Cognitive Remediation Works But How Should We Provide It? An Adaptive Randomized Controlled Trial of Delivery Methods Using a Patient Nominated Recovery Outcome in First-Episode Participants.

BACKGROUND AND HYPOTHESIS: Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes. STUDY DESIGN: A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles. STUDY RESULTS: We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen's d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen's d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen's d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment. CONCLUSIONS: Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation. TRIAL REGISTRATION: ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed.

Treating common mental disorder including psychotic experiences in the primary care improving access to psychological therapies programme (the TYPPEX study): protocol for a stepped wedge cluster randomised controlled trial with nested economic and process evaluation of a training package for therapists.

INTRODUCTION: At least one in four people treated by the primary care improving access to psychological therapies (IAPT) programme in England experiences distressing psychotic experiences (PE) in addition to common mental disorder (CMD). These individuals are less likely to achieve recovery. IAPT services do not routinely screen for nor offer specific treatments for CMD including PE. The Tailoring evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences study will evaluate the clinical and cost-effectiveness of an enhanced training for cognitive behavioural therapists that aims to address this clinical gap. METHODS AND ANALYSIS: This is a multisite, stepped-wedge cluster randomised controlled trial. The setting will be IAPT services within three mental health trusts. The participants will be (1) 56-80 qualified IAPT cognitive behavioural therapists and (2) 600 service users who are triaged as appropriate for cognitive behavioural therapy in an IAPT service and have PE according to the Community Assessment of Psychic Experiences-Positive 15-items Scale. IAPT therapists will be grouped into eight study clusters subsequently randomised to the control-intervention sequence. We will obtain pseudonymous clinical outcome data from IAPT clinical records for eligible service users. We will invite service users to complete health economic measures at baseline, 3, 6, 9 and 12-month follow-up. The primary outcome will be the proportion of patients with common mental disorder psychotic experiences who have recovered by the end of treatment as measured by the official IAPT measure for recovery. ETHICS AND DISSEMINATION: The study received the following approvals: South Central-Berkshire Research Ethics Committee on 28 April 2020 (REC reference 20/SC/0135) and Health Research Authority (HRA) on 23 June 2020. An amendment was approved by the Ethics Committee on 01 October 2020 and HRA on 27 October 2020. Results will be made available to patients and the public, the funders, stakeholders in the IAPT services and other researchers. TRIAL REGISTRATION NUMBER: ISRCTN93895792.

Clinical and cost-effectiveness of social recovery therapy for the prevention and treatment of long-term social disability among young people with emerging severe mental illness (PRODIGY): randomised controlled trial.

BACKGROUND: Young people with social disability and severe and complex mental health problems have poor outcomes, frequently struggling with treatment access and engagement. Outcomes may be improved by enhancing care and providing targeted psychological or psychosocial intervention. AIMS: We aimed to test the hypothesis that adding social recovery therapy (SRT) to enhanced standard care (ESC) would improve social recovery compared with ESC alone. METHOD: A pragmatic, assessor-masked, randomised controlled trial (PRODIGY: ISRCTN47998710) was conducted in three UK centres. Participants (n = 270) were aged 16-25 years, with persistent social disability, defined as under 30 hours of structured activity per week, social impairment for at least 6 months and severe and complex mental health problems. Participants were randomised to ESC alone or SRT plus ESC. SRT was an individual psychosocial therapy delivered over 9 months. The primary outcome was time spent in structured activity 15 months post-randomisation. RESULTS: We randomised 132 participants to SRT plus ESC and 138 to ESC alone. Mean weekly hours in structured activity at 15 months increased by 11.1 h for SRT plus ESC (mean 22.4, s.d. = 21.4) and 16.6 h for ESC alone (mean 27.7, s.d. = 26.5). There was no significant difference between arms; treatment effect was -4.44 (95% CI -10.19 to 1.31, P = 0.13). Missingness was consistently greater in the ESC alone arm. CONCLUSIONS: We found no evidence for the superiority of SRT as an adjunct to ESC. Participants in both arms made large, clinically significant improvements on all outcomes. When providing comprehensive evidence-based standard care, there are no additional gains by providing specialised SRT. Optimising standard care to ensure targeted delivery of existing interventions may further improve outcomes.

Social recovery therapy for young people with emerging severe mental illness: the Prodigy RCT.

BACKGROUND: Young people with social disability and non-psychotic severe and complex mental health problems are an important group. Without intervention, their social problems can persist and have large economic and personal costs. Thus, more effective evidence-based interventions are needed. Social recovery therapy is an individual therapy incorporating cognitive-behavioural techniques to increase structured activity as guided by the participant's goals. OBJECTIVE: This trial aimed to test whether or not social recovery therapy provided as an adjunct to enhanced standard care over 9 months is superior to enhanced standard care alone. Enhanced standard care aimed to provide an optimal combination of existing evidence-based interventions. DESIGN: A pragmatic, single-blind, superiority randomised controlled trial was conducted in three UK centres: Sussex, Manchester and East Anglia. Participants were aged 16-25 years with persistent social disability, defined as < 30 hours per week of structured activity with social impairment for at least 6 months. Additionally, participants had severe and complex mental health problems, defined as at-risk mental states for psychosis or non-psychotic severe and complex mental health problems indicated by a Global Assessment of Functioning score ≤ 50 persisting for ≥ 6 months. Two hundred and seventy participants were randomised 1 : 1 to either enhanced standard care plus social recovery therapy or enhanced standard care alone. The primary outcome was weekly hours spent in structured activity at 15 months post randomisation. Secondary outcomes included subthreshold psychotic, negative and mood symptoms. Outcomes were collected at 9 and 15 months post randomisation, with maintenance assessed at 24 months. RESULTS: The addition of social recovery therapy did not significantly increase weekly hours in structured activity at 15 months (primary outcome treatment effect -4.44, 95% confidence interval -10.19 to 1.31). We found no evidence of significant differences between conditions in secondary outcomes at 15 months: Social Anxiety Interaction Scale treatment effect -0.45, 95% confidence interval -4.84 to 3.95; Beck Depression Inventory-II treatment effect -0.32, 95% confidence interval -4.06 to 3.42; Comprehensive Assessment of At-Risk Mental States symptom severity 0.29, 95% confidence interval -4.35 to 4.94; or distress treatment effect 4.09, 95% confidence interval -3.52 to 11.70. Greater Comprehensive Assessment of At-Risk Mental States for psychosis scores reflect greater symptom severity. We found no evidence of significant differences at 9 or 24 months. Social recovery therapy was not estimated to be cost-effective. The key limitation was that missingness of data was consistently greater in the enhanced standard care-alone arm (9% primary outcome and 15% secondary outcome missingness of data) than in the social recovery therapy plus enhanced standard care arm (4% primary outcome and 9% secondary outcome missingness of data) at 15 months. CONCLUSIONS: We found no evidence for the clinical superiority or cost-effectiveness of social recovery therapy as an adjunct to enhanced standard care. Both arms made large improvements in primary and secondary outcomes. Enhanced standard care included a comprehensive combination of evidence-based pharmacological, psychotherapeutic and psychosocial interventions. Some results favoured enhanced standard care but the majority were not statistically significant. Future work should identify factors associated with the optimal delivery of the combinations of interventions that underpin better outcomes in this often-neglected clinical group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47998710. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 25, No. 70. See the NIHR Journals Library website for further project information.

Young people with social disability and non-psychotic severe and complex mental health problems are an important group. Their problems are often long-standing and they often have difficulty doing 'structured activity', such as work, sports and leisure activities (e.g. going shopping or to the cinema). They often avoid such activities because of anxiety or low mood. Other barriers may include financial and practical issues, and stigma from activity providers. Non-participation in structured activity increases the risk that mental health problems will continue and prevent these young people from reaching meaningful goals. We tested whether or not social recovery therapy might help. This is a talking and activity therapy, in which young people (participants) work individually with a social recovery therapy therapist. Social recovery therapy aims to help participants identify what activities they would like to do, practise spending more time doing them, and work through barriers to maintaining increased activity. By improving structured activity, young people feel more hopeful and better able to manage their symptoms. However, social recovery therapy has never been evaluated properly using the best research methods. The best way to evaluate treatments like this is a randomised controlled trial in which participants are allocated by chance, like tossing a coin, to have the new therapy or not to have the therapy. Both groups are followed up for a period to see if the new therapy works. We tested social recovery therapy in this way. We also tested whether or not it was cost-effective. We recruited 270 16- to 25-year-old participants in Sussex, East Anglia and Manchester. Participants had non-psychotic severe and complex mental health problems (not psychosis) and were doing < 30 hours of structured activity per week at the start of the study. All participants had enhanced standard care. This involved standard NHS treatment plus a full assessment and feedback from the study team, and a best practice guide to local support services that encouraged the best provision of standard evidence-based interventions. Half of the participants were randomly allocated to have social recovery therapy in addition to enhanced standard care over 9 months. All participants were invited to assessments 9, 15 and 24 months later. Therapists recorded the tasks and activities undertaken with participants. We asked both participants and therapists what they thought of the trial and the social recovery therapy. We found no evidence that adding social recovery therapy improved outcomes. Participants in both arms made large and clinically worthwhile improvements in structured activity and mental health outcomes. If anything, there was some evidence that people allocated to enhanced standard care improved more than those allocated to social recovery therapy plus enhanced standard care. The differences were small, however, and could have occurred by chance.

The Early Youth Engagement in first episode psychosis (EYE-2) study: pragmatic cluster randomised controlled trial of implementation, effectiveness and cost-effectiveness of a team-based motivational engagement intervention to improve engagement.

BACKGROUND: Early Intervention in Psychosis (EIP) services improve health outcomes for young people with psychosis in the medium-long term, but 25% of young people disengage in the first 12 months with costs to their mental health, families, society and the NHS. This study will evaluate the effectiveness, cost-effectiveness and implementation of a team-based motivational Early Youth Engagement (EYE-2) intervention. METHOD: The study design is a cluster randomised controlled trial (RCT) with economic evaluation, comparing the EYE-2 intervention + standardised EIP service to standardised EIP service alone, with randomisation at the team level. A process evaluation will evaluate the delivery of the intervention qualitatively and quantitatively across contexts. The setting is 20 EIP teams in 5 sites: Manchester, South London, East Anglia, Thames Valley and Hampshire. Participants are young people (14-35 years) with first episode psychosis, and EIP staff. The intervention is the team-based motivational engagement (EYE-2) intervention, delivered alongside standardised EIP services, and supported by additional training, website, booklets and social groups. The comparator is the standardised EIP service. Both interventions are delivered by EIP clinicians. The primary outcome is time to disengagement (time in days from date of allocation to care coordinator to date of last contact following refusal to engage with EIP service, or lack of response to EIP contact for a consecutive 3-month period). Secondary outcomes include mental and physical health, deaths, social and occupational function, recovery, satisfaction and service use at 6, 12, 18 and 24 months. A 12-month within-trial economic evaluation will investigate cost-effectiveness from a societal perspective and from an NHS perspective. DISCUSSION: The trial will provide the first test of an engagement intervention in standardised care, with the potential for significant impact on the mental health and wellbeing of young people and their families, and economic benefits for services. The intervention will be highly scalable, supported by the toolkit including manuals, commissioning guide, training and resources, adapted to meet the needs of the diverse EIP population, and based on an in-depth process evaluation. TRIAL REGISTRATION: ISRCTN 51629746 prospectively registered 7th May 2019. Date assigned 10th May 2019.

Psychological interventions for people with psychotic experiences: A systematic review and meta-analysis of controlled and uncontrolled effectiveness and economic studies.

OBJECTIVE: Many people with psychotic experiences do not develop psychotic disorders, yet those who seek help demonstrate high clinical complexity and poor outcomes. In this systematic review and meta-analysis, we evaluated the effectiveness and cost-effectiveness of psychological interventions for people with psychotic experiences. METHOD: We searched 13 databases for studies of psychological interventions for adults with psychotic experiences, but not psychotic disorders. Our outcomes were the proportion of participants remitting from psychotic experiences (primary); changes in positive and negative psychotic symptoms, depression, anxiety, functioning, distress, and quality of life; and economic outcomes (secondary). We analysed results using multilevel random-effects meta-analysis and narrative synthesis. RESULTS: A total of 27 reports met inclusion criteria. In general, there was no strong evidence for the superiority of any one intervention. Five studies reported on our primary outcome, though only two reports provided randomised controlled trial evidence that psychological intervention (specifically, cognitive behavioural therapy) promoted remission from psychotic experiences. For secondary outcomes, we could only meta-analyse trials of cognitive behavioural therapy. We found that cognitive behavioural therapy was more effective than treatment as usual for reducing distress (pooled standardised mean difference: -0.24; 95% confidence interval = [-0.37, -0.10]), but no more effective than the control treatment for improving any other outcome. Individual reports indicated that cognitive behavioural therapy, mindfulness-based cognitive therapy, sleep cognitive behavioural therapy, systemic therapy, cognitive remediation therapy, and supportive treatments improved at least one clinical or functional outcome. Four reports included economic evaluations, which suggested cognitive behavioural therapy may be cost-effective compared with treatment as usual. CONCLUSION: Our meta-analytic findings were primarily null, with the exception that cognitive behavioural therapy may reduce the distress associated with psychotic experiences. Our analyses were limited by scarcity of studies, small samples and variable study quality. Several intervention frameworks showed preliminary evidence of positive outcomes; however, the paucity of consistent evidence for clinical and functional improvement highlights a need for further research into psychological treatments for psychotic experiences. PROSPERO PROTOCOL REGISTRATION NUMBER: CRD42016033869.

Increasing access to CBT for psychosis patients: a feasibility, randomised controlled trial evaluating brief, targeted CBT for distressing voices delivered by assistant psychologists (GiVE2).

BACKGROUND: The National Institute for Health and Care Excellence (NICE) recommends that Cognitive Behaviour Therapy for psychosis (CBTp) is offered to all patients with a psychosis diagnosis. However, only a minority of psychosis patients in England and Wales are offered CBTp. This is attributable, in part, to the resource-intensive nature of CBTp. One response to this problem has been the development of CBTp in brief formats that are targeted at a single symptom and the mechanisms that maintain distress. We have developed a brief form of CBTp for distressing voices and reported preliminary evidence for its effectiveness when delivered by highly trained therapists (clinical psychologists). This study will investigate the delivery of this intervention by a cost-effective workforce of assistant psychologists following a brief training and evaluate the acceptability and feasibility of conducting a future, definitive, randomised controlled trial (RCT). METHODS: This is a feasibility study for a pragmatic, three-arm, parallel-group, superiority 1:1:1 RCT comparing a Guided self-help CBT intervention for voices and treatment as usual (GiVE) to Supportive Counselling and treatment as usual (SC) to treatment as usual alone (TAU), recruiting across two sites, with blinded post-treatment and follow-up assessments. A process evaluation will quantitatively and qualitatively explore stakeholder experience. DISCUSSION: Expected outcomes will include an assessment of the feasibility of conducting a definitive RCT, and data to inform the calculation of its sample size. If evidence from a subsequent, fully powered RCT suggests that GiVE is clinically and cost-effective when delivered by briefly trained assistant psychologists, CBTp offered in these less resource-intensive forms has the potential to generate benefits for individual patients (reduced distress, enhanced recovery and enhanced quality of life), service-level patient benefit (increased access to evidence-based psychological therapies) and economic benefits to the NHS (in terms of the reduced use of mental health inpatient services). TRIAL REGISTRATION: Current Controlled Trials, ISRCTN registration number: 16166070. Registered on 5 February 2019.

A contingency management intervention to reduce cannabis use and time to relapse in early psychosis: the CIRCLE RCT.

BACKGROUND: Cannabis is the most prevalent illicit substance among people with psychosis, and its use is associated with poorer clinical and social outcomes. However, so far, there has been limited evidence that any treatment is effective for reducing use. Contingency management (CM) is an incentive-based intervention for substance misuse that has a substantial evidence base across a range of substances and cohorts. However, to date there have been no randomised controlled trials (RCTs) of CM as a treatment for cannabis use specifically in psychosis. OBJECTIVE: To conduct a RCT investigating the clinical effectiveness and cost-effectiveness of CM in reducing cannabis use among Early Intervention in Psychosis (EIP) service users. DESIGN: The CIRCLE (Contingency Intervention for Reduction of Cannabis in Early Psychosis) trial was a rater-blinded, multicentre RCT with two arms. Participants were randomised 1 : 1 to either an CM arm, in which participants received CM for cannabis use alongside an optimised treatment-as-usual programme including structured psychoeducation, or a control arm in which participants received the treatment as usual only. SETTING: EIP services across the Midlands and the south-east of England. PARTICIPANTS: The main eligibility criteria were EIP service users with a history of psychosis, aged 18-36 years, and having used cannabis at least once per week during 12 of the previous 24 weeks. INTERVENTION: The CM intervention offered financial incentives (i.e. shopping vouchers) for cannabis abstinence over 12 once-weekly sessions, confirmed using urinalysis. The maximum value in vouchers that participants could receive was £240. MAIN OUTCOME MEASURES: The main outcome was time to relapse, operationalised as admission to an acute mental health service or hospital. The primary outcome was assessed at 18 months post inclusion using electronic patient records. Secondary outcomes assessed the clinical effectiveness and cost-effectiveness of the intervention, for which data were collected at 3 and 18 months. RESULTS: A total of 278 participants were randomised to the CM arm and 273 were randomised to the control arm. In total, 530 (96%) participants were followed up for the primary outcome. There was no significant difference in time to admission between trial arms by 18 months following consent (hazard ratio 1.03, 95% confidence interval 0.76 to 1.40). There were no statistically significant differences in most secondary outcomes, including cannabis use, at either follow-up assessment. There were 58 serious adverse events, comprising 52 inpatient episodes, five deaths and one arrest. LIMITATIONS: Participant retention was low at 18 months, limiting the assessment of secondary outcomes. A different CM intervention design or reward level may have been effective. CONCLUSIONS: The CM intervention did not appear to be effective in reducing cannabis use and acute relapse among people with early psychosis and problematic cannabis use. FUTURE WORK: Cannabis use is still a significant clinical concern in this population. A pressing need remains to identify suitable treatments. A wider perspective on the social circumstances of young people with psychosis may be needed for a successful intervention to be found. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33576045. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 45. See the NIHR Journals Library website for further project information.

A large proportion of people with psychosis use cannabis, despite the negative impact that it has on their recovery. So far, a clearly effective way of helping young people in the early stages of psychosis to cut down their cannabis use has not been found. The CIRCLE trial investigated if an approach known as contingency management (CM) would be beneficial for this group. This approach involves offering voucher rewards for not using cannabis. It has been effective in addressing drug use problems in general, but there is not much evidence about its effects on cannabis use in those with psychosis. A total of 551 service users with psychosis who used cannabis agreed to enter the trial. Half of the sample group was chosen by a chance method to receive CM. The other half formed a comparison group. The CM group received shopping vouchers if urine samples showed that they had not used cannabis for the previous week, measured over 12 weekly sessions. Participants could obtain £240-worth of vouchers if they did not use cannabis during the treatment period. The participants in both groups were also offered a six-session psychoeducation programme about the pros and cons of cannabis use and ways to reduce use of it. The main comparison in the trial was the average length of time in each group before a relapse of psychosis occurred, which was recorded for each participant over 18 months after they joined the trial. The results found no difference between the two trial groups in this measure. Furthermore, there were no differences found between the groups in terms of the levels of cannabis use, clinical symptoms, or engagement with work or education. However, a cost-effectiveness analysis found an 85% chance of CM being more effective than the treatment-as-usual psychoeducation package, which appears to be because of the lower use of inpatient services by those receiving CM. However, it is difficult to understand why this was, because there was no drop in cannabis use. The results suggest that CM is unlikely to be clinically effective and that alternative treatments are still needed.

Clinical and cost-effectiveness of contingency management for cannabis use in early psychosis: the CIRCLE randomised clinical trial.

BACKGROUND: Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. METHODS: CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. RESULTS: Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. CONCLUSIONS: Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

Psychological interventions for people with psychotic experiences: protocol for a systematic review and meta-analysis.

BACKGROUND: Many people who have common mental disorders, such as depression and anxiety, also have some psychotic experiences. These experiences are associated with higher clinical complexity, poor treatment response, and negative clinical outcomes. Psychological interventions have the potential to improve outcomes for people with psychotic experiences. The aims of this systematic review are to (1) synthesise the evidence on the effectiveness and cost-effectiveness of psychological interventions to reduce psychotic experiences and their associated distress and (2) identify key components of effective interventions. METHODS: Our search strategy will combine terms for (1) psychological interventions, (2) psychotic experiences, and (3) symptoms associated with psychotic experiences. We will search the following online databases: MEDLINE, Embase, PsycINFO, all Cochrane databases, British Nursing Index (BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Management Information Consortium (HMIC), Education Resources Information Center (ERIC), and EconLit. Our primary outcome is the proportion of people who recovered or remitted from psychotic experiences after the intervention. Our secondary outcomes are changes in positive psychotic symptoms, negative psychotic symptoms, depression, anxiety, functioning (including social, occupational, and academic), quality of life, and cost-effectiveness. Two independent reviewers will judge each study against pre-specified inclusion and exclusion criteria and will extract study characteristics, outcome data, and intervention components. Risk of bias and methodological quality will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and the Drummond Checklist. Results will be synthesised using random-effects meta-analysis and narrative synthesis. DISCUSSION: The identification of effective psychological interventions and of specific components associated with intervention effectiveness will augment existing evidence that can inform the development of a new, tailored intervention to improve outcomes related to psychotic symptoms, anxiety and depression, distress, functioning, and quality of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033869.

The CIRCuiTS study (Implementation of cognitive remediation in early intervention services): protocol for a randomised controlled trial.

BACKGROUND: Cognitive problems in people with schizophrenia predict poor functional recovery even with the best possible rehabilitation opportunities and optimal medication. A psychological treatment known as cognitive remediation therapy (CRT) aims to improve cognition in neuropsychiatric disorders, with the ultimate goal of improving functional recovery. Studies suggest that intervening early in the course of the disorder will have the most benefit, so this study will be based in early intervention services, which treat individuals in the first few years following the onset of the disorder. The overall aim is to investigate different methods of CRT. METHODS: This is a multicentre, randomised, single-blinded, controlled trial based in early intervention services in National Health Service Mental Health Trusts in six English research sites. Three different methods of providing CRT (intensive, group, and independent) will be compared with treatment as usual. We will recruit 720 service users aged between 16 and 45 over 3 years who have a research diagnosis of non-affective psychosis and will be at least 3 months from the onset of the first episode of psychosis. The primary outcome measure will be the degree to which participants have achieved their stated goals using the Goal Attainment Scale. Secondary outcome measures will include improvements in cognitive function, social function, self-esteem, and clinical symptoms. DISCUSSION: It has already been established that cognitive remediation improves cognitive function in people with schizophrenia. Successful implementation in mental health services has the potential to change the recovery trajectory of individuals with schizophrenia-spectrum disorders. However, the best mode of implementation, in terms of efficacy, service user and team preference, and cost-effectiveness is still unclear. The CIRCuiTS trial will provide guidance for a large-scale roll-out of CRT to mental health services where cognitive difficulties impact recovery and resilience. TRIAL REGISTRATION: ISRCTN, ISRCTN14678860 , Registered on 6 June 2016.

Cost-effectiveness of early intervention services for psychosis and fidelity to national policy implementation guidance.

AIM: Early intervention services (EIS) for psychosis are being implemented, internationally. It is important to learn from established examples and define the components and intensity of services that provide good value for money. This study aims to assess the cost-effectiveness of EIS according to how closely they adhered to the recommendations of the English Department of Health 2001 Policy Implementation Guide (PIG). METHODS: EIS from the National Eden Study were assessed using a measure of fidelity to the PIG that rated the presence or absence of 64 recommended items relating to team structure and practice. EIS were then classified into three groups: those with fidelity of 75-80%, 81-90% and 91-95%. Patient-level resource use and outcomes were measured 1 year following inception into the service; costs were calculated and combined with quality-adjusted life years (QALYs) gained. RESULTS: At a threshold of £20 000 per QALY, the 81-90% fidelity group had a 56.3% likelihood of being the most cost-effective option followed by 75-80% fidelity at 35.8% and 91-95% fidelity group (7.9%). CONCLUSIONS: The results from England suggest that striving to maximize fidelity may not be warranted, but that dropping below a certain level of fidelity may result in inefficient use of resources.

Ambient concentrations and deposition rates of selected reactive nitrogen species and their contribution to PM2.5 aerosols at three locations with contrasting land use in southwest China.

The fast economic development of southwest China has resulted in significant increases in the concentrations of reactive nitrogen (Nr) in the atmosphere. In this study, an urban (Chengdu, CD), suburban (Shifang, SF) and agriculture (Yanting, YT) - dominated location in the Sichuan Province, southwest China, were selected to investigate the atmospheric composition of Nr, their concentrations and deposition rates. We measured Nr concentrations in precipitation (NH4+, NO3- and organic N (DON)), the gas phase (NH3 and NO2), and the aerosol particles (PM2.5), and calculated their fluxes over a two year period (2014-2016). Total annual N deposition rates were 49.2, 44.7 and 19.8 kg N ha-1 yr-1 at CD, SF and YT, respectively. Ammonia concentrations were larger at the urban and suburban sites than the agricultural site (12.2, 14.9, and 4.9 µg N m-3 at CD, SF and YT, respectively). This is consistent with the multitude of larger sources of NH3, including city garbage, livestock and traffic, in the urban and suburban areas. Monthly NO2 concentrations were lower in warmer compared to the colder months, but seasonal differences were insignificant. Daily PM2.5 concentrations ranged from 7.7 to 236.0, 5.0-210.4 and 4.2-128.4 µg m-3 at CD, SF and YT, respectively, and showed significant correlations with fine particulate NH4+ and NO3- concentrations. Ratios of reduced to oxidized N were in the range of 1.6-2.7. This implies that the control of reduced Nr especially in urban environments is needed to improve local air quality.

Prevention and treatment of long-term social disability amongst young people with emerging severe mental illness with social recovery therapy (The PRODIGY Trial): study protocol for a randomised controlled trial.

BACKGROUND: Young people who have social disability associated with severe and complex mental health problems are an important group in need of early intervention. Their problems often date back to childhood and become chronic at an early age. Without intervention, the long-term prognosis is often poor and the economic costs very large. There is a major gap in the provision of evidence-based interventions for this group, and therefore new approaches to detection and intervention are needed. This trial provides a definitive evaluation of a new approach to early intervention with young people with social disability and severe and complex mental health problems using social recovery therapy (SRT) over a period of 9 months to improve mental health and social recovery outcomes. METHODS: This is a pragmatic, multi-centre, single blind, superiority randomised controlled trial. It is conducted in three sites in the UK: Sussex, Manchester and East Anglia. Participants are aged 16 to 25 and have both persistent and severe social disability (defined as engaged in less than 30 hours per week of structured activity) and severe and complex mental health problems. The target sample size is 270 participants, providing 135 participants in each trial arm. Participants are randomised 1:1 using a web-based randomisation system and allocated to either SRT plus optimised treatment as usual (enhanced standard care) or enhanced standard care alone. The primary outcome is time use, namely hours spent in structured activity per week at 15 months post-randomisation. Secondary outcomes assess typical mental health problems of the group, including subthreshold psychotic symptoms, negative symptoms, depression and anxiety. Time use, secondary outcomes and health economic measures are assessed at 9, 15 and 24 months post-randomisation. DISCUSSION: This definitive trial will be the first to evaluate a novel psychological treatment for social disability and mental health problems in young people presenting with social disability and severe and complex non-psychotic mental health problems. The results will have important implications for policy and practice in the detection and early intervention for this group in mental health services. TRIAL REGISTRATION: Trial Registry: International Standard Randomised Controlled Trial Number (ISRCTN) Registry. TRIAL REGISTRATION NUMBER: ISRCTN47998710 (registered 29/11/2012).

Economic Evaluation Alongside a Randomized Controlled Crossover Trial of Modified Group Cognitive-Behavioral Therapy for Anxiety Compared to Treatment-as-Usual in Adults With Asperger Syndrome.

Background: There is a growing interest in using group cognitive-behavioral therapy (CBT) with people who have Asperger syndrome (AS) and comorbid mental health problems. This study aims to assess the cost-effectiveness of modified group CBT for adults with AS experiencing co-occurring anxiety compared to treatment-as-usual. Methods: Economic evaluation alongside a pilot, multicenter, single-blind, randomized controlled crossover trial. Costs from the UK public sector (National Health Service and Social Services) and societal perspectives, quality-adjusted life years (QALYs), incremental net (monetary) benefit (INB), expected value of perfect information, expected value of sample information, expected net gain of sampling, and efficient sample size of a future trial are reported. Results: Over 48 weeks, from the societal perspective, CBT results in additional costs of £6,647, with only a 0.015 incremental gain in QALYs, leading to a negative INB estimate of £6,206 and a 23% probability of cost-effectiveness at a threshold of £30,000/QALY. Results from sensitivity analyses support the unlikely cost-effectiveness of CBT but indicate the potential for cost-effectiveness over longer time horizons. Eliminating decision uncertainty is valued at £277 million, and the efficient sample size for a future trial is estimated at 1,200 participants per arm. Limitations: Relatively small sample size and prevalence of missing data present challenges to the interpretation of the results. Conclusions: Current evidence from this small pilot study suggests that, on average, modified group CBT is not cost-effective. However, there is much decision uncertainty so such a conclusion could be wrong. A large, full-scale trial to reduce uncertainty would be an efficient investment for the UK health economy.

A randomised controlled trial of the clinical and cost-effectiveness of a contingency management intervention compared to treatment as usual for reduction of cannabis use and of relapse in early psychosis (CIRCLE): a study protocol for a randomised controlled trial.

BACKGROUND: Around 35-45 % of people in contact with services for a first episode of psychosis are using cannabis. Cannabis use is associated with delays in remission, poorer clinical outcomes, significant increases in the risk of relapse, and lower engagement in work or education. While there is a clear need for effective interventions, so far only very limited benefits have been achieved from psychological interventions. Contingency management (CM) is a behavioural intervention in which specified desired behavioural change is reinforced through financial rewards. CM is now recognised to have a substantial evidence base in some contexts and its adoption in the UK is advocated by the National Institute for Health and Care Excellence (NICE) guidance as a treatment for substance or alcohol misuse. However, there is currently little published data testing its effectiveness for reducing cannabis use in early psychosis. METHODS: CIRCLE is a two-arm, rater-blinded randomised controlled trial (RCT) investigating the clinical and cost-effectiveness of a CM intervention for reducing cannabis use among young people receiving treatment from UK Early Intervention in Psychosis (EIP) services. EIP service users (n = 544) with a recent history of cannabis use will be recruited. The experimental group will receive 12 once-weekly CM sessions, and a voucher reward if urinalysis shows that they have not used cannabis in the previous week. Both the experimental and the control groups will be offered an Optimised Treatment as Usual (OTAU) psychoeducational package targeting cannabis use. Assessment interviews will be performed at consent, at 3 months, and at 18 months. The primary outcome is time to relapse, defined as admission to an acute mental health service. Secondary outcomes include proportion of cannabis-free urine samples during the intervention period, severity of positive psychotic symptoms, quality-adjusted life years, and engagement in work or education. DISCUSSION: CIRCLE is a RCT of CM for cannabis use in young people with a recent history of psychosis (EIP service users) and recent cannabis use. It is designed to investigate whether the intervention is a clinically and cost-effective treatment for cannabis use. It is intended to inform future treatment delivery, particularly in EIP settings. TRIAL REGISTRATION: ISRCTN33576045 : doi 10.1186/ISRCTN33576045 , registered on 28 November 2011.

Public Figures, Professional Ethics, and the Media.

Death certificates and autopsy reports contain personal identifying information and clinical information protected under the Health Insurance Portability and Accountability Act (HIPAA) of 1996. These documents are used, for example, by the families of the deceased for settling estates, bereavement and closure, and genetic counseling of relatives. Insurance companies, public health and law enforcement officials, and the legal community also have legitimate claims to this information. Critical ethical questions have not yet been settled about whether and when this information should be public and under which circumstances making this kind of information public incurs benefits, harms, or both. Additional considerations include which organizations-the media, academic institutions, or government agencies, for example-are best suited to interpret these questions and respond to them.

The course of negative symptom in first episode psychosis and the relationship with social recovery.

AIMS: To investigate trajectories of negative symptoms during the first 12months of treatment for first episode psychosis (FEP), their predictors and relationship to social recovery. METHOD: 1006 participants were followed up for 12months following acceptance into Early Intervention in Psychosis services. Negative symptom trajectories were modelled using latent class growth analysis (LCGA) and predictors of trajectories examined using multinomial regression. Social recovery trajectories - also modelled using LCGA - of members of each negative symptom trajectory were ascertained and the relationship between negative symptom and social recovery trajectories examined. RESULTS: Four negative symptom trajectories were identified: Minimal Decreasing (63.9%), Mild Stable (13.5%), High Decreasing (17.1%) and High Stable (5.4%). Male gender and family history of non-affective psychosis predicted stably high negative symptoms. Poor premorbid adolescent adjustment, family history of non-affective psychosis and baseline depression predicted initially high but decreasing negative symptoms. Members of the Mild Stable, High Stable and High Decreasing classes were more likely to experience stably low functioning than the Minimal Decreasing class. CONCLUSIONS: Distinct negative symptom trajectories are evident in FEP. Only a small subgroup present with persistently high levels of negative symptoms. A substantial proportion of FEP patients with elevated negative symptoms at baseline will achieve remission of these symptoms within 12months. However, elevated negative symptoms at baseline, whether or not they remit, are associated with poor social recovery, suggesting targeted interventions for service users with elevated baseline negative symptoms may help improve functional outcomes.

En Bloc Examination of the Neck in Pediatric Homicide Cases: A Proper Way for Complete Assessment of Neck Trauma.

The necks of infants and young children are not only anatomically different from adults, but are also supported by much weaker musculoskeletal systems and are therefore prone to trauma as a result of extension/flexion (shaking) or contact trauma to the head. Shaking cervical spine injuries can occur at much lower levels of head velocity and acceleration than those reported for shaken baby syndrome. The proper method for a comprehensive and detailed examination of the neck in pediatric homicide and suspected homicide cases is the en bloc examination of the neck, because the standard examination of the spinal cord not only distorts the anatomical relationship of the cord and osteocartilagenous structures, but also excludes the cervical nerves, ganglia, and the vertebral arteries from being evaluated. Interpretation of gross and microscopic findings using this method requires experience and knowledge of the anatomical relationship and common artifacts, such as epidural, focal intradural, or even isolated nerve hemorrhage to avoid misinterpretation. It is our opinion that this method should be applied to all pediatric homicide or suspected homicide cases, but is not suited for routine or nonsuspicious cases as it will add to the time and cost of medical examiner's operations.

Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment.

Despite the reduction in late thrombotic events with newer-generation drug-eluting stents (DES), late stent failure remains a concern following stent placement. In-stent neoatherosclerosis has emerged as an important contributing factor to late vascular complications including very late stent thrombosis and late in-stent restenosis. Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification. The development of neoatherosclerosis may occur in months to years following stent placement, whereas atherosclerosis in native coronary arteries develops over decades. Pathologic and clinical imaging studies have demonstrated that neoatherosclerosis occurs more frequently and at an earlier time point in DES when compared with bare metal stents, and increases with time in both types of implant. Early development of neoatherosclerosis has been identified not only in first-generation DES but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown; however, either absence or abnormal endothelial functional integrity following stent implantation may contribute to this process. In-stent plaque rupture likely accounts for most thrombotic events associated with neoatherosclerosis, while it may also be a substrate of in-stent restenosis as thrombosis may occur either symptomatically or asymptomatically. Intravascular optical coherence tomography is capable of detecting neoatherosclerosis; however, the shortcomings of this modality must be recognized. Future studies should assess the impact of iterations in stent technology and risk factor modification on disease progression. Similarly, refinements in imaging techniques are also warranted that will permit more reliable detection of neoatherosclerosis.