Accelerating the development of a psychological intervention to restore treatment decision-making capacity in patients with schizophrenia-spectrum disorder: a study protocol for a multi-site, assessor-blinded, pilot Umbrella trial (the DEC:IDES trial).

BACKGROUND: A high proportion of patients diagnosed with schizophrenia-spectrum disorders will at some point in their lives be assessed as not having the capacity to make their own decisions about pharmacological treatment or inpatient care ('capacity'). Few will be helped to regain it before these interventions proceed. This is partly because effective and safe methods to do so are lacking. Our aim is to accelerate their development by testing, for the first time in mental healthcare, the feasibility, acceptability and safety of running an 'Umbrella' trial. This involves running, concurrently and under one multi-site infrastructure, multiple assessor-blind randomised controlled trials, each of which is designed to examine the effect on capacity of improving a single psychological mechanism ('mechanism'). Our primary objectives are to demonstrate feasibility of (i) recruitment and (ii) data retention on the MacArthur Competence Assessment Tool-Treatment (MacCAT-T; planned primary outcome for a future trial) at end-of-treatment. We selected three mechanisms to test: 'self-stigma', low self-esteem and the 'jumping to conclusions' bias. Each is highly prevalent in psychosis, responsive to psychological intervention, and hypothesised to contribute to impaired capacity. METHODS: Sixty participants with schizophrenia-spectrum diagnoses, impaired capacity and one or more mechanism(s) will be recruited from outpatient and inpatient mental health services in three UK sites (Lothian, Scotland; Lancashire and Pennine; North West England). Those lacking capacity to consent to research could take part if the key criteria were met, including either proxy consent (Scotland) or favourable Consultee advice (England). They will be allocated to one of three randomised controlled trials, depending on which mechanism(s) they have. They will then be randomised to receive, over an 8-week period and in addition to treatment as usual (TAU), 6 sessions of either a psychological intervention which targets the mechanism, or 6 sessions of assessment of the causes of their incapacity (control condition). Participants are assessed at 0 (baseline), 8 (end-of-treatment) and 24 (follow-up) weeks post-randomisation using measures of capacity (MacCAT-T), mechanism, adverse events, psychotic symptoms, subjective recovery, quality of life, service use, anxiety, core schemata and depression. Two nested qualitative studies will be conducted; one to understand participant and clinician experiences and one to investigate the validity of MacCAT-T appreciation ratings. DISCUSSION: This will be the first Umbrella trial in mental healthcare. It will produce the first 3 single-blind randomised controlled trials of psychological interventions to support treatment decision-making in schizophrenia-spectrum disorder. Demonstrating feasibility will have significant implications not only for those seeking to support capacity in psychosis, but also for those who wish to accelerate the development of psychological interventions for other conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04309435 . Pre-registered on 16 March 2020.

Discerning the adverse effects of psychological therapy: Consensus between experts by experience and therapists.

Measurement of adverse effects of psychological therapy is inconsistent due to ambiguity about the concept. The perspective of people undertaking psychological therapy (that is, experts by experience) has largely been overlooked. This study will investigate whether there is consensus between the opinions of professionals and experts by experience. The Delphi method was used. In Round 1 thematic analysis was used to analyse qualitative responses. Wilcoxon rank-sum tests were used to examine group differences in Rounds 2 and 3. The study protocol was prospectively registered, reference osf.io/f9wp7. Fifty-one professionals and 51 experts by experience generated 147 potential adverse effects in Round 1, across 9 themes; including 'therapy amplifies problem', 'emotional lability' and 'sense of self'. Each item was rated for overall consensus in Rounds 2 (n = 62) and 3 (n = 63). Thirty-eight items were rated as essential, very important or important to include on a list of potential adverse effects. A further 12 items were rated as important by the expert by experience group only. Professionals were more conservative in their ratings. There appeared to be consensus between professionals and experts by experience on what to include in a list of adverse effects of psychological therapy (the EDAPT), including novel adverse effects which have not been previously considered. Further research is required to understand which adverse effects are necessary, unnecessary, or indeed harmful to psychotherapy outcomes.

A network meta-analysis of psychological interventions for schizophrenia and psychosis: Impact on symptoms.

BACKGROUND: Evidence for the effectiveness of psychological interventions for schizophrenia/psychosis is growing, however there is no consensus on the psychological intervention most likely to reduce symptoms. METHODS: A network meta-analysis was conducted to identify all randomised controlled trials (RCTs) of psychological interventions for adults with schizophrenia/psychosis. A systematic review of the literature using MEDLINE, PsycINFO, EMBASE and CENTRAL led to an analysis of 90 RCTs with 8440 randomised participants across 24 psychological intervention, and control groups. Psychological interventions were categorised and rated for treatment fidelity and risk of bias. Data for total symptoms were extracted and network meta-analysis, using a frequentist approach, was undertaken using Stata SE v15 to compare the direct and indirect evidence for the effectiveness of each psychological intervention. FINDINGS: Psychological interventions were more likely to reduce symptoms than control groups, and one intervention, mindfulness-based psychoeducation, was consistently ranked as most likely to reduce total symptoms. Subgroup analyses identified differential effectiveness in different settings and for different subgroups. INTERPRETATION: Mindfulness-based psychoeducation was consistently ranked as most likely to reduce symptoms; however all studies were based in China. More RCTs in a variety of cultural contexts would help to elucidate whether these findings generalise internationally. A number of psychological interventions could potentially be more effective than interventions recommended by NICE guidelines, such as CBT and family therapy, and additional RCTs and meta-analyses are needed to generate more conclusive evidence in this regard.

The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis.

BACKGROUND: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. OBJECTIVE: To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. DESIGN, SETTING, AND PARTICIPANTS: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. INTERVENTION: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1-3, and cisplatin 50 mg/m2 on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. RESULTS AND LIMITATIONS: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants. CONCLUSIONS: BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. PATIENT SUMMARY: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.

Psychological interventions for ICD-11 complex PTSD symptoms: systematic review and meta-analysis.

BACKGROUND: The 11th revision to the WHO International Classification of Diseases (ICD-11) identified complex post-traumatic stress disorder (CPTSD) as a new condition. There is a pressing need to identify effective CPTSD interventions. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) of psychological interventions for post-traumatic stress disorder (PTSD), where participants were likely to have clinically significant baseline levels of one or more CPTSD symptom clusters (affect dysregulation, negative self-concept and/or disturbed relationships). We searched MEDLINE, PsycINFO, EMBASE and PILOTS databases (January 2018), and examined study and outcome quality. RESULTS: Fifty-one RCTs met inclusion criteria. Cognitive behavioural therapy (CBT), exposure alone (EA) and eye movement desensitisation and reprocessing (EMDR) were superior to usual care for PTSD symptoms, with effects ranging from g = -0.90 (CBT; k = 27, 95% CI -1.11 to -0.68; moderate quality) to g = -1.26 (EMDR; k = 4, 95% CI -2.01 to -0.51; low quality). CBT and EA each had moderate-large or large effects on negative self-concept, but only one trial of EMDR provided useable data. CBT, EA and EMDR each had moderate or moderate-large effects on disturbed relationships. Few RCTs reported affect dysregulation data. The benefits of all interventions were smaller when compared with non-specific interventions (e.g. befriending). Multivariate meta-regression suggested childhood-onset trauma was associated with a poorer outcome. CONCLUSIONS: The development of effective interventions for CPTSD can build upon the success of PTSD interventions. Further research should assess the benefits of flexibility in intervention selection, sequencing and delivery, based on clinical need and patient preferences.

Cognitive-behavioural therapy for clozapine-resistant schizophrenia: the FOCUS RCT.

BACKGROUND: Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome. DESIGN: The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU). SETTING: Secondary care mental health services in five cities in the UK. PARTICIPANTS: People with CRS aged ≥ 16 years, with an International Classification of Diseases, Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms. INTERVENTIONS: Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services. MAIN OUTCOME MEASURES: The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs. RESULTS: Participants were allocated to CBT (n = 242) or TAU (n = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) -3.32 to 1.55 points; p = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (-2.40 points, 95% CI -4.79 to -0.02 points; p = 0.049). CBT was associated with a net cost of £5378 (95% CI -£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46; p = 0.58). CONCLUSIONS: Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99672552. 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. 7. See the NIHR Journals Library website for further project information.

Cognitive Analytic Therapy for psychosis: A case series.

OBJECTIVES: Cognitive Analytic Therapy (CAT) is an effective psychological intervention for several different mental health conditions. However, whether it is acceptable, safe, and beneficial for people with psychosis remains unclear, as is the feasibility of providing and evaluating it within a research context. The aim of this study was to begin to address these questions and to obtain for the first time a rich and detailed understanding of the experience of receiving CAT for psychosis. DESIGN: A mixed-methods case series design. METHOD: Seven individuals who experienced non-affective psychosis received CAT. They completed assessments at the start of CAT, 16 weeks, and 28 weeks post-baseline. Qualitative interviews were completed with four individuals following completion of or withdrawal from therapy. RESULTS: Six participants attended at least four sessions of therapy and four went on to complete therapy. There were no serious adverse events, and self-reported adverse experiences were minimal. Qualitative interviews suggested CAT is acceptable and provided a way to understand and work therapeutically with psychosis. There was limited evidence of change in psychotic symptoms, but improvement in perceived recovery and personality integration was observed. CONCLUSIONS: The results suggest that CAT is a safe and acceptable intervention for psychosis. Personality integration, perceived recovery, and functioning are relevant outcomes for future evaluations of CAT for psychosis. PRACTITIONER POINTS: It is feasible to conduct research evaluating CAT for people with psychosis. Within this case series, CAT appears acceptable and safe to individuals with psychosis. Within this case series, clients reported that CAT was a positive and helpful experience. There is a mixed picture with regard to secondary outcomes, but the design and aims of this case series limit conclusion that can be drawn from this data.

Decision-making ability in psychosis: a systematic review and meta-analysis of the magnitude, specificity and correlates of impaired performance on the Iowa and Cambridge Gambling Tasks.

To identify factors which may help or hinder decision-making ability in people with psychosis, we did a systematic review and meta-analysis of their performance on the Iowa and Cambridge Gambling Tasks. Analysis of 47 samples found they had moderately poorer performance than healthy individuals (N = 4264, g = -0.57, 95% confidence interval (CI) -0.66 to -0.48). Few studies (k = 8) used non-psychotic clinical comparator groups, although very low-quality evidence (k = 3) found people with bipolar disorder may perform better. Negative symptoms (k = 13, N = 648, r = -0.17, 95% CI -0.26 to -0.07) and lower IQ (k = 11, N = 525, r = 0.20, 95% CI 0.29-0.10), but not positive symptoms (k = 10, N = 512, r = -0.01, 95% CI -0.11 to 0.08), each had small-moderate associations with poorer decision-making. Lower quality evidence suggested general symptoms, working memory, social functioning, awareness of emotional responses to information, and attentional bias towards gain are associated with decision-making, but not education, executive functioning or overall symptoms. Meta-regression suggested an inverse association between decision-making and depression severity (k = 6, Q = 6.41, R2 100%, p = 0.01). Those taking first-generation (k = 6, N = 305, g = -0.17, 95% CI -0.40 to 0.06, p = 0.147) or low-dose antipsychotics (k = 5, N = 442, g = -0.19, 95% CI -0.44 to 0.06, p = 0.139) had unimpaired decision-making. Although meta-regression found no linear association between dose and performance, non-reporting of the dose was common and associated with larger impairments (k = 46, Q = 4.71, R2 14%, p = 0.03). Those supporting people with psychosis to make decisions, including treatment decisions, should consider the potential effect of these factors. Interventionist-causal trials are required to test whether reducing antipsychotic dose and treating anxiety and depression can improve decision-making in this group.

The Effect of Reducing the "Jumping to Conclusions" Bias on Treatment Decision-Making Capacity in Psychosis: A Randomized Controlled Trial With Mediation Analysis.

BACKGROUND: Evidence-based psychological interventions to support treatment decision-making capacity (capacity) in psychosis do not currently exist. This study sought to establish whether reducing the extent to which this group form conclusions based on limited evidence, also known as the "jumping-to-conclusions" (JTC) bias, could improve capacity. METHODS: In a randomized controlled open trial, 37 patients aged 16-65 years diagnosed with schizophrenia-spectrum disorders were randomly assigned (1:1) to receive a single-session intervention designed to reduce the JTC bias (MCT-JTC; adapted from Metacognitive Training [MCT]) or an attention control (AC) condition designed to control for therapist attention, duration, modality, and face validity. Primary outcomes were treatment decision-making capacity measured by the MacArthur Competency Assessment Tool for Treatment (MacCAT-T) and the jumping-to-conclusions reasoning bias measured by draws to decision on the beads task, each of which were administered by the psychologist delivering the intervention. RESULTS: Those receiving MCT-JTC had large improvements in overall capacity (d = 0.96, P < .05) and appreciation (d = 0.87, P < .05) compared to those receiving AC. Reduction in JTC mediated a large proportion of the effect of group allocation on understanding, appreciation, reasoning, and overall MacCAT-T scores. CONCLUSION: This is the first experimental investigation of the effect of a psychological intervention on treatment decision-making capacity in psychosis. It provides early evidence that reducing the JTC bias is associated with large and rapid improvements in capacity. Due to limited resources, assessments were administered by the researchers delivering the intervention. Results should therefore be considered preliminary and a larger, definitive trial addressing methodological limitations is warranted.

A systematic review and meta-analysis of group treatments for adults with symptoms associated with complex post-traumatic stress disorder.

BACKGROUND: No previous meta-analyses have specifically investigated the effectiveness of psychological group therapy for symptoms associated with complex interpersonal trauma, including whether trauma memory processing (TMP) therapies are superior to psychoeducational approaches alone. METHODS: A systematic review identified 36 randomised control trials (RCTs) which were included in the meta-analysis. RESULTS: Large significant effect sizes were evident for TMP interventions when compared to usual care for three outcome domains including: PTSD (k = 6, g = -0.98, 95% CI -1.53, -0.43), Depression (k = 7, g = -1.12, 95% CI -2.01, -0.23) and Psychological Distress (k = 6, g = -0.98, 95% CI 1.66, -0.40). When TMP and psychoeducation interventions were directly compared, results indicated a small non-significant effect in favour of the former for PTSD symptoms, (k = 4, g = -0.34, 95% CI -1.05, 0.36) and small non-significant effect sizes in favour of the latter for Depression (k = 3, g = 0.29, 95% CI -0.83, 1.4) and Psychological Distress (k = 6, g = 0.19, 95% CI -0.34, 0.71). LIMITATIONS: Heterogeneity and a limited number of high quality RCTs, particularly in the Substance Misuse and Dissociation domains, resulted in uncertainty regarding meta-analytical estimates and subsequent conclusions. CONCLUSIONS: Results suggest that TMP interventions are useful for traumatic stress whereas non-TMP interventions can be useful for symptoms of general distress (e.g. anxiety and depression). Thus, both TMP and psychoeducation can be useful for the treatment of complex interpersonal trauma symptoms and further research should unravel appropriate sequencing and dose of these interventions.

A feasibility study of a cross-diagnostic, CBT-based psychological intervention for acute mental health inpatients: Results, challenges, and methodological implications.

OBJECTIVES: Acute psychiatric inpatient wards are characterized by minimal provision of therapeutic activities and high readmission rates. Implementation of a comprehensive inpatient psychological intervention service has been recommended to overcome these problems; however, whether this is feasible or effective remains unclear. METHODS: This non-randomized parallel cluster feasibility trial examined the feasibility of delivering and evaluating cross-diagnostic psychologically informed acute psychiatric care the Edinburgh-Acute Psychological Inpatient Therapy Service (EDAPTS) and gathered preliminary clinical outcome data. Patients able to consent and complete questionnaires were recruited from two adult acute wards (i.e., clusters) and received either EDAPTS plus TAU or TAU. RESULTS: Between October 2015 and October 2016, 96 inpatients were recruited. Findings suggested that there were good data completion rates for several clinical outcomes, that several EDAPTS components were successfully delivered, and that some initial effects appeared to favour the intervention, depending on outcome. However, difficulties relating to the recruitment process were also identified, as well as problems relating to adequate delivery of group therapies, participant engagement in some intervention components, and data completion at follow-up. CONCLUSION: These issues, and the feasibility of randomization and rater-blinding, have important implications for the design of future trials. Overall, this study provides an important insight into the challenges and complexities of developing and evaluating a comprehensive psychological intervention service in an acute psychiatric setting. PRACTITIONER POINTS: Individual therapy sessions can be delivered in the acute environment. The EDAPTS intervention showed some promise on outcomes of distress and self-efficacy. Delivery of nurse-led groups was challenging and may need to be embedded into routine clinical practice to increase intervention and outcome reach. More parameters, for example, randomization at cluster level, should be tested before progressing to an adequately powered, single-blind, definitive cluster RCT.

Suicidal Ideation in People With Psychosis Not Taking Antipsychotic Medication: Do Negative Appraisals and Negative Metacognitive Beliefs Mediate the Effect of Symptoms?

Between 5% and 10% of people with psychosis will die by suicide, a rate which is 20-75 times higher than the general population. This risk is even greater in those not taking antipsychotic medication. We examined whether negative appraisals of psychotic experiences and negative metacognitive beliefs about losing mental control mediated a relationship between psychotic symptoms and suicidal ideation in this group. Participants were diagnosed with schizophrenia spectrum disorders, antipsychotic-free for 6 months at baseline, and were participating in an 18-month randomized controlled trial of cognitive therapy vs treatment as usual. We conducted a series of mediation analyses with bootstrapping on baseline (N = 68), follow-up data (9-18 mo; n = 49), and longitudinal data (n = 47). Concurrent general symptoms were directly associated with suicidal ideation at baseline, and concurrent negative symptoms were directly associated with suicidal ideation at 9-18 months. Concurrent positive, negative, general, and overall symptoms were each indirectly associated with suicidal ideation via negative appraisals and/or negative metacognitive beliefs, at baseline and 9-18 months, except for negative symptoms at baseline. Controlling for baseline suicidal ideation and treatment allocation, baseline general symptoms were indirectly associated with later suicidal ideation, via baseline negative appraisals and negative metacognitive beliefs. Baseline negative metacognitive beliefs also had a direct association with later suicidal ideation. These findings suggest the clinical assessment of suicidal ideation in psychosis may be enhanced by considering metacognitive beliefs about the probability and consequences of losing mental control.

The paranoia as defence model of persecutory delusions: a systematic review and meta-analysis.

BACKGROUND: An influential psychological model of persecutory delusions proposed that they are caused by a bias towards holding others responsible for negative events (an externalising attributional bias), preventing the individual from becoming aware of underlying low self-esteem. An early version of the model predicted self-esteem would, therefore, be preserved in people with these delusions, but a later version suggested it would be unstable, and that there would be a discrepancy between explicit and implicit self-esteem, with the latter being lower. We did a comprehensive meta-analytical test of the key predictions of this model and assessed the quality of evidence. METHODS: We searched PubMed from Jan 1, 1994, to July 31, 2018, and collated systematic reviews of the defensive model's predictions in relation to persecutory delusions. We also searched PsycINFO, MEDLINE, Embase, and Web of Science for articles published from Jan 1, 2012, to Sept 10, 2016. Cross-sectional data from case-control, longitudinal, or experimental studies that examined self-esteem or the externalising attributional bias in individuals diagnosed as having schizophrenia-spectrum disorder were eligible for meta-analyses of group differences if at least 50% of participants with psychosis also had current persecutory delusions. Uncontrolled and longitudinal studies were included in meta-analyses of correlations and self-esteem instability, respectively. Study and outcome quality were assessed with the Agency for Healthcare Research and Quality assessment tool, and a modified version of Grading of Recommendations Assessment, Development and Evaluation, respectively. The study protocol is registered with PROSPERO, number CRD42016032782. FINDINGS: We screened 3053 records, examined 104 full-text reports, and included 64 eligible studies. Consistent with the predictions of both versions of the model, paranoia severity in psychosis was positively correlated with the degree of externalising attributional bias (21 studies involving 1128 individuals; r=0·18, 95% CI 0·08 to 0·27, with moderate quality evidence). People with persecutory delusions also had a greater externalising attributional bias than non-clinical individuals (27 studies involving 1442 individuals; g=0·48, 95% CI 0·23 to 0·73) and depressed individuals (ten studies involving 421 individuals; g=1·06, 0·48 to 1·63), and people with psychosis without persecutory delusions (11 studies involving 480 individuals; g=0·40, 0·12 to 0·68), all based on moderate quality evidence. Contrary to the predictions in the early version of the model, paranoia severity in psychosis was negatively correlated with explicit self-esteem (23 studies involving 1866 individuals; r=-0·26, 95% CI -0·34 to -0·17, with high quality evidence). People with persecutory delusions also had lower explicit self-esteem than non-clinical individuals (22 studies involving 1256 individuals; g=-0·88, 95% CI -1·10 to -0·66, with high quality evidence) and explicit self-esteem similarly low to that in people with psychosis without persecutory delusions (11 studies involving 644 individuals; g=-0·26, -0·54 to 0·02, with moderate quality evidence). Consistent with the predictions in the later version of the model, self-esteem instability was positively correlated with paranoia severity in psychosis (four studies involving 508 individuals; r=0·23, 95% CI 0·11-0·34, with high quality evidence), and people with persecutory delusions had a greater discrepancy between their implicit and explicit self-esteem than depressed individuals (seven studies involving 398 individuals; g=0·61, 95% CI 0·37 to 0·85, with moderate quality evidence). They had higher explicit self-esteem than depressed individuals (13 studies involving 647 individuals; g=0·89, 95% CI 0·51 to 1·28, with moderate quality evidence), but similarly low implicit self-esteem (seven studies involving 398 individuals; g=-0·19, -0·45 to 0·07, with low quality evidence). In contrast to the later predictions, people with persecutory delusions did not have a greater self-esteem discrepancy than non-clinical individuals (ten studies involving 592 individuals; g=-0·17, 95% CI -0·45 to 0·12), although the evidence was very low quality. People with psychosis with or without persecutory delusions did not differ for implicit self-esteem (four studies involving 167 individuals; g=-0·24, 95% CI -0·77 to 0·30, with low quality evidence) or self-esteem discrepancies (four studies involving 165 individuals; g=0·17, -0·19 to 0·53, with moderate quality evidence). INTERPRETATION: The predictions that self-esteem would be preserved in people with persecutory delusions in the early version of the paranoia as defence model and that implicit-explicit self-esteem discrepancy would be greater in people with persecutory delusions than in non-clinical individuals and people with psychosis without persecutory delusions in the later version of the model were not supported. By contrast, the later version correctly predicted that people with persecutory delusions have a greater self-esteem discrepancy than people with depression and a greater externalising attributional bias than all control groups, and that both this bias and self-esteem instability are associated with increased paranoia severity. Nevertheless, the reviewed data had limitations. Experimental studies, which might include interventionist-causal trials, are needed. FUNDING: None.

Cognitive Behavioral Therapy for antipsychotic-free schizophrenia spectrum disorders: Does therapy dose influence outcome?

This study investigated the effect of "dose" and the components of Cognitive Behavioral Therapy (CBT) on treatment effects. It is a secondary analysis of the ACTION (Assessment of Cognitive Therapy Instead of Neuroleptics) trial which investigated CBT for people with schizophrenia spectrum disorders that chose not to take antipsychotic medication. Using instrumental variable methods, we found a "dose-response" such that each CBT session attended, reduced the primary outcome measure (the PANSS total score) by approximately 0.6 points (95% CI -1.20 to -0.06, p = 0.031). This suggests that length of therapy is important for those that receive CBT in the absence of antipsychotic medication. Secondly, using principal stratification we examined the process variables that modified treatment effects. Findings revealed that those who received a longitudinal formulation in the first 4 sessions of CBT had poorer treatment effects than those who did not, however this finding was not statistically significant (95% CI -37.244, 6.677, p = 0.173). However, it is important to note that these findings were evident in an exploratory analysis with a small sample. Future larger scale studies are needed to help understand components of effective treatment.

Psychological therapy for inpatients receiving acute mental health care: A systematic review and meta-analysis of controlled trials.

OBJECTIVES: The effectiveness of psychological therapies for those receiving acute adult mental health inpatient care remains unclear, partly because of the difficulty in conducting randomized controlled trials (RCTs) in this setting. The aim of this meta-analysis was to synthesize evidence from all controlled trials of psychological therapy carried out with this group, to estimate its effects on a number of important outcomes and examine whether the presence of randomization and rater blinding moderated these estimates. METHOD: A systematic review and meta-analysis of all controlled trials of psychological therapy delivered in acute inpatient settings was conducted, with a focus on psychotic symptoms, readmissions or emotional distress (anxiety and depression). Studies were identified through ASSIA, EMBASE, CINAHL, Cochrane, MEDLINE, and PsycINFO using a combination of the key terms 'inpatient', 'psychological therapy', and 'acute'. No restriction was placed on diagnosis. The moderating effect of the use of assessor-blind RCT methodology was examined via subgroup and sensitivity analyses. RESULTS: Overall, psychological therapy was associated with small-to-moderate improvements in psychotic symptoms at end of therapy but the effect was smaller and not significant at follow-up. Psychological therapy was also associated with reduced readmissions, depression, and anxiety. The use of single-blind randomized controlled trial methodology was associated with significantly reduced benefits on psychotic symptoms and was also associated with reduced benefits on readmission and depression; however, these reductions were not statistically significant. CONCLUSIONS: The provision of psychological therapy to acute psychiatric inpatients is associated with improvements; however, the use of single-blind RCT methodology was associated with reduced therapy-attributable improvements. Whether this is a consequence of increased internal validity or reduced external validity is unclear. Trials with both high internal and external validity are now required to establish what type, format, and intensity of brief psychological therapy is required to achieve sustained benefits. PRACTITIONER POINTS: Clinical implications: This review provides the first meta-analytical synthesis of brief psychological therapy delivered in acute psychiatric inpatient settings. This review suggests that brief psychological therapy may be associated with reduced emotional distress and readmissions. LIMITATIONS: The evidence in this review is of limited quality. The type, format, and intensity of brief psychological therapy required to achieve sustained benefits are yet to be established.

Practitioner Review: Therapist variability, patient-reported therapeutic alliance, and clinical outcomes in adolescents undergoing mental health treatment - a systematic review and meta-analysis.

BACKGROUND: Previous meta-analyses have only found small correlations (r = .10 to r = .19) between therapeutic alliance and clinical outcomes in samples of adolescents receiving psychological therapy. Although study-level variables have been found to moderate this, little is known about the impact of therapist variability. The present meta-analysis aimed to address this gap by using patient-therapist ratio as a moderator variable. METHODS: Contrary to previous reviews of adolescent alliance, individual effect sizes were extracted using a preregistered conceptual hierarchy. Controlling for treatment-level confounds, a random effects meta-analysis assessed the moderating effect of patient-therapist ratio on the alliance-outcome relationship in predefined single-predictor and multipredictor meta-regressions. RESULTS: The alliance-outcome relationship was found to be larger than previously thought (k = 28, N = 2,911, r = .29, 95% Confidence Interval 0.21, 0.37; p < .0001, I2  = 80%). When study samples exceeding the adolescent 12-19 age range were removed, the correlation rose (k = 15, N = 1,797, r = .34, 95% Confidence Interval 0.23, 0.45; p < .0001, I2  = 83%). In contrast to research with adults, patient-therapist ratio did not moderate this relationship in either single-predictor (p = .26) or multi-predictor (p = .22) models. CONCLUSIONS: The alliance-outcome relationship for adolescents was larger than previously thought, and comparable to estimates in adult samples. The failure of patient-therapist ratio to moderate its strength, however, challenges the hypothesis that variability in therapist characteristics is an important determinant of the alliance-outcome effect in this age group.

Loneliness in Psychosis: A Meta-analytical Review.

Loneliness may be related to psychotic symptoms but a comprehensive synthesis of the literature in this area is lacking. The primary aim of the current study is to provide a systematic review and meta-analysis of the association between loneliness and psychotic symptoms in people with psychosis. A search of electronic databases was conducted (PsychINFO, MEDLINE, EMBASE, and Web of Science). A random effects meta-analysis was used to compute a pooled estimate of the correlation between loneliness and psychotic symptoms. Study and outcome quality were assessed using adapted versions of the Agency for Healthcare Research and Quality (AHRQ) tool and GRADE approach, respectively. Thirteen studies were included, providing data from 15 647 participants. A moderate association between psychosis and loneliness was observed (k = 13, N = 15 647, r = .32, 95% CI 0.20, 0.44; I2 = 97.56%; moderate quality evidence). Whether loneliness was assessed by a single-item or a more comprehensive measure had no moderating effect on the estimate. Results indicate that there is a significant positive relationship between loneliness and psychosis. Further studies are needed to determine the causal status of this relationship, but this robust finding should be considered in clinical practice and treatment provision for those with psychotic disorders.

Systematic review and meta-analysis of factors that help or hinder treatment decision-making capacity in psychosis.

BackgroundThe evidence on factors that may influence treatment decisional capacity ('capacity') in psychosis has yet to be comprehensively synthesised, which limits the development of effective strategies to improve or support it.AimsTo determine the direction, magnitude and reliability of the relationship between capacity in psychosis and a range of clinical, demographic and treatment-related factors, thus providing a thorough synthesis of current knowledge.MethodWe conducted a systematic review, meta-analytical and narrative synthesis of factors that help or hinder treatment decision-making capacity in psychosis, assessing the direction, magnitude, significance and reliability of reported associations.ResultsWe identified 23 relevant studies (n = l823). Psychotic symptoms had small, moderate and strong associations with appreciation, understanding and reasoning respectively. Both verbal cognitive functioning and duration of education had small to moderate correlations with understanding and reasoning. Better capacity was also associated with better insight, better metacognitive ability, higher anxiety and lower perceived coercion. No linear relationship with depression was observed. Interventions linked to improved capacity over time were in-patient care, information simplification, shared decision-making and metacognitive training.ConclusionsAlthough much is known about the role of symptoms and other clinical variables, effective and acceptable psychological interventions to support capacity in this group are lacking.