Effectiveness of pharmacological treatments for severe agitation in real-world emergency settings: protocol of individual-participant-data network meta-analysis.

BACKGROUND: Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. METHODS: We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. DISCUSSION: This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023402365.

Targeted psychological and psychosocial interventions for auditory hallucinations in persons with psychotic disorders: Protocol for a systematic review and meta-analysis.

BACKGROUND: In recent years, a growing body of evidence has demonstrated the efficacy of non-pharmacological interventions for schizophrenia spectrum disorders (SSD) including positive symptoms such as auditory hallucinations (AH). However, clinical trials predominantly examine general treatment effects for positive symptoms. Therefore, previous research is lacking in comprehensive and clear evidence about psychological and psychosocial approaches that are primarily tailored to treat AH. To overcome this knowledge gap in the current literature, we will conduct a systematic review and meta-analysis to assess the efficacy of clearly targeted psychological and psychosocial interventions for AH in persons with SSD. METHODS AND ANALYSIS: This study protocol has been developed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We will include all randomized controlled trials analyzing the efficacy of targeted psychological and psychosocial interventions especially aimed at treating AH in SSD. We will include studies on adult patients with SSD experiencing AH. The primary outcome will be the change on a published rating scale measuring AH. Secondary outcomes will be delusions, overall symptoms, negative symptoms, depression, social functioning, quality of life, and acceptability (drop-out). We will search relevant databases and the reference lists of included literature. The study selection process will be conducted by two independent reviewers. We will conduct a random-effect meta-analysis to consider heterogeneity across studies. Analyses will be carried out by software packages in R. The risk of bias in each study will be evaluated using the Cochrane Risk of Bias tool. Assessment of heterogeneity and sensitivity analysis will be conducted. DISCUSSION: The proposed study will augment the existing evidence by providing an overview of effective treatment approaches and their overall efficacy at treating AH in SSD. These findings will complement existing evidence that may impact future treatment implementations in clinical practice by addressing effective strategies to treat AH and therefore improve outcomes for the addressed population. ETHICS AND DISSEMINATION: No ethical issues are foreseen. We will publish the results from this study in peer-reviewed journals and at relevant scientific conferences. TRIAL REGISTRATION: PROSPERO registration number: CRD42023475704.

The role of control groups in non-pharmacological randomised controlled trials of treatment-resistant schizophrenia: A systematic review and meta-analysis.

Control groups used in randomised controlled trials investigating psychological interventions for depression and anxiety disorders have effects of their own. This has never been investigated for schizophrenia, in particular treatment-resistant schizophrenia. This systematic review and meta-analysis aimed to examine how control groups in randomised controlled trials on psychological interventions for treatment-resistant schizophrenia behave in their effects on general symptomatology. In a search of various databases until July 2023, 31 eligible studies with 3125 participants were found whose control groups were assigned to four categories: active, inactive, treatment as usual and waitlist. The analyses showed that psychological interventions had a greater effect on symptom reduction to all control groups combined. When separating the control groups, only compared to TAU and waitlist controls the psychological interventions were superior. The difference was larger when less active control groups (e.g. waitlist - or treatment as usual control groups) were used. All control groups were associated with an improvement in symptoms from pre- to post-measurement point, with the greatest improvement observed in the inactive control group. The results are preliminary, but they suggest that the choice of the control group has a considerable impact on study effects as it has been shown in other psychiatric diagnoses.

Non-invasive brain stimulation for treatment-resistant schizophrenia: protocol of a systematic review and network meta-analysis.

BACKGROUND: Non-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia. METHODS: We will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel-Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach. DISCUSSION: Our network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-ID CRD42023410645.

Psychological and psychosocial interventions for treatment-resistant schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Many patients with schizophrenia have symptoms that do not respond to antipsychotics. This condition is called treatment-resistant schizophrenia and has not received specific attention as opposed to general schizophrenia. Psychological and psychosocial interventions as an add-on treatment to pharmacotherapy could be useful, but their role and comparative efficacy to each other and to standard care in this population are not known. We investigated the efficacy, acceptability, and tolerability of psychological and psychosocial interventions for patients with treatment-resistant schizophrenia. METHODS: In this systematic review and network meta-analysis (NMA), we searched for published and unpublished randomised controlled trials (RCTs) through a systematic database search in BIOSIS, CINAHL, Embase, LILACS, MEDLINE, PsychInfo, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform for articles published from inception up to Jan 31, 2020. We also searched the Cochrane Schizophrenia Group registry for studies published from inception up to March 31, 2022, and PubMed and Cochrane CENTRAL for studies published from inception up to July 31, 2023. We included RCTs that included patients with treatment-resistant schizophrenia. The primary outcome was overall symptoms. We did random-effects pairwise meta-analyses and NMAs to calculate standardised mean differences (SMDs) or risk ratios with 95% CIs. No people with lived experience were involved throughout the research process. The study protocol was registered in PROSPERO, CRD42022358696. FINDINGS: We identified 30 326 records, excluding 24 526 by title and abstract screening. 5762 full-text articles were assessed for eligibility, of which 5540 were excluded for not meeting the eligibility criteria, and 222 reports corresponding to 60 studies were included in the qualitative synthesis. Of these, 52 RCTs with 5034 participants (1654 [33·2%] females and 3325 [66·8%] males with sex indicated) comparing 20 psychological and psychosocial interventions provided data for the NMA. Mean age of participants was 38·05 years (range 23·10-48·50). We aimed to collect ethnicity data, but they were scarcely reported. According to the quality of evidence, cognitive behavioural therapy for psychosis (CBTp; SMD -0·22, 95% CI -0·35 to -0·09, 35 trials), virtual reality intervention (SMD -0·41, -0·79 to -0·02, four trials), integrated intervention (SMD -0·70, -1·18 to -0·22, three trials), and music therapy (SMD -1·27, -1·83 to -0·70, one study) were more efficacious than standard care in reducing overall symptoms. No indication of publication bias was identified. INTERPRETATION: We provide robust findings that CBTp can reduce the overall symptoms of patients with treatment-resistant schizophrenia, and therefore clinicians can prioritise this intervention in their clinical practice. Other psychological and psychosocial interventions showed promising results but need further investigation. FUNDING: DAAD-ASFE.

Update of the World Health Organization's Mental Health Gap Action Programme Guideline for Psychoses (Including Schizophrenia).

BACKGROUND AND HYPOTHESIS: The World Health Organization's (WHOs) Mental Health Gap Action Programme (mhGAP) aims to improve healthcare for mental, neurological, and substance use disorders in nonspecialized settings, with a focus on low- and middle-income countries (LMICs). mhGAP includes guidelines for the treatment of psychoses (including schizophrenia), which were recently updated in 2023. The complexity of the WHO guideline update process and the updated recommendations on psychoses are presented. STUDY DESIGN: The WHO guideline development process is outlined as well as the evidence appraisal and the translation of the evidence into recommendations following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The guideline update process includes a review of the literature, a compilation of systematic reviews, and extracting data related to critical and important outcomes. The updated recommendations and the justifying evidence are discussed. STUDY RESULTS: The WHO mhGAP guidelines for psychoses are adapted to LMICs, and consist of 13 recommendations in 2023, whereof 5 were updated, and 1 recommendation was newly developed. Background information on how these recommendations were obtained, and significant changes since the previous guideline update in 2015 are provided. CONCLUSIONS: Unlike other guidelines, the WHO must consider various countries, contextual factors, and the WHO Model Lists of Essential Medicines when developing its guidelines. A transformation of the WHO guideline for psychoses into a living guideline would ensure always up-to-date recommendations and facilitate shared decision-making.

Cognitive behavioural therapy added to standard care for first-episode and recent-onset psychosis.

BACKGROUND: Cognitive behavioural therapy (CBT) can be effective in the general population of people with schizophrenia. It is still unclear whether CBT can be effectively used in the population of people with a first-episode or recent-onset psychosis. OBJECTIVES: To assess the effects of adding cognitive behavioural therapy to standard care for people with a first-episode or recent-onset psychosis. SEARCH METHODS: We conducted a systematic search on 6 March 2022 in the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing CBT added to standard care vs standard care in first-episode or recent-onset psychosis, in patients of any age. DATA COLLECTION AND ANALYSIS: Two review authors (amongst SFM, CC, LK and IB) independently screened references for inclusion, extracted data from eligible studies and assessed the risk of bias using RoB2. Study authors were contacted for missing data and additional information. Our primary outcome was general mental state measured on a validated rating scale. Secondary outcomes included other specific measures of mental state, global state, relapse, admission to hospital, functioning, leaving the study early, cognition, quality of life, satisfaction with care, self-injurious or aggressive behaviour, adverse events, and mortality. MAIN RESULTS: We included 28 studies, of which 26 provided data on 2407 participants (average age 24 years). The mean sample size in the included studies was 92 participants (ranging from 19 to 444) and duration ranged between 26 and 52 weeks. When looking at the results at combined time points (mainly up to one year after start of the intervention), CBT added to standard care was associated with a greater reduction in overall symptoms of schizophrenia (standardised mean difference (SMD) -0.27, 95% confidence interval (CI) -0.47 to -0.08, 20 RCTs, n = 1508, I2 = 68%, substantial heterogeneity, low certainty of the evidence), and also with a greater reduction in positive (SMD -0.22, 95% CI -0.38 to -0.06, 22 RCTs, n = 1565, I² = 52%, moderate heterogeneity), negative (SMD -0.20, 95% CI -0.30 to -0.11, 22 RCTs, n = 1651, I² = 0%) and depressive symptoms (SMD -0.13, 95% CI -0.24 to -0.01, 18 RCTs, n = 1182, I² = 0%) than control. CBT added to standard care was also associated with a greater improvement in the global state (SMD -0.34, 95% CI -0.67 to -0.01, 4 RCTs, n = 329, I² = 47%, moderate heterogeneity) and in functioning (SMD -0.23, 95% CI -0.42 to -0.05, 18 RCTs, n = 1241, I² = 53%, moderate heterogeneity, moderate certainty of the evidence) than control. We did not find a difference between CBT added to standard care and control in terms of number of participants with relapse (relative risk (RR) 0.82, 95% CI 0.57 to 1.18, 7 RCTs, n = 693, I² = 48%, low certainty of the evidence), leaving the study early for any reason (RR 0.87, 95% CI 0.72 to 1.05, 25 RCTs, n = 2242, I² = 12%, moderate certainty of the evidence), adverse events (RR 1.29, 95% CI 0.85 to 1.97, 1 RCT, n = 43, very low certainty of the evidence) and the other investigated outcomes. AUTHORS' CONCLUSIONS: This review synthesised the latest evidence on CBT added to standard care for people with a first-episode or recent-onset psychosis. The evidence identified by this review suggests that people with a first-episode or recent-onset psychosis may benefit from CBT additionally to standard care for multiple outcomes (overall, positive, negative and depressive symptoms of schizophrenia, global state and functioning). Future studies should better define this population, for which often heterogeneous definitions are used.

Cognitive behavioural therapy without medication for schizophrenia.

BACKGROUND: Cognitive behavioural therapy (CBT) can be effective in people with schizophrenia when provided in combination with antipsychotic medication. It remains unclear whether CBT could be safely and effectively offered in the absence of concomitant antipsychotic therapy. OBJECTIVES: To investigate the effects of CBT for schizophrenia when administered without concomitant pharmacological treatment with antipsychotics. SEARCH METHODS: We conducted a systematic search on 6 March 2022 in the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, and WHO ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people with schizophrenia comparing CBT without antipsychotics to standard care, standard care without antipsychotics, or the combination of CBT and antipsychotics. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for inclusion, extracted data from eligible studies, and assessed risk of bias using Cochrane's RoB 2 tool. We contacted study authors for missing data and additional information. Our primary outcome was general mental state measured with a validated rating scale. Key secondary outcomes were specific symptoms of schizophrenia, relapse, service use, number of participants leaving the study early, functioning, quality of life, and number of participants actually receiving antipsychotics during the trial. We also assessed behaviour, adverse effects, and mortality. MAIN RESULTS: We included 4 studies providing data for 300 participants (average age 21.94 years). The mean sample size was 75 participants (range 61 to 90 participants). Study duration was between 26 and 39 weeks for the intervention period and 26 to 104 weeks for the follow-up period. Three studies employed a blind rater, while one study was triple-blind. All analyses included data from a maximum of three studies. The certainty of the evidence was low or very low for all outcomes. For the primary outcome overall symptoms of schizophrenia, results showed a difference favouring CBT without antipsychotics when compared to no specific treatment at long term (> 1 year mean difference measured with the Positive and Negative Syndrome Scale (PANSS MD) -14.77, 95% confidence interval (CI) -27.75 to -1.79, 1 RCT, n = 34). There was no difference between CBT without antipsychotics compared with antipsychotics (up to 12 months PANSS MD 3.38, 95% CI -2.38 to 9.14, 2 RCTs, n = 63) (very low-certainty evidence) or compared with CBT in combination with antipsychotics (up to 12 months standardised mean difference (SMD) 0.30, 95% CI -0.06 to 0.65, 3 RCTs, n = 125). Compared with no specific treatment, CBT without antipsychotics was associated with a reduction in overall symptoms (as described above) and negative symptoms (PANSS negative MD -4.06, 95% CI -7.50 to -0.62, 1 RCT, n = 34) at longer than 12 months. It was also associated with a lower duration of hospital stay (number of days in hospital MD -22.45, 95% CI -28.82 to -16.08, 1 RCT, n = 74) and better functioning (Personal and Social Performance Scale MD -12.42, 95% CI -22.75 to -2.09, 1 RCT, n = 40, low-certainty evidence) at up to 12 months. We did not find a difference between CBT and antipsychotics in any of the investigated outcomes, with the exception of adverse events measured with the Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) at both 6 and 12 months (MD -4.94, 95% CI -8.60 to -1.28, 2 RCTs, n = 48; MD -6.96, 95% CI -11.55 to -2.37, 2 RCTs, n = 42). CBT without antipsychotics was less effective than CBT combined with antipsychotics in reducing positive symptoms at up to 12 months (SMD 0.40, 95% CI 0.05 to 0.76, 3 RCTs, n = 126). CBT without antipsychotics was associated with a lower number of participants experiencing at least one adverse event in comparison with CBT combined with antipsychotics at up to 12 months (risk ratio 0.36, 95% CI 0.17 to 0.80, 1 RCT, n = 39, low-certainty evidence). AUTHORS' CONCLUSIONS: This review is the first attempt to systematically synthesise the evidence about CBT delivered without medication to people with schizophrenia. The limited number of studies and low to very low certainty of the evidence prevented any strong conclusions. An important limitation in the available studies was that participants in the CBT without medication group (about 35% on average) received antipsychotic treatment, highlighting the challenges of this approach. Further high-quality RCTs are needed to provide additional data on the feasibility and efficacy of CBT without antipsychotics.