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BACKGROUND: Sleep disturbance is common and problematic for young people at ultra-high risk of psychosis. Sleep disruption is a contributory causal factor in the occurrence of mental health problems, including psychotic experiences, anxiety, and depression. The implication is that treating sleep problems might have additional benefits on mental health outcomes in individuals at high risk. The present study had two aims: first, to establish the feasibility and acceptability of a randomised controlled trial to treat sleep problems with the aim of reducing psychotic experiences in young people at ultra-high risk of psychosis; and second, to provide proof of concept of the clinical efficacy of the treatment. METHODS: We did a parallel group, single-blind, randomised controlled feasibility trial in two National Health Service trusts in England. Eligible participants were aged 14-25 years, a patient of mental health services, assessed as being at ultra-high risk of psychosis on the Comprehensive Assessment of At-Risk Mental States, and having current sleep problems (score of \u226515 on the self-report Insomnia Severity Index [ISI]). Participants were randomly assigned (1:1) to either a targeted psychological therapy for sleep problems (SleepWell) plus usual care or usual care alone via an automated online system, with non-deterministic minimisation that balanced participants for ISI score and referring service. The SleepWell therapy was delivered on an individual basis in approximately eight 1-h sessions over 12 weeks. Assessments were done at 0, 3, and 9 months, with trial assessors masked to treatment allocation. The key feasibility outcomes were the numbers of patients identified, recruited, and retained, treatment uptake, and data completion. Treatment acceptability was measured with the Abbreviated Acceptability Rating Profile (AARP). In preliminary clinical assessments, the primary clinical outcome was insomnia at 3 and 9 months assessed with the ISI, reported by randomised group (intention-to-treat analysis). Safety was assessed in all randomly assigned participants. The trial was prospectively registered on ISRCTN, 85601537, and is completed. FINDINGS: From Nov 18, 2020, to Jan 26, 2022, 67 young people were screened, of whom 40 (60%) at ultra-high risk of psychosis were recruited. Mean age was 16\u00b79 years (SD 2\u00b75; range 14-23), and most participants identified as female (n=19 [48%]) or male (n=19 [48%]) and as White (n=32 [80%]). 21 participants were randomly assigned to SleepWell therapy plus usual care and 19 to usual care alone. All participants provided data on at least one follow-up visit. 39 (98%) of 40 participants completed the primary outcome assessment at 3 and 9 months. 20 (95%) of 21 participants assigned to SleepWell therapy received the prespecified minimum treatment dose of at least four sessions. The median treatment acceptability score on the AARP was 48 (IQR 46 to 48; n=17; maximum possible score 48). At the post-intervention follow-up (3 months), compared with the usual care alone group, the SleepWell therapy group had a reduction in insomnia severity (ISI adjusted mean difference -8\u00b712 [95% CI -11\u00b760 to -4\u00b763]; Cohen's d=-2\u00b767 [95% CI -3\u00b781 to -1\u00b752]), which was sustained at 9 months (ISI adjusted mean difference -5\u00b783 [-9\u00b731 to -2\u00b735]; Cohen's d=-1\u00b791 [-3\u00b706 to -0\u00b777]). Among the 40 participants, eight adverse events were reported in six participants (two [11%] participants in the usual care group and four [19%] participants in the SleepWell therapy group). One serious adverse event involving hospital admission for a physical health problem was reported in the SleepWell therapy group, and one patient in the usual care alone group transitioned to psychosis. None of these events were classed as being related to trial treatment or procedures. INTERPRETATION: A randomised controlled trial of a targeted psychological sleep therapy for young people at ultra-high risk of psychosis is feasible. Patients can be retained in the trial and assessments done by masked assessors. Uptake of the sleep therapy was high, and we found preliminary evidence of sustained reductions in sleep problems. A definitive multicentre trial is now needed. FUNDING: NIHR Research for Patient Benefit and NIHR Oxford Health Biomedical Research Centre.
\n \n\n \n \nPURPOSE: Acceptance and Commitment Therapy for psychosis (ACTp) is a contextual behavioural intervention that promotes psychological flexibility by fostering active acceptance, cognitive defusion, values construction and committed action to enhance well-being and recovery. Multiple studies have shown that ACTp is acceptable and efficacious, but questions remain as to its distinction from similar approaches and the conditions under which it would be implemented most effectively. METHODS: We present the current evidence for processes and outcomes of ACTp and summarise the qualitative findings of experiences of service users in ACT programmes. We compare ACTp with other cognitive behavioural therapies and mindfulness-informed interventions for psychosis. RESULTS: Acceptance and commitment therapy for psychosis is promising as a pragmatic, process-driven intervention model. Further efforts are needed to investigate psychological flexibility in the context of psychosis with observational, experimental and intervention studies that will inform model scope and treatment refinement. Additionally, implementation research is the necessary next step, including how support persons can be trained in ACTp. Lower intensity and technology-assisted approaches have the potential to reduce barriers to accessing ACTp and extend impact. CONCLUSIONS: Over the last 20\u2009years, ACTp has demonstrated meaningful effects in individual and group formats in a range of settings, targeting outcomes such as rehospitalisation, depression, psychotic symptom distress and impact. Future work should focus on how best to integrate ACTp with other current evidence-based interventions for psychosis.
\n \n\n \n \nDepression and anxiety are common psychological consequences of stroke. Here, we investigated the relationships between cognitive change following stroke, awareness of cognitive impairments, and mood to further understanding of change processes influencing psychological outcomes post-stroke in line with the \u201cY-shaped\u201d process model. Stroke patients (n = 143) were assessed at 3-weeks (T1) and 6-months (T2) post stroke and had completed the Oxford Cognitive Screen (T1 and T2), the Cognitive Failures Questionnaire (CFQ; T2), and the Hospital Anxiety and Depression Scale (HADS; T2). An ANCOVA controlling for disability relating to activities of daily living (ADL) revealed that awareness of cognitive impairment was significantly lower in participants with moderate-severe cognitive impairment. Regression analysis indicated that greater awareness of cognitive impairment and greater independence in ADL were associated with lower HADS scores at T2. Finally, cognitive improvement over time was associated with lower HADS scores at T2. This was moderated by acute cognitive impairment, suggesting that this effect was largest for those most cognitively impaired at T1. Together, predictors explained 36.9% variance in the model, whereby the interaction variable explained 2.2% variance. Targeting those most cognitively impaired post-stroke with cognitive rehabilitation may positively impact their long-term emotional adjustment.
\n \n\n \n \nBACKGROUND: Individuals from marginalised groups experience higher levels of mental health difficulties and lower levels of wellbeing which may be due to the exposure to stress and adversity. This study explores trajectories of mental health over time for young women and girls and young people with other marginalised identities. METHODS: We conducted a secondary analysis on N\u2009=\u200914,215 children and young people (7,501 or 52.8% female, 6,571 or 46.2% male, and 81 or 0.6% non-binary or questioning) who completed a survey at age 11 to 12 years and at least one other annual survey aged 12 to 13 years and/or aged 13 to 14 years. We used group-based trajectory models to examine mental health difficulties. RESULTS: Except for behavioural difficulties, young women's and girls' trajectories showed that they consistently had higher levels of mental health difficulties compared to young men and boys. A similar pattern was shown for non-binary and questioning children and young people. Children and young people with economic disadvantage and/or special education needs, and/or for whom there were welfare concerns, were generally more likely to experience higher levels of mental health difficulties. CONCLUSIONS: This information could inform public policy, guidance and interventions.
\n \n\n \n \nINTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.
\n \n\n \n \nLymph node (LN) fine needle aspiration (LN FNA) represents a powerful technique for minimally invasive sampling of human LNs in vivo and has been used effectively to directly study aspects of the human germinal center response. However, systematic deep phenotyping of the cellular populations and cell-free proteins recovered by LN FNA has not been performed. Thus, we studied human cervical LN FNAs as a proof-of-concept and used single-cell RNA-sequencing and proteomic analysis to benchmark this compartment, define the purity of LN FNA material, and facilitate future studies in this immunologically pivotal environment. Our data provide evidence that LN FNAs contain bone-fide LN-resident innate immune populations, with minimal contamination of blood material. Examination of these populations reveals unique biology not predictable from equivalent blood-derived populations. LN FNA supernatants represent a specific source of lymph- and lymph node-derived proteins, and can, aided by transcriptomics, identify likely receptor-ligand interactions. This represents the first description of the types and abundance of immune cell populations and cell-free proteins that can be efficiently studied by LN FNA. These findings are of broad utility for understanding LN physiology in health and disease, including infectious or autoimmune perturbations, and in the case of cervical nodes, neuroscience.
\n \n\n \n \nAIM: Clinical services for early psychosis seek to improve prognosis for a range of adverse outcomes. For some individuals, perpetration of violence is an important potential outcome to reduce. How these clinical services currently assess this risk however is uncertain. This study aimed to address this gap by using qualitative methods to examine in depth current approaches, attitudes and challenges to assessing violence risk in this clinical setting, from the perspectives of multidisciplinary clinicians, patients and carers. METHODS: Participants were recruited from two UK Early Intervention in Psychosis services. Semi-structured individual interviews were undertaken using a topic guide. In addition, clinical vignettes were presented to clinician participants as a probe to prompt discussion. Data were analysed using thematic analysis, informed by the constant comparative method. RESULTS: We conducted 30 qualitative interviews, of 18 clinicians and 12 patients and carers. Themes developed from clinician interviews included key difficulties of low confidence, limited training, accessing collateral information and variation in how risk is appraised and communicated. Potential stigma and sensitivity of the topic of violence\u00a0were perceived as barriers to its discussion. Patient and carer perspectives provided insight into how to address barriers, and highlighted the importance of an open approach, including with families. CONCLUSIONS: We recommend developing contextually appropriate pathways to collaboratively assess violence risk and identify modifiable needs to reduce this risk, and for practical improvements in training and information-sharing.
\n \n\n \n \nBACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25\u00a0years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12\u00a0weeks in 260 children and young people with TRS (12-24\u00a0years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12\u00a0weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12\u00a0months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12\u00a0weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.
\n \n\n \n \nAbstract\nThe frequency spectrum is a central method for representing the dynamics within electrophysiological data. Some widely used spectrum estimators make use of averaging across time segments to reduce noise in the final spectrum. The core of this approach has not changed substantially since the 1960s, though many advances in the field of regression modelling and statistics have been made during this time. Here, we propose a new approach, the General Linear Model (GLM) Spectrum, which reframes time averaged spectral estimation as multiple regression. This brings several benefits, including the ability to do confound modelling, hierarchical modelling, and significance testing via non-parametric statistics. We apply the approach to a dataset of EEG recordings of participants who alternate between eyes-open and eyes-closed resting state. The GLM-Spectrum can model both conditions, quantify their differences, and perform denoising through confound regression in a single step. This application is scaled up from a single channel to a whole head recording and, finally, applied to quantify age differences across a large group-level dataset. We show that the GLM-Spectrum lends itself to rigorous modelling of within- and between-subject contrasts as well as their interactions, and that the use of model-projected spectra provides an intuitive visualisation. The GLM-Spectrum is a flexible framework for robust multilevel analysis of power spectra, with adaptive covariate and confound modelling.
\n \n\n \n \nSleep restriction therapy is a behavioural component within cognitive behavioural therapy for insomnia and is an effective standalone treatment for insomnia, but its effect on depressive symptoms remains unclear. This review aimed to synthesise and evaluate the impact of single-component sleep restriction therapy on depressive symptoms relative to a control intervention. We searched electronic databases and sleep-related journals for randomised controlled trials and uncontrolled clinical trials, published from 1 January 1986 until 19 August 2023, that delivered sleep restriction therapy to adults with insomnia. Random-effects meta-analysis of standardised mean differences and Cochrane risk of bias assessment were performed on randomised controlled trials, while uncontrolled clinical trials were discussed narratively. The meta-analysis was pre-registered on PROSPERO (ID: CRD42020191803). We identified seven randomised controlled trials (N\u2009=\u20091102) and two uncontrolled clinical trials (N\u2009=\u200922). Findings suggest that sleep restriction therapy is associated with a medium effect for improvement in depressive symptoms at post-treatment (Nc \u2009=\u20096, g\u2009=\u2009-0.45 [95% confidence interval\u2009=\u2009-0.70 to -0.21], p\u2005
\n \n\n \n \nBACKGROUND: 'POD Adventures' is a gamified problem-solving intervention delivered via smartphone app, and supported by non-specialist counsellors for a target population of secondary school students in India during the COVID-19 pandemic. AIMS: To evaluate the feasibility and acceptability of undertaking a randomised controlled trial of POD Adventures when delivered online with telephone support from counsellors. METHOD: We conducted a parallel, two-arm, individually randomised pilot-controlled trial with 11 secondary schools in Goa, India. Participants received either the POD Adventures intervention delivered over 4 weeks or usual care comprising information about local mental health services and national helplines. Outcomes were assessed at two timepoints: baseline and 6 weeks post-randomisation. RESULTS: Seventy-nine classroom sensitisation sessions reaching a total of 1575 students were conducted. Ninety-two self-initiated study referrals (5.8%) were received, but only 11 participants enrolled in the study. No intervention arm participants completed the intervention. Outcomes at 6 weeks were not available for intervention arm participants (n = 5), and only four control arm participants completed outcomes. No qualitative interviews or participant satisfaction measures were completed because participants could not be reached by the study team. CONCLUSIONS: Despite modifications to address barriers arising from COVID-19 restrictions, online delivery was not feasible in the study context. Low recruitment and missing feasibility and acceptability data make it difficult to draw conclusions about intervention engagement and indicative clinical outcomes. Prior findings showing high uptake, adherence and engagement with POD Adventures when delivered in a school-based context suggest that an online study and delivery posed the biggest barriers to study participation and engagement.
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