest rank of the effectiveness, its license has been withdrawn in many countries due to its adverse effects. Hence, Sibutramine should not be adopted to treat antipsychotic-induced weight gain.
Insight, social knowledge and working memory in schizophrenia.
BACKGROUND: There is evidence that insight and social judgements are impaired in schizophrenia. The influence of these factors on the decision to treat compulsorily in schizophrenia is poorly understood. AIMS: To investigate the contribution of insight, social knowledge, and working memory to the determination to treat coercively in schizophrenia. METHOD: Insight rating scale, social knowledge questionnaire and working memory tests were administered to detained patients with schizophrenia. Results were compared with those of a control group of voluntary in-patients with schizophrenia. RESULTS: Detained patients scored worse on insight and social knowledge, yet there was no significant correlation between these scores. There was no significant difference in severity of psychopathology between the experimental and control groups. Results for working memory were inconclusive. CONCLUSION: Insight and social knowledge are significantly, but independently, associated with the determination to treat coercively in schizophrenia. This suggests that insight and social knowledge are distinct skills. The contribution of working memory remains unclear.
A cross-sectional examination of the clinical significance of autistic traits in individuals experiencing a first episode of psychosis.
Autism traits are found at elevated rates in individuals with schizophrenia spectrum disorders, however, there is a lack of evidence regarding potential clinical impact. The current research aimed to examine potential associations between autism traits and symptoms of psychosis, social and role functioning, and quality of life. 99 individuals experiencing a first episode of psychosis took part in a cross-sectional interview and self-report questionnaire which assessed current symptoms of psychosis, autism traits, functioning, and quality of life. Participants were found to have a high level of autism traits. Higher autism traits were associated with poorer quality of life, functioning, and current psychotic symptoms. Receiver operating characteristic curve (ROC) analyses indicated that optimal AQ cut-off scores to predict severity of psychosis symptoms, functioning, and quality of life were lower than those used to suggest likely autism-spectrum diagnosis. Results suggest that autism traits are associated with poorer clinical presentation in first-episode psychosis populations, even in those whose traits fall below potentially diagnostic thresholds for autism. Psychosis services should be prepared to adequately address the needs of individuals with higher autism traits.
The psychosis metabolic risk calculator (PsyMetRiC) for young people with psychosis: International external validation and site-specific recalibration in two independent European samples.
BACKGROUND: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors. METHODS: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered. FINDINGS: We included 1024 participants (PsyMetab n=558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n=466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration. INTERPRETATION: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality. FUNDING: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section.
The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.
BACKGROUND: The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. FINDINGS: Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). INTERPRETATION: Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.
Cultural and social influences of negative illness appraisals in first-episode psychosis.
BACKGROUND: In the UK, there has been growing concern about the incidence and prognosis of psychosis in minority ethnic groups for a number of years. Negative self-appraisals after first-episode psychosis (FEP) are associated with post-psychotic depression, poor functioning and suicidality. In carers, appraisals of loss and decreased control are linked with high expressed emotion and relapse; however, as yet there has been no investigation as to how ethnicity and culture relate to these negative appraisals in FEP. AIMS: The study aims to investigate the occurrence of negative illness appraisals, for example, loss and shame, in FEP within different ethnic and social-cultural groups. In addition, it aims to explore influence of insight, recovery style and carers' appraisals in the development of negative appraisals. METHODS: There were 67 patients and 46 carers who completed reliable and valid measures on beliefs about illness, insight and recovery style. Data on ethnicity and deprivation were also collected. RESULTS: Black patients experienced significantly less loss, lack of control and entrapment than White, Asian and mixed ethnicity patients, yet these were not explained by lower levels of insight or recovery style. Patient's and carer's appraisals were highly correlated. CONCLUSION: Black patients, in spite of higher incidence and poorer outcome in FEP, experienced less loss and shame. Possible explanations, including a protective aspect of alternative health belief models, are explored. This area provides much scope for further investigation. Strong relationships between patient and carer appraisals indicate that family interventions are essential to improved clinical outcomes.
A prospective study of PTSD following recovery from first-episode psychosis: the threat from persecutors, voices, and patienthood.
OBJECTIVES: Approximately one third of people with early psychosis report post-traumatic symptoms, some of which are thought to arise from traumatic experiences associated with psychosis itself. This prospective study tested hypotheses based on retrospective findings that threat appraisals of voices, persecutors, or the new label of 'mental health patient' predict symptoms of post-traumatic stress disorder (PTSD). METHODS: Appraisals of power and threat from voices and other persecutors and appraisals of the threat posed to identity by the diagnosis were assessed during the first acute phase of psychosis. Eighteen months later, PTSD symptom levels and diagnosis were established. DESIGN: Prospective. RESULTS: Of 39 participants who completed the follow-up phase, 12 (31%) met criteria for PTSD diagnosis. Nineteen (49%) of the participants were still distressed by memories of their psychosis or the associated treatment. During the acute phase of psychosis, appraisals of threat from voices and persecutors were strongly associated with distress. With the exception of the perceived ability to cope with threat, none of these appraisals were predictive of subsequent post-traumatic stress however. Similarly, only one appraisal of the diagnosis (loss of control) was predictive of PTSD. CONCLUSION: It may be that retrospective studies have overestimated the influence of candidate appraisals in predicting PTSD. It might also be that assessments made during the acute phase of psychosis preceded a key phase of psychological processing that takes place during the immediate aftermath of the psychotic episode. A staged prospective design is required to uncover the true impact of psychosis on PTSD.
'Schizophrenia postdrome': a study of low-level psychotic experience after remission of first-episode schizophrenia.
BACKGROUND: Despite remission being the primary objective following the first episode of schizophrenia, clinically stabilized patients nevertheless relapse. AIM: To assess the extent and fluctuation of low-level psychotic symptoms in patients who are in remission after first-episode schizophrenia and consider whether this is equivalent to symptomatology experienced by those at 'ultra high risk' (UHR) of developing first-episode psychosis. METHODS: We examined the phenomenological characteristics of 11 patients who fulfilled international remission criteria using the Structured Interview for Prodromal Symptoms and compared this cohort with an UHR sample. RESULTS: Remitted patients were experiencing attenuated positive symptoms (73%) and brief limited intermittent psychotic symptoms (18%), features that were similarly prevalent in the UHR group. There was no significant fluctuation in these low-level symptoms over the course of four interviews. CONCLUSIONS: Although further research is required in this novel field, such features could form the building blocks for better prediction of psychotic relapse.
Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.
BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.
Development and validation of multivariable prediction models of remission, recovery, and quality of life outcomes in people with first episode psychosis: a machine learning approach.
BACKGROUND: Outcomes for people with first-episode psychosis are highly heterogeneous. Few reliable validated methods are available to predict the outcome for individual patients in the first clinical contact. In this study, we aimed to build multivariable prediction models of 1-year remission and recovery outcomes using baseline clinical variables in people with first-episode psychosis. METHODS: In this machine learning approach, we applied supervised machine learning, using regularised regression and nested leave-one-site-out cross-validation, to baseline clinical data from the English Evaluating the Development and Impact of Early Intervention Services (EDEN) study (n=1027), to develop and internally validate prediction models at 1-year follow-up. We assessed four binary outcomes that were recorded at 1 year: symptom remission, social recovery, vocational recovery, and quality of life (QoL). We externally validated the prediction models by selecting from the top predictor variables identified in the internal validation models the variables shared with the external validation datasets comprised of two Scottish longitudinal cohort studies (n=162) and the OPUS trial, a randomised controlled trial of specialised assertive intervention versus standard treatment (n=578). FINDINGS: The performance of prediction models was robust for the four 1-year outcomes of symptom remission (area under the receiver operating characteristic curve [AUC] 0·703, 95% CI 0·664-0·742), social recovery (0·731, 0·697-0·765), vocational recovery (0·736, 0·702-0·771), and QoL (0·704, 0·667-0·742; p<0·0001 for all outcomes), on internal validation. We externally validated the outcomes of symptom remission (AUC 0·680, 95% CI 0·587-0·773), vocational recovery (0·867, 0·805-0·930), and QoL (0·679, 0·522-0·836) in the Scottish datasets, and symptom remission (0·616, 0·553-0·679), social recovery (0·573, 0·504-0·643), vocational recovery (0·660, 0·610-0·710), and QoL (0·556, 0·481-0·631) in the OPUS dataset. INTERPRETATION: In our machine learning analysis, we showed that prediction models can reliably and prospectively identify poor remission and recovery outcomes at 1 year for patients with first-episode psychosis using baseline clinical variables at first clinical contact. FUNDING: Lundbeck Foundation.
The relapse rate and predictors of relapse in patients with first-episode psychosis following discontinuation of antipsychotic medication.
BACKGROUND: To determine the "real world" relapse rate in patients with first-episode psychosis (FEP) who had discontinued antipsychotic medication and identify socio-demographic and clinical factors associated with the risk of relapse. METHODS: Quantitative data were obtained via case-note review on 63 patients with FEP who had discontinued antipsychotic medication from Birmingham Early Intervention Service between 2012 and 2015. The follow-up period was until either: an occurrence of a relapse; end of 12-month study period; end of patient's case-note record. Relapse was defined as a return of symptoms requiring one of the following: home treatment, hospital admission or was based on clinical teams' decision as having a relapse. A pro-forma targeted pre-defined socio-demographic and clinical factors. Survival analysis was undertaken to estimate the 12-month relapse rate following discontinuation of antipsychotics and Cox regression performed to identify relapse predictors. RESULTS: The Kaplan-Meier 12-month relapse estimate was 67% (95% confidence interval, 54%, 80%). Significant factors (P < .05) independently associated with an increased risk of relapse following discontinuation of antipsychotic medication were: male gender, not being in education, employment or training (NEET) and number of previous psychiatric hospital admissions. CONCLUSIONS: Relapse is common after discontinuation of antipsychotic medication following recovery from a FEP. It is important that patients who wish to discontinue their medication are informed of the high relapse rates and the associated risks. Furthermore, male patients, patients with NEET status and those who have had previous hospital admissions may require closer monitoring.
Treatment of depression in schizophrenia: systematic review and meta-analysis.
BackgroundDepression in schizophrenia predicts poor outcomes, including suicide, yet the effectiveness of antidepressants for its treatment remains uncertain.AimsTo synthesise the evidence of the effectiveness of antidepressants for the treatment of depression in schizophrenia.MethodMultiple databases were searched and inclusion criteria included participants aged over 18 years with schizophrenia or related psychosis with a depressive episode. Papers were quality assessed used the Cochrane risk bias tool. Meta-analyses were performed for risk difference and standardised mean difference of all antidepressants, antidepressant class and individual antidepressant where sufficient studies allowed.ResultsA total of 26 moderate- to low-quality trials met inclusion criteria. In meta-analysis a significant risk difference was found in favour of antidepressant treatment, with a number needed to treat of 5 (95% CI 4-9). Studies using tools specifically designed to assess depression in schizophrenia showed a larger effect size. However, after sensitivity analysis standardised mean difference of all antidepressants did not show a statistically significant improvement in depression score at end-point, neither did any individual antidepressant class.ConclusionsAntidepressants may be effective for the treatment of depression in schizophrenia, however, the evidence is mixed and conclusions must be qualified by the small number of low- or moderate-quality studies. Further sufficiently powered, high-quality studies are needed.
The views of early intervention service staff on the treatment of first episode bipolar disorder.
OBJECTIVE: Little is known about how first episode bipolar disorder (BD) is managed in early intervention for psychosis services (EIS). We aimed to investigate the knowledge and views of EIS staff on the assessment and treatment of BD. METHODS: A 27-item anonymised online questionnaire was distributed to EIS mental health professionals in England. Descriptive data analysis was undertaken. RESULTS: Responses were received from 117 EIS staff. Most were 'fairly confident' in their knowledge about causes, presentations and relapse indicators of BD, but less confident on pharmacological and psychological treatments. Eighty five percent expressed the view that more BD training was necessary in this area with 78% reporting no clear care packages within the service. Seventy two percent believe early BD should be treated within EIS only if patients have psychosis. CONCLUSIONS: Clearer care packages and staff training are needed for EIS staff to optimise care for BD.
Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: systematic review and meta-analyses.
BACKGROUND: A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.AimsTo synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness. METHOD: Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses. RESULTS: In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified. CONCLUSIONS: Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.Declaration of interestNone.